CC BY 4.0 · SynOpen 2024; 08(01): 1-38
DOI: 10.1055/a-2212-0996
review

Synthesis of Bioactive 1,2,3-Triazole-Fused Macrocycles via Azide-Alkyne Cycloaddition

Nasrin Jahan
,
Arkadip Pal
,
Inul Ansary
We sincerely thank the Department of Science and Technology and Biotechnology (Government of West Bengal) for providing financial assistance until the year 2022. N. Jahan is grateful to the Government of West Bengal for her research fellowship, Swami Vivekananda Merit Cum Means Fellowship.
 


Abstract

A systematic highlight of syntheses reported since 2006 of 1,2,3-triazole-fused macrocycles possessing biological activities such as anticancer, antibacterial, antiviral, anti-inflammatory and antilarval action, is presented in this review. The well-renowned Cu-catalyzed azide-alkyne cycloaddition reaction was noted to be highly efficient and is one the most common methods utilized by scientists for the synthesis of 1,4-disubstituted triazole-fused macrocycles, whereas Ru-catalyzed cycloaddition is common for the formation of 1,5-disubstituted bioactive triazoles. This review would thus be extremely beneficial for both synthetic organic and medicinal chemists.

1 Introduction

2 Anticancer Derivatives

3 Antibacterial Derivatives

4 Derivatives with Dual Activity

5 Antilarval Derivatives

6 Anti-inflammatory Derivatives

7 Antiviral Derivatives

8 Anti-trypanosomal Derivatives

9 Derivatives with Miscellaneous Activities

10 Conclusion


#

Biographical Sketches

Zoom Image

Nasrin Jahan was born in 1993 in Durgapur, West Bengal, India. She graduated in Chemistry (2015) from the University of Burdwan, West Bengal, India and obtained her M.Sc. degree (2017) from Kazi Nazrul University, West Bengal, India. Currently, she is pursuing her Ph.D. degree in synthetic organic chemistry at the University of Burdwan under the supervision of Dr. Inul Ansary.

Zoom Image

Arkadip Pal was born in Malda, West Bengal, India, in 1999. He is an INSPIRE Scholar under DST and obtained his B.Sc. (Hons.) degree in 2021 from Bankura University, West Bengal, India. Subsequently, he obtained his M.Sc. degree in Chemistry in 2023 from The University of Burdwan, West Bengal, India, and completed his project-based term paper under the supervision of Dr. Inul Ansary for the fulfilment of his final semester examination.

Zoom Image

Dr. I. Ansary was born in 1983 in Raghunathpur, Purulia, West Bengal, India. He obtained his B.Sc. in Chemistry (2004) from The University of Burdwan, Burdwan, India and his M.Sc. degree (2006) from the University of Calcutta, Kolkata, India. He received his Ph.D. in Chemistry (July, 2013) under the supervision of Dr. B. Roy from the University of Kalyani. He joined as an Assistant Professor in Chemistry in November 2012 at The University of Burdwan, West Bengal and teaches Organic Chemistry in the postgraduate level. His research interests are in the areas of development of new synthetic routes and methodologies to construct nitrogen and oxygen heterocycles of different ring sizes and their application on the basis of molecular modeling and docking studies. Recently, he has been working in the field of pesticide residue analysis. He has published 30 research articles, 1 review and 2 book chapters. He also reviewed several research articles in internationally reputed journals. Under his supervision two students have been awarded Ph.D. degree and currently three students are still working in his group. He also supervised more than 50 M.Sc. students who successfully submitted their project-based term papers.

1

Introduction

Over a long period, the evolution of therapeutic compounds required for treatment of a wide range of diseases has revolved around the construction of various natural products as well as their synthetic analogues. Based on their improved physicochemical potential and pharmacokinetics compared with acyclic molecules, macrocycles have provided continuously emerging targets for drug discovery despite their synthetic challenges.[1] [2] Macrocyclic compounds have been reported to display a wide range of bioactivities viz. anticancer, antibacterial, antifungal, immunosuppressant and more, and thus have proven themselves to be extremely effective in the field of medicine.[3] In particular, 1,2,3-triazole-fused macrocycles have exhibited promising biological activities such as anticancer,[4] [5] [6] antibacterial,[7] anti-inflammatory,[8] antiviral,[9] and more;[10] [11] [12] hence, the synthesis of triazole-based macrocycles has become a hot topic for researchers. Published reports revealed that significant efforts have been made towards the synthesis of triazole scaffolds involving Ag(I)-, Cu(I)-, and Ru(II)-catalyzed azide–alkyne cycloaddition (AAC) reactions, microwave-assisted reactions, and ultrasound-promoted reactions etc.[13] The deep impact of the well-renowned Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction upon synthetic organic chemistry has persuaded several researchers to utilize this reaction while developing the triazole-based analogues of naturally occurring macrocyclic compounds. Through a literature survey, we realized that no recent review on the synthesis of bioactive 1,2,3-triazole fused macrocycles was available. Being currently engaged in the synthesis of macrocycles,[14] we herein report a review article summarizing the synthetic protocols undertaken to construct bioactive triazole-fused macrocycles since 2006. Throughout the article, we focus on CuAAC and RuAAC reactions that have been utilized for the preparation of 1,2,3-triazoles. We are optimistic that this review will be extremely beneficial for synthetic organic and medicinal chemistry researchers and will provide guidance on the development of novel macrocycles that are essential for drug discovery.


# 2

Anticancer Derivatives

In order to combat a worldwide health problem – cancer – researchers have paid avid attention towards the two ‘D’s in therapeutic development: Detection and Diagnosis. Early detection of this fatal disease is essential for appropriate diagnosis and the needs of the affected people could only be met through proper treatment via medicinal resources. Scientists have devoted countless numbers of years in cancer therapy to not just curing patients but also to improving their quality of life post-treatment.

Zoom Image
Scheme 1 Synthesis of STAT3 inhibitor 7
Zoom Image
Scheme 2 Synthesis of apicidin analogues 16a,b and 17

Continuous activation of signal transducers and activators of transcription 3 (STAT3) has been directly linked to oncogenesis and the process serves as a target for molecular drug design. In 2007, Chen et al. designed a conformationally constrained macrocycle 7 by following the ‘click-chemistry’ methodology as a crucial step (Scheme [1]).[15] The synthetic procedure advanced with the condensation between Boc-l-6-hydroxynorleucine 1 and O-t-butyl-l-threonine methyl ester 2, in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), hydroxybenzotriazole (HOBt) and N,N-diisopropylethylamine (DIPEA) in dichloromethane. Three consecutive steps provided the azide moiety 3, which was further converted into the macrocyclic precursor 4 via condensation with (S)-propargylglycine methyl ester. On constituting both the azide-alkyne groups within itself, 4 was subjected to an intramolecular copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction in the presence of copper sulfate and sodium ascorbate in a t-BuOH/H2O solvent system to furnish the 1,4-disubstituted triazole-fused macrocycle 5 in 80% yield. This key intermediate was further exposed to nine more sequential reactions to afford the target macromolecule 7. A fluorescence-polarization-based binding assay was conducted next to confirm that 7 expressed an effective binding affinity with STAT3 and was found to be more potent when compared with the peptide 8. The target drug 7 was thus established to be an anticancer agent with a strong inhibition of STAT3.

Histone deacetylases (HDACs) are enzymes that play an important part in the regulation of gene transcription and, over the years, inhibition of HDACs have resulted in the evolution of anticancer chemotherapy. Apicidin, a naturally occurring cyclic tetrapeptide, was found to exhibit cytotoxic activity by inhibiting the action of HDACs. In 2009, Horne et al. developed few triazole-modified apicidin analogues 16a,b, 17, 25ac and carried out the HDAC inhibition assay (Scheme [2] and Scheme [3]).[4] The synthetic procedure commenced with the preparation of the two key fragments, 11 and 14, from the starting materials bromoketal 9 and the Boc-protected lactone 12, respectively. Compound 9 was initially converted into the Grignard derivative and then reacted with the lactone 10 to produce the amino acid derivative 11. The synthesis of the alkyne moiety 14 proceeded with the conversion of the Boc-protected lactone 12 into the acid 13, which was further subjected to a three-step reaction. The two synthons 11 and 14 were exposed to solution-phase peptide synthesis via six sequential reactions to prepare the azide-alkyne cycloaddition precursors 15a and 15b, which finally underwent intramolecular cycloaddition using catalytic CuI, 2,6-lutidine, tris(benzyltriazolylmethyl)amine (TBTA) and DIPEA in acetonitrile for 48 h to afford the desired 1,4-disubtituted triazole fused macrocycles 16a and 16b, respectively. The macrocyclic precursor 15a was alternatively exposed to microwave conditions in DMF at 220 °C, which led to the production of a mixture of 1,5-disubstituted triazole fused macrocycle 17 (8%) and macrocycle 16a in a 2:1 ratio (Scheme [2]). Next, multiple conformations of 17 were investigated by replacing the β-substituted amino acid Ile with a Leu residue. The Fmoc-protected 2-amino 8-oxodecanoic acid (Aoda) on resin 18 was treated with piperidine to remove the protection and subsequently the de-protected 19 was coupled with the N3-Ala-OH (d/l) 20 to afford the amide 21. To ensure the intermolecular cycloaddition reaction, the azido-amide 21 and Fmoc-Leu-CCH (d/l) 22 were treated with a Ru-based catalyst [Cp*Ru(cod)Cl] in toluene at 45 °C for 16 h and the triazole-moiety 23 was afforded. Four subsequent steps led to the formation of the linear pseudotetrapeptides 24ac, which finally underwent macrolactamization through HATU peptide coupling to afford the desired macrocycles 25ac, differing at the Ala and Leu positions, in yields greater than 95% (Scheme [3]). The bioactivities of all the apicidin analogues were assessed in nuclear extracts of HeLa cells and they were found to exhibit HDAC inhibitor activity.

In 2010, the McAlpine group synthesized a set of macrocyclic triazole derivatives 33 and assessed their HDAC inhibitory activity (Scheme [4]).[16] The synthetic procedure commenced with the conversion of aldehyde 26 into alkyne 27 with Bestmann–Ohira reagent. Four sequential reactions involving condensation of 27 with the Boc-protected amino acids 28 and 29 resulted in the development of the residue 30, which was, in turn, HATU/TBTU coupled with azide 31 to afford the linear precursor 32. Finally, the crucial macrocyclization step was undertaken via CuAAC reaction using copper sulfate and sodium ascorbate in a methanol/water solvent system to afford the desired macrocycles 33 in 3–9% yield. The biological evaluation of these compounds revealed inhibition of deacetylase activity against HeLa cell lysates. Compounds 33a and 33b were found to be the most potent.

Zoom Image
Scheme 3 Synthesis of Apicidin analogues 25ac
Zoom Image
Scheme 4 Synthesis of anticancer agents 33

The Sewald group, in 2010, developed a bioactive triazole analogue 44 of the antitumor agent ‘Cryptophycin-52’ using the Cu-mediated cycloaddition reaction as one of the crucial steps (Scheme [5] and Scheme [6]).[17] The synthesis advanced with the creation of alkyne 35 in two steps from the starting material 34. The other building block 38 was afforded through condensation of acid 36 and alcohol 37 and was subsequently exposed to CuAAC reaction using CuI and DIPEA in DMF for 14 h at ambient temperature for the construction of the triazole 39 (Scheme [5]).

Zoom Image
Scheme 5 Synthesis of cryptophycin-52 analogue 44

Hydrogenolytic deprotection of the Bn group in 39 with subsequent esterification with the alcohol moiety 40 resulted in the formation of the macrocyclic precursor 41. Final cleavage of the protecting groups with macrocyclization under pseudo-high-dilution conditions furnished the key intermediate 42 in 74% yield. An alternative procedure to synthesize 42 was also developed from the Boc-deprotected moiety 45 (Scheme [6]). Thus, the acid 43 was coupled with the alkyne-amine moiety 45 using EDC/HOBt in order to achieve the amide 46, which was further subjected to condensation with the silyl protected compound 47. Sequential silyl-deprotection and esterification with acid 36 afforded the macrocyclic precursor 49, which, upon exposure to CuAAC reaction with the CuI/DIPEA catalytic system in toluene at room temperature for 20 h, formed a mixture of triazole-fused macrocycles (monomer and dimer) in 84% combined yield. The free diols 42 and 50 were finally obtained through acidic cleavage. The key compound 42 was gradually exposed to diol-epoxide conversion in three steps to afford the target macrocycle 44 in 59% yield (Scheme [5]). Biological assay of 44 against the multidrug-resistant human cervix carcinoma cell line KB-V1 showed promising results, being only five times less potent than the parent compound cryptophycin-52. Thus, the efficiency of triazole analogue as an anticancer agent was established.

Zoom Image
Scheme 6 Synthesis of fragment 42 for the development of analogue 44

Pirali et al., in 2010, synthesized certain macrocyclic peptide mimetics 56a,b and 61a,b through intramolecular [3+2] cycloaddition and biologically evaluated them as HDAC inhibitors (Scheme [7] and Scheme [8]).[18] Initially, the synthetic procedure for the first set of macrocycles commenced with the preparation of the aldehydes 53a,b from their corresponding alcohols using Dess–Martin reagent through oxidation. With the other fragments α-isocyanoacetamide 51 and the amine 52 in hand, a three-component reaction was conducted using NH4Cl as a catalyst to afford the 5-aminooxazole 54a,b. Subsequently, the crucial macrocyclization step was carried out via CuAAC reaction with catalytic CuI and DIPEA in THF at room temperature for 13 h in order to furnish the macrocycles 55a and 55b in 83% and 70% yields, respectively (Scheme [7]).

Zoom Image
Scheme 7 Synthesis of macrocyclic peptide mimetics 56a,b
Zoom Image
Scheme 8 Synthesis of macrocyclic peptide mimetics 61a,b

Three subsequent reactions upon 55a,b afforded the targeted hydroxamic macrocycles 56a,b in 39% and 37% yield, respectively. To generate the second set of macrocycles, a similar ammonium chloride catalyzed methodology was followed using the aldehyde 53b, the alkyne 58, and the azides 57a,b as starting materials for the development of the macrocyclic precursors 59a,b (Scheme [8]). A CuI supported cycloaddition following the aforementioned method took place next to graft the macrocycles 60a and 60b in 61% and 80% yields, respectively. Finally, the desired hydroxamic compounds 61a,b were synthesized in 34% and 42% yields in three subsequent steps. Biological evaluation of 56a,b and 61a,b through MTT assay determined their inhibitory activity in SHSY-5Y cells. It was further predicted through molecular docking that 55b and 61b would display inhibition of histone deacetylases.

In the same year, Sun et al. synthesized the cyclopeptidic Smac mimetics 70a,b utilizing the CuAAC reaction as the macrocyclization pathway and evaluated their anticancer activities (Scheme [9]).[19] The process was initiated with the condensation of l-proline benzyl ester hydrochloride 62 and N-Boc-l-6-hydroxynorleucine to achieve the amide 63. Mesylation of 63, followed by treatment with sodium azide, afforded the azido derivative 64, which was further subjected to azide-alkyne cycloaddition with 65a/65b to graft the key intermediates 66a,b, respectively. Four subsequent reaction steps resulted in the development of the macrocyclic precursors 67a,b, which underwent the crucial Cu-catalyzed AAC reaction with copper sulfate and sodium ascorbate in t-BuOH/H2O medium to synthesize the macrocycles 68a (38%) and 68b (35%), respectively. After removing the protecting groups, condensation was carried out between 69a,b and N-methyl-N-Boc-l-alanine to construct the amides. Ultimate Boc deprotection afforded the desired compounds 70a (79%) and 70b (72%), which were further biologically evaluated. Through an FP-based binding assay, it was found that the binding affinity of 70a was more than that of 70b towards binding to XIAP, cIAP-1 and cIAP-2 proteins. When the inhibition activity of the target macrocycles was evaluated against growth of MDA-MB-231 breast cancer and SK-OV-3 ovarian cancer cell lines, compound 70a was reported to be more potent than parent compound 71, whereas 70b was noted to be weaker than 71.

Zoom Image
Scheme 9 Synthesis of cyclopeptidic Smac mimetics 70a,b

Heat shock protein 90 (Hsp90) is a captivating target for medicinal chemists with respect to cancer therapy. Day et al., in 2010, synthesized a series of macrocyclic analogues (82ae) of the naturally occurring Hsp90 inhibitor ‘radicicol’ (Scheme [10]).[5] The synthetic route advanced with the conversion of 4-chlororesorcinol 72 into the homophthalate ester 73 in two steps, which further underwent six reactions to afford the intermediate 74. The substituted diethyl malonates 75ad were next transformed into their corresponding acid chlorides 76ad by treatment with thionyl chloride. Subsequently, the chlorides 76ad were coupled with the anhydride 74, using tetramethylguanidine (TMG), to produce 77ad, which were eventually transformed into the isocoumarins 78ad. Treatment of 78bd with excess lithium hydroxide resulted in their ring-opening to give the alkyne moieties 79ae, which were subsequently treated with either 2-azidoethanol or 3-azidopropanol under Mitsunobu conditions to achieve the macrocyclic precursors 80ae. The crucial macrocyclization took place using copper sulfate and sodium ascorbate in t-BuOH/H2O medium to afford the macrocyclic triazoles 81ae in 8–33% yields. Final deprotection of the MOM groups was conducted with TFA in dichloromethane to furnish the desired compounds 82ae in 21–84% yields. Biological evaluation of 82ae for Hsp90 inhibition showed reduced binding activity with loss of potency when compared with radicicol and analogue NP261.

Zoom Image
Scheme 10 Synthesis of radicicol analogues 82ae
Zoom Image
Scheme 11 Synthesis of epothilone analogue 92 and its dimer 94
Zoom Image
Scheme 12 Synthesis of macrocyclic glycoconjugates 113c, 114c and 115c

In 2012, Duan et al. synthesized a triazole-fused analogue of epothilone 92 and reported its computational docking studies (Scheme [11]).[6] Initially, the Weinreb amide 83 was used to prepare fragment 84, which was later made to react with a Grignard reagent to afford the keto-alcohol 85. Compound 85 underwent subsequent Horner–Wadsworth–Emmons reaction and desilylation to afford alcohol 86, which was successively coupled with 87 to form alkyne 88. Five sequential reactions upon 88 furnished intermediate 89 and further treatment with p-toluenesulphonyl chloride and sodium azide helped to generate the macrocyclic precursor 90. The ring-closure was conducted using Cu2O-nanoparticles in acetonitrile medium at 37 °C to afford the triazole-fused macrocycles 91 (monomer) and 93 (dimer) in 74% and 6% yields, respectively. Acidic cleavage of both of these compounds finally afforded the target macrocycle 92 (92%) and its corresponding dimer 94 (87%). Through molecular docking studies, it was found that the binding energy of 92 to that of α,β-tubulin was higher than that of natural epothilones. The target molecule 92 was reported to exhibit lower bioactivity against MCF-7 cell lines than epothilone. Interestingly, dimer 94 also showed bioactivity against the same cell lines even though it was about 200 times less potent than the parent compound Epothilone D.

Ajay et al., in 2012, reported the synthesis of some triazole-fused macrocyclic glycoconjugates and also tested their biological activities (Scheme [12]).[20] The process advanced with the preparation of glycopyranosyl butenones (97ac, 98) from d-glucose and d-mannose. In three subsequent steps, the azido-glycopyranosyl derivatives (99ac, 100) were prepared and then subjected to CuAAC reaction with the alkynol moieties in the presence of copper sulfate and sodium ascorbate in t-BuOH/H2O medium at room temperature for 3-4 h, which afforded the triazole derivatives 101103 in excellent yields (83–87%). Action of tosyl chloride in dichloromethane with triethylamine resulted in the formation of tosylated products 104a, 105a and 106b in poor yields; hence, an alternate pathway for the synthesis of the desired macrocycles was considered. The previously used alkynols were tosylated to create 107ac and then made to undergo the CuAAC reaction with 99ac, 100 under the previously decribed reaction conditions to furnish the tosyloxy triazoles 104ac, 105ac, 106ac and 108ac in excellent yields (85–89%). Further exposure to sodium azide in DMF at 80 °C formed the macrocyclic precursors 109ac, 110ac, 111ac and 112ac, which underwent subsequent macrocyclization using tetrabutylammonium hydrogen sulfate (TBAHS) in DMF at 100 °C for 24–36 h to afford the di-triazole-fused macrocyclic compounds 113ac, 114ac, 115ac and 116ac in 64–76% yields. The glucose derived compounds were further deacetylated to afford 117ac, 118ac, and 119ac. On conducting the biological assessment of macrocycles 113ac, 114ac, 115ac and 117a against breast cancer MCF-7 cell line, compounds 113c, 114c, and 115c were noted to exhibit good to moderate activity.

In 2012, Davis et al. developed a peptidomimetic macrocycle 126 through CuAAC methodology, and investigated its bioactivity (Scheme [13]).[21] The synthesis was initiated through the amide coupling of acid 120 and amine 121 in the presence of TBTU and DIPEA. Subsequent acidic deprotection with TFA afforded the key intermediate 122, which was further subjected with two consecutive reactions to produce the azide 123. Next, the previously prepared alkyne fragment 124 was further coupled with 123 in the presence of TBTU/DIPEA to achieve the macrocyclic precursor 125. The key macrocyclization step was finally conducted using l-ascorbic acid, NaHCO3 and copper sulfate in MeOH/H2O medium to graft the desired macrocycle 126 (7.5%). The synthesized macrocycle 126 was evaluated in HeLa cervical cancer cell lines and was noted to inhibit the growth. Its level of cytotoxicity was found to be on par with its parent compound Sansalvamide A.

Zoom Image
Scheme 13 Synthesis of sansalvamide-A analogue 126
Zoom Image
Scheme 14 Synthesis of macrocyclic inhibitors of CT-L protease 138, 139
Zoom Image
Scheme 15 Synthesis of macrocyclic heptapeptide 145

In 2013, Neilsen et al. developed two triazole-fused macrocyclic inhibitors (138, 139) of CT-L protease using the Cu-mediated click-methodology in the crucial macrocyclization step (Scheme [14]).[22] The synthetic procedure advanced with the development of the key azide fragments 129 and 130, from the starting materials 127, 128, under standard amide forming conditions with Leu-Ot-Bu using EDCI. Subsequent acidic deprotection led to the formation of 131 and 132, which were individually coupled with the amino-alkyne moiety 133 under similar EDCI conditions to afford the azide-alkyne containing macrocyclic precursors 134 and 135. Next, the key macrocyclization step was undertaken in the presence of CuBr and DBU in dichloromethane, which grafted the triazole fused macrocycles 136 and 137 in 70% yields each. Further exposure of these compounds to oxidation with Dess–Martin periodinane (DMP) afforded the aldehyde-based macrocycles 138 and 139 in 80% yields, respectively. Biological evaluation against the protease CT-L showed 138 and 139 both possessed activity as potential inhibitors. The compounds also exhibited potency when tested against a panel of four sarcoma cancer cell lines WE-68, VH-64, STA-ET-1 and TC-252.

Zoom Image
Scheme 16 Synthesis of triazole analogue 157 of natural product LL-Z1640-2

Tahoori et al., in 2014, designed a macrocyclic heptapeptide 145 by following Ugi-4CR and Huisgen cycloaddition reactions, and reported its anticancer activity (Scheme [15]).[23] To initiate the synthetic process, the 4-cyanobenzaldehyde 140, azide fragment 141, the carboxylic acid with a propargyl group 142 and cyclohexyl isocyanide 143 reacted in methanol as a four-component Ugi reaction to afford the macrocyclic precursor 144. For the click-reaction, CuI·P(OEt)3 was used as a catalyst with DIPEA in dichloromethane at room temperature for 5 days to obtain the heptapeptidic triazole fused macrocycle 145 in 75% yield. Upon testing its biological properties, macrocycle 145 was seen to exhibit promising anticancer activity against A549 human lung cancer cell line.

In the same year, Goh et al. reported the synthesis of a triazole analogue 157 of natural product LL-Z1640-2 and evaluated its biological activity (Scheme [16]).[24] Initially, the commercially available 2,4,6- trihydroxybenzoic acid 146 was converted into the triflate 147 in three steps. The reaction progressed as the acetonide 148 underwent Colvin rearrangement in the presence of TMS diazomethane and n-BuLi to produce the alkyne 149 and further hydrostannylation produced the trans-vinyl stannane 150. Subsequently, triflate 147 and stannane 150 were subjected to Stille coupling with PdCl2(PPh3)2 to afford alcohol 151, which, upon further treatment with diphenylphosphoryl azide, constructed the key azide fragment 152. Next, the latter was reacted with (S)-pent-4-yn-ol 153 in two different pathways; the first reaction was conducted in the presence of NaH to produce the macrocyclization precursor 154, whereas the second pathway followed standard CuAAC conditions with copper sulfate and sodium ascorbate in t-BuOH/H2O medium to furnish the triazole 155 in 78% yield. Intramolecular click-reaction of 154 under similar CuAAC conditions established the macrocycle 156 in very poor yield (15%), whereas the intramolecular transesterification of 155 with NaH afforded the desired compound 156 in 63% yield. Final deprotection of 156 by acidification grafted the target triazole analogue 157 in 76% yield. Biological assessment of 157 with several kinases showed its ability to act as a potent inhibitor with an inhibition higher than or comparable to its parent LL-Z1640-2. Besides exhibiting good activity against MNK2 kinase, the targeted analogue 157 was also active against AXL and MET and thus, served as a good target for anticancer therapy.

Zoom Image
Scheme 17 Synthesis of apoptosis protein inhibitor 169

Zhang et al., in 2015, synthesized a dimeric macrocycle 169, which served as an inhibitor of apoptosis proteins (Scheme [17]).[25] To initiate the synthetic procedure, commercially available 2-naphthyl alanine 158 was coupled with the prolines 159a,b using EDCI and HOAt to achieve the compounds 160a,b, which were further subjected to five successive steps to develop the key fragments 161a,b. The starting materials 162 and 163 gave rise to the tyrosine derivatives 164 and 166, which were, in turn, HATU coupled with 161a,b to afford the pentapeptides 165 and 167, respectively. The crucial macrocyclization took place between the azide-alkyne fragments 165 and 167 by employing the renowned CuAAC-RCM methodologies. The cycloaddition was conducted overnight at room temperature in the presence of CuSO4 and sodium ascorbic acid in THF/t-BuOH/H2O medium to form the triazole linked moiety 168 in 68% yield. Subsequent RCM reaction with Hoveyda-Grubbs-II catalyst, TFA mediated deprotection, and Pd-catalyzed hydrogenation furnished the desired dimeric macrocycle 169 in 57% yield. Biological assessment of 169 showed its binding ability to XIAP and cIAP proteins. The target compound also exhibited inhibition towards growth of human melanoma and colorectal cell lines by demonstrating prominent antitumor activity in the A875 human melanoma xenograft mode.

In 2015, Seigal et al. established a DNA-programmed library of cyclic peptidomimetics 171ad, 172ad, and 173176 utilizing the Cu-catalyzed 1,3-dipolar cycloaddition reaction (Scheme [18]).[26] The linear precursors were prepared on DNA solid-phase support using a reported DPC method. The crucial macrocyclization step took place by exposing the precursors 170ad to Cu(II) (Z)-2,2,6,6-tetramethyl-5-oxohept-3-en-3-olate, ascorbic acid, DIPEA and 2,6-dimethylpyridine in DMF/THF (1:1) solvent system, which provided the desired set of monomeric macrocycles 171ad after deprotection and resin cleavage with TFA. The dimers 172ad were simultaneously synthesized as a by-product of the aforementioned reaction but, their yields were increased by utilizing a higher substitution density in the solid-phase synthesis, which resulted in the enhancement of intermolecular cyclization. The monomeric macrocycle 173 was produced by inverting the P2 linker in 170a and exposing it to similar macrocyclization conditions, whereas the dimeric macrocycles 174176 were produced by modifying all the P1, P2 and P3 linkers. The macrocycles 171a and 171b were noted to bind potently to cIAP1 BIR3 and XIAP BIR3 in Fluorescence Polarization Assays (FPA), with IC50 values around 3–8-fold lower in the case of the latter. Compound 171b showed less potency in the caspase-3 rescue assay, weak inhibition towards cell growth in human triple negative breast cancer type I MDA-MB-231 cell-lines, and no inhibition in type II A875 melanoma cell-lines. Dimer 172b displayed an improved affinity against BIR2 and BIR3 when compared with its corresponding monomer 171b. Macrocycle 172b exhibited good caspase-3 rescue activity along with measurable antiproliferative activity in both type I and II cell lines, despite being potent towards the cIAP1 BIR3 domain. Dimer 172a showed good binding towards the BIR domain and good caspase-3 rescue activity but no antiproliferation in either I or II cell-lines. Compound 173 had a slight effect on BIR3 affinity but a prominent reduction in BIR2 affinity. Macrocycles 174 and 175 portrayed prominent activity against type I cancer cell lines while showing sub-μM IC50 values against type II A875 cells. Compounds 172c,d were noted to exhibit low IC50 values when evaluated against MDA-MB-231 cells and A875 cells, whereas compound 176 was found to display IC50 values comparable to that of 172b.

Zoom Image
Scheme 18 Synthesis of a few macrocyclic anticancer agents

Cao et al., in 2016, synthesized a set of triazole-fused macrocyclic derivatives 186193 and investigated their antitumor activities (Scheme [19]).[27] The synthetic procedure commenced with the conversion of carboxylic acid 177 into the Boc-protected ester 178 in two steps with further insertion of the alkyne group and subsequent Boc-deprotection to afford the synthon 179. Next, the acid 180 was transformed into its corresponding ester 181 in two steps, which was followed by treatment with sodium azide and subsequent hydrolysis to afford the synthon 182. The synthon 179 was coupled with 182 to form the amide 183 under reaction conditions involving HOBt, EDCI with triethylamine in dichloromethane. On subjecting the macrocyclic precursor 183 to CuAAC reaction with CuI in refluxing toluene for 2 h, the 1,4-disubstituted triazole fused macrocycle 184 was achieved in 55% yield, whereas exposure to RuAAC reaction with catalytic [Cp*RuCl]4 in toluene at 80 °C for 4 h, afforded the 1,5-disubstituted triazole-fused macrocycle 185 in 42% yield. Subsequently, the macrocyclic esters 184 and 185 were changed into their respective acid derivatives 186 and 190, which were further made to undergo condensation with several amines to form the amide derivatives 187189 and 191193 in good yields. Biological evaluation of macrocycles 186193 against lung cancer cell line A549, breast cancer cell line MDA-MB-231, and hepatocarcinoma cell line Hep G2 revealed moderate antitumor activity.

Zoom Image
Scheme 19 Synthesis of antitumor agents 186193

Migrastatin, an anti-metastatic agent originating from microbes, was isolated by Imoto and co-workers in 2000. In 2017, Gabba et al. synthesized the migrastatin-triazole derivatives 201 and 204 and evaluated their biological activities (Scheme [20]).[28] In order to prepare the target macrocycles, the synthons 194 and 198ac were first synthesized. Activation of 5-hexen-1-ol 194 with methanesulfonyl chloride followed by treatment with sodium azide led to the formation of alkenylazide 195. Preparation of synthons 198ac commenced with the use of aldehyde 196; seven subsequent steps furnished the advanced intermediates 197ac, which were made to react in the presence of trimethylsilyl diazomethane and LDA to afford the required alkynes 198ac. Next, the azide-alkyne cycloaddition reaction was conducted upon the alkyne 198a in two different pathways. Initially, 198a was coupled with the azide 195 in the presence of CuSO4·5H2O and sodium ascorbate in THF/water (1:1) medium under 10 min microwave irradiation (60 W) at 60 °C to afford 1,4-disubstituted triazole derivative 199 (73%). The latter was further subjected to macrocyclization in presence of Grubbs’ 2nd generation catalyst to furnish compound 200, and subsequent removal of the TBS protecting group produced the desired compound 201 in 60% yield. A Ru-catalyzed azide-alkyne cycloaddition of 198a and 195 was also conducted by Adele Gabba and her co-workers using catalytic [Cp*Ru(cod)Cl] in DMA through 100 W irradiation at 100 °C for 30 min to prepare the derivative 202 (40%). Exposure to metathesis conditions ensured the macrocyclization process and afforded the triazole-fused macrocycle 203. Further deprotection of the TBS group yielded the second desired product 204 in 96% yield. Compounds 201 and 204 were biologically evaluated using the MDA-MB-361 cell line (human breast cancer) and were found to exhibit a significant effect to retard the process while being comparable to a well-known inhibitor of human tumor cell migrastatin 205.

Zoom Image
Scheme 20 Synthesis of migrastatin analogues 201 and 204

In 2017, Jithin Raj and Bahulayan developed a three-step multi-component coupling (MCR)-click strategy to synthesize a library of coumarin-tagged macrocycles 211 with ring-size ranging from 11 to 18 (Scheme [21]).[29] The protocol commenced with an initial Mannich type reaction conducted with 3-acetyl coumarin 206, alkyne 207, and bromo nitriles 208 to afford the alkyne compounds 209. Next, the azide group was introduced within the compound by treatment with sodium azide in DMF using potassium carbonate as a base. This action led to the formation of macrocycle precursor 210, which underwent intramolecular CuAAC reaction using copper sulfate and sodium ascorbate in the solvent system t-BuOH/H2O/DMSO (4:2:1) for 48 h to afford the desired macrocycles 211 in 64–73% yields. The set of macrocycles were biologically evaluated and were found to show excellent cytotoxicity towards human breast cancer cell line (MCF-7), indicating them to be potential anticancer agents.

Zoom Image
Scheme 21 Synthesis of coumarin-tagged macrocycles 211
Zoom Image
Scheme 22 Synthesis of triazole fused macrocycles 219

In 2018, Eduardo Hernandez-Vazquez and his co-workers reported the synthesis of a series of 20–22-membered triazole fused macrocycles 219 (Scheme [22]).[30] They described a multicomponent approach that involved a Ugi four-component reaction (Ugi 4-CR) to assemble an acyclic precursor. Final macrocyclization was then carried out by intramolecular CuAAC reaction. The synthetic procedure commenced from the azido synthon 213, which was prepared from p-hydroxyphenylacetic acid 212 in four consecutive steps and then treated with an aldehyde 215, various amines 216, isonitriles 217, and under Ugi 4-CR conditions to generate the acylamino carboxamides 218. The Ugi adducts were next exposed to microwave radiation with CuBr/DBU in toluene for 1.5 h to ensure the formation of triazoles. Thus, macrocyclization led to the production of the triazole-fused compounds 219 in moderate to good yields (29–83%). On being biologically evaluated, most compounds were seen to exhibit cytotoxicity against prostate (PC-3) and breast (MCF-7) cancer cells. IC50 values of 219a,b showed more than 50% PC-3 inhibition and 219a also caused high levels of apoptosis in PC-3.

Prabhakaran et al., in 2018, developed a synthetic route to synthesize a triazole-fused macrocycle 223 and evaluated its anticancer activity (Scheme [23]).[7] The synthesis proceeded with the intermolecular click-reaction between alkyne 220 and azide 221 in the presence of copper sulfate and sodium ascorbate, in THF/H2O medium at room temperature. This afforded the triazole-based macrocyclic precursor 222 in 88% yield, which was subsequently subjected to reflux in toluene with sarcosine in a Dean–Stark apparatus to provide the target macrocycle 223 (70%). Biological investigation showed that 223 displayed prominent anticancer activity against human adenocacinoma breast cancer cell lines MCF-7.

Zoom Image
Scheme 23 Synthesis of triazole-fused macrocycle 223

In 2019, Cruz-Lopez et al. constructed an 18-membered triazole-fused macrocycle 231 through double CuAAC reaction (Scheme [24]).[31] The synthetic pathway commenced as the commercially available 6-chloro-1H-pyrazolo[3,4-d]pyrimidine 224 was iodinated with N-iodosuccinimide followed by propargylation with propargyl bromide to afford the intermediate 225. Subsequent steps ensured the introduction of a second alkyne group within the moiety and led to the development of dialkyne compound 226, which was further assembled with 1,3-bis(azidomethyl)benzene 227 in the presence of copper iodide, sodium ascorbate, and triethylamine in dioxane/H2O medium at room temperature for 36 h to achieve the macrocycle 228 (23%). The desired macrocyclic compound 231, analogue of multikinase inhibitor eSM119, was obtained in 51% yield when 228 was cross-coupled with 6-(4-Boc-piperazinyl)pyridyl-3-boronic acid pinacol ester 229 and Boc-deprotected under acidic conditions. The desired compound 231 was found to display selective inhibitory activity against the receptor tyrosine kinase AXL.

Zoom Image
Scheme 24 Synthesis of triazole-fused macrocycle 231
Zoom Image
Scheme 25 Synthesis of thymidine analogue 235

Rahman et al., in 2020, developed a thymidine analogue with linked triazoles 235 and tested its anti-proliferative activities (Scheme [25]).[32] Commercially available thymidine 232 was initially converted into its di-azide derivative 233 in three sequential steps and subsequently exposed to CuAAC reaction with 1,3-diethynyl benzene 234 using a CuI/DIPEA system in acetonitrile for 36 h to afford the macrocyclic thymidine analogue 235 (56%). Biological assessment showed that 235 expressed significant toxicity when tested against C6 glioblastoma cancer cell lines, MCF7 breast cancer cell lines and HT29 colorectal adenocarcinoma cell lines.

Zoom Image
Scheme 26 Synthesis of anticancer agents 241243
Zoom Image
Scheme 27 Synthesis of anticancer agents 250252

In 2021, Srinivas and Rao reported a series of triazole-fused macrocycles 241243 and 250252 and assessed their anticancer activity (Scheme [26] and Scheme [27]).[33] They implemented their idea by using 1-(2-hydroxyphenyl)ethan-1-one 236 as their starting material (Scheme [26]). Compound 236 was converted into azide 237 by the consecutive action of 1,4-dibromopropane and sodium azide. Subsequently, 237 was subjected to cycloaddition reaction with 238 using copper sulfate and sodium ascorbate in a dichloromethane/water solvent system to afford triazole 239 in 76% yield. Three steps were then followed to furnish the triazole-fused macrocycle 240 in 92% yield. Finally, compound 240 was heated at reflux using three different core reagents viz. hydroxylamine, hydrazine hydrochloride and guanidine hydrochloride to achieve the target macrocycles 241 (67%), 242 (63%) and 243 (73%). Another set of macrocycles were prepared using 244 as the starting material (Scheme [27]). After subjecting 244 to three reaction steps, the TBS-protected compound 245 was achieved, which was further propargylated to create the alkyne moiety 246. Deprotection of the TBS group resulted in the formation of 247, which, upon exposure to azide-alkyne cycloaddition reaction conditions with 237, furnished triazole 248 in 77% yield. Two subsequent steps helped graft the intermediate 249 (70.58%). The latter was allowed to react in three different pathways to afford the target macrocycles 250 (64%), 251 (68%) and 252 (61%) by following a similar methodology described earlier. Biological evaluation of these compounds showed promising anticancer activity of 241 and 252 against MCF-7 cell line, whereas compounds 242, 243, 250 and 251 were noted to exhibit activity against MDA-MB-231 and HeLa cell lines.

In 2021, Vazquez-Miranda and co-workers extended their previous synthesis of triazole-fused macrocycles 258 and explored the anticancer activity of the reported compounds (Scheme [28]).[34] Through the Ugi four-component reaction, amines 253, isonitriles 254, azides 255 and the alkyne moiety 256 were made to react together using a catalytic amount of InCl3 in methanol to afford a set of macrocyclic precursors 257. The final macrocyclization was conducted via CuAAC reaction, in the presence of CuBr and DBU in toluene under microwave irradiation, to afford the desired set of compounds 258 in 25–79% yields. The newly synthesized cyclophanes were biologically evaluated against prostate (PC-3 and DU-145) and breast (MCF-7) tumour cells and were reported to exhibit significant cytotoxicity. Compound 259 (Figure [1]) was reported to induce apoptosis in PC-3 in their previous work[30] and was treated as a reference for this work. Compound 258a was noted to display a two-fold higher inhibition towards PC-3 compared with 259, and a lower toxicity towards healthy line COS-7. The derivative 258b was also noted to be one of the most biologically active compounds from the entire set. From all of the observations noted, the Hernandez-Vazquez group concluded that the higher activity could be attributed to the presence of cyclohexyl and 4-isopropylaniline groups.

Zoom Image
Scheme 28 Synthesis of anticancer agents 258
Zoom Image
Figure 1 Macrocycle 259 for potency comparison of 258

# 3

Antibacterial Derivatives

Antibiotic resistance, another global threat, has been an important research scope for scientists. Significant progress has been made so far in this field to treat bacterial infections. Many bioactive molecules are known to have the smallest cyclic peptides, diketopiperazines (DKPs), within their frameworks. Peptide or peptidometric incorporated macrocycles can modulate biological systems and are thus extremely important in the medicinal chemistry field. Isidro-Llobet et al., in 2011, synthesized macrocyclic peptidometric framework 264, the structure of which was inspired by a bioactive molecule (+)-piperzainomycin (Scheme [29]).[35] Amide coupling in between the alkyne moiety 260 and azide 261 using EDC and HOBt led to the production of the macrocyclic precursor 262. Subsequently, the latter was subjected to CuAAC conditions with catalytic CuI and DBU in refluxing toluene to afford the triazole-fused macrocycle 263 in 45% yield. The final DKP formation was achieved using solid-supported NMM under microwave heating at 150 °C for 9 h to furnish the target compound 264 in 40% yield. Biological assessment showed that the target macrocycle 264 exhibited prominent antibacterial property against the Gram-positive bacteria Staphylococcus aureus.

Zoom Image
Scheme 29 Synthesis of macrocyclic peptidometric framework 264
Zoom Image
Scheme 30 Synthesis of antibacterial agents of Re-complexes 271a,b
Zoom Image
Scheme 31 Synthesis of triazole fragments 276, 279 required for 285, 286

Noor et al., in 2014, reported the development of a set of triazole-fused macrocycles that formed stable [Re(CO)3]+ complexes 271a,b and evaluated their antibacterial activities (Scheme [30]).[36] The synthetic procedure progressed with the conversion of the tosylated derivative 265 into the 2,6-bis(azidomethyl)pyridine 266 by the action of sodium azide in DMF/H2O at 80 °C for 24 h. The azide moiety was then treated with dialkyne 267 in the presence of copper sulfate and sodium ascorbate in DMF/H2O (4:1) medium at room temperature for 72 h to afford macrocycle 268 in 42% yield. The latter was further converted into 269 in two reaction steps, which was subsequently exposed to another intermolecular Cu-catalyzed cycloaddition with two alkynes, under reaction conditions similar to those described earlier, to furnish compounds 270a,b (77%, 76%). Subsequently, the rhenium(I) complexes 271a,b were prepared in 92% and 61% yields by refluxing 270a,b in methanol with [Re(CO)3(H2O)3]Br for 24 h. Biological evaluation helped in detection of the inhibitory activity of compounds 271a,b against bacterial strains Staphylococcus aureus and Escherichia coli.

Zoom Image
Scheme 32 Synthesis of antibacterial peptide macrocycles 285, 286

Guo et al., in 2017, constructed the thanatin derived 1,2,3-triazole bridged disulfide surrogated peptides 285, 286 and tested their antibacterial activities (Scheme [31] and Scheme [32]).[37] The process commenced by installing the t-butyl group, followed by Fmoc protection on 2-propargyl-Lglycine 272 to afford the fragment 273, which was clicked with azide 274 via [Cp*RuCl(cod)] catalyzed reaction in DMF at 40 °C to form the triazole moiety 275. Three subsequent reactions led to the production of a key fragment 276 in 95% yield. In a separate pathway, 273 was coupled with azide 277 in the presence of the CuI/DIPEA system in DMF and the triazole 278 was furnished in 84.1% yield. TFA-mediated deprotection of 278 produced the second key fragment 279 in 96.3% yield. The peptidomimetics 285 and 286 were synthesized from the Rink amide AM resin by suitable assembly of Fmoc/t-Bu SPPS, using the coupling reagent HCTU, to create the macrocyclic precursors 281, 282. Successful cleavage of the allyl and Alloc groups with [Pd(PPh3)4]/PhSiH3 was followed by cyclization with PyAOP, NMM and HOAt to graft the cyclic peptides 283, 284. After the remaining amino acids were united, deprotection and acidic cleavage afforded the compounds 285 and 286 in 29.7% and 34.5 yields, respectively. Through biological assessment, it was realized that both of the 1,5- and 1,4-disubstituted triazole peptides showed 50% less inhibition against Pseudomonas aeruginosa compared with thanatin.

Zoom Image
Scheme 33 Synthesis of antibacterial agents 291aj
Zoom Image
Scheme 34 Synthesis of antibacterial agent 294a

Prabhakaran et al., in 2018, developed a synthetic route to synthesize triazole-fused macrocycles 291aj and then evaluated their bioactivities (Scheme [33]).[7] The synthesis involved propargylation of salicylaldehyde 287 to afford the derivative 288 followed by aldol condensation with various methyl ketones to achieve the unsaturated ketones 289ai. In addition, the only unsaturated ester 289j was synthesized via Wittig reaction of 288. Subsequently, intermolecular cycloaddition of 289aj with O-alkylazidoaldehyde 221 in the presence of copper sulfate and sodium ascorbate in THF/H2O (1:1) at room temperature for 12 h furnished the 1,2,3-triazole-linked moieties 290aj in 85–95% yields. Final cyclization of the aldehydes 290aj with sarcosine in toluene at 120 °C for 12 h afforded the desired macrocycles 291aj in 75–85% yields. Several biological assessments conducted on 291aj concluded that these macrocycles showed significant antibacterial activity against Bacillus cereus­ and Klebsiella pneumoniae.

Zoom Image
Scheme 35 Synthesis of antibacterial agents 294a,b
Zoom Image
Scheme 36 Synthesis of tricyclic hexapeptide 306

Biaryl ethers have always been an interesting scaffold for researchers because they possess various bioactivities. In 2018, Singh et al. developed vancomycin-like 44-membered biphenyl ether based macrocycles with triazole linkers 294a,b and evaluated their antibacterial activities (Scheme [34] and Scheme [35]).[38] Their syntheses were undertaken by using the azido-biphenyls 293a and 293b along with the propargylated sugar moieties 292 and 296. The initial Cu-catalyzed AAC reaction conducted between 293a and 292 in the CuI/DIPEA system in acetonitrile/water medium at 30 °C for 48 h afforded the target macrocycle 294a and its isomer 295 as an inseparable mixture with a combined yield 12% (Scheme [34]). Thus, in order to selectively afford the target compound, the substrate 296 was clicked with the biazides 293a and 293b, respectively, in the presence of copper sulfate and sodium ascorbate in t-BuOH/water medium at 30 °C for 3–4 h. This afforded the key intermediates 297a,b in excellent yields of 98% and 96%, respectively (Scheme [35]). Two subsequent steps led to the formation of the bialkyne 298, which was finally subjected to CuAAC reaction with azides 293a/293b in the CuI/DIPEA system under reaction conditions similar to those described earlier. This afforded the desired triazole fused macrocyclic compounds 294a and 294b in 16% and 18% yields, respectively. Through biological investigation, it was reported that both of the compounds exhibited antibacterial activity against Staphylococcus aureus. It was noted that the fluoro substituted compound 294b displayed significant activity against both Methicillin-resistant SA and Vancomycin-resistant SA strains.

In 2022, the Liskamp group constructed a tricyclic hexapeptide 306 that mimicked the topology of a potent antibiotic vancomycin (Scheme [36]).[39] The process was initiated with coupling of the amine (E)-299 and the acid fragment 300 under DCC/HOAt conditions in dichloromethane to achieve the amide 301. After acidic treatment of 301, Boc deprotection resulted in the formation of 302, which was further converted into the macrocyclic precursor 304 in four consecutive reactions. Subsequently, the crucial intramolecular macrocyclization step was conducted using [Cp*RuCl]4 catalyst in THF/MeOH (4:1) medium at 80 °C under microwave irradiation for 2 h to furnish the tricyclic compound 305 in 16% yield. Finally, Boc deprotection with acid yielded the target compound 306, which displayed significant antibacterial activity against Staphylococcus aureus.

Zoom Image
Scheme 37 Synthesis of oligomeric triazolophanes 312321
Zoom Image
Figure 2 Oligomeric triazolophanes 312319

# 4

Derivatives with Dual Activity

Research on the synthesis of macrocyclic compounds has led to the development of certain compounds that exhibit dual bioactivities. Selvarani et al., in 2018, synthesized a series of 1:1 and 2:2 oligomeric triazolophanes 312321 and evaluated their antibacterial activities (Scheme [37], Figure [2] and Figure [3]).[40] The synthetic process advanced with the preparation of bispropargyl-5-nitroisophthalate 307 and the respective bisazides 322, 308311. The building block 307 was obtained by propargylating 5-nitroisophthaloyl chloride, whereas the bisazides were synthesized using 1,4-dibromobutane and various diols as the starting materials. For the crucial macrocyclization step, the fragment 307 was coupled with each of the bisazides (322, 308311) using a catalytic amount of copper sulfate and sodium ascorbate in THF/H2O (3:1) solvent system at room temperature for 12 h (Scheme [37]). The 1:1 triazolophanes (312316) were obtained in 25–38% yields, whereas the 2:2 triazolophanes 317321 were received in 25–30% yields through the advancement of the CuAAC reaction (Figure [2], Figure [3]). Biological screening of the synthesized triazole-fused macrocycles 312321 was conducted with four bacterial strains viz. Staphylococcus aureus (MTCC96), Bacillus subtilis (MTCC441), Salmonella typhi (ATCC 6539) and Escherichia coli (MTCC 1698). When tested against the standard tetracycline, all the compounds showed significant inhibition, with compounds 312 and 314 exhibiting a greater zone of inhibition compared with 312, 313 and 315. Macrocycle 317 was seen to display a stronger inhibition towards the Gram-positive bacteria S. aureus and B. subtilis than the Gram-negative bacteria E. coli and S. typhi. Further, molecular docking studies via Glide XP established the binding ability of macrocycles 313316 with the target protein CTXM-enzyme in complex with cefotaxime. Selvarani et al. also investigated the bioactivities of 312321 against the larvae of vector Aedes aegypti. The compounds shown in Figure [2] and Figure [3] exhibited larvicidal activity, with 90% mortality rate in the case of 316. Macrocycles 314 and 315 were reported to display 80% mortality rate whereas 312313 showed moderate rate and 317321 showed low mortality.

Zoom Image
Scheme 38 Synthesis of antilarval sugar-embedded macrocycles 326, 329 and 333

# 5

Antilarval Derivatives

The cowpea aphid or Aphis craccivora Koch has been a major problem for agriculture because it affects the growth of leguminous crops by sucking the sap from leaves and transmits viruses, which ultimately causes economic damage. Researchers are investing efforts to eradicate these pests by developing new macrocyclic drugs to help vegetation flourish.

In 2017, Rana and co-workers reported the synthesis of a few triazole-fused sugar-embedded macrocycles 326, 329, 333 and presented their bioactivities in 2018 (Scheme [38]).[10] [41] The synthetic process was carried out with the preparation of the macrocyclic precursors 325, 328 and 332. The alkyne moiety 323 and the azide moiety 324 were exposed to CuI-catalyzed AAC reaction in water at 70 °C for 2 h to achieve the intermolecular click product 325 in 78% yield. Subsequently, ring-closing metathesis (RCM) reaction was conducted upon 325 in the presence of Grubbs-II catalyst in two different pathways with varying amount of catalyst added in the reaction mixtures. For method A, the substrate was heated at reflux in dichloromethane for 3 h, which afforded the triazole fused macrocycle 326 in 83% yield. Simultaneously, for method B, the substrate was heated at 75 °C in ethyl acetate for 2 h and the desired macrocycle 326 was grafted in 39% yield. The fragments 327 and 324 were coupled under similar CuAAC reaction conditions to synthesize the macrocyclic precursor 328 (91%), which was further subjected to two different RCM reactions following the conditions mentioned earlier. The target macrocycle 329 was afforded in yields of 82% (method A) and 92% (method B), respectively. Compounds 330 and 331 were clicked together to afford 332 (87%), which underwent macrocyclization via RCM and formed the desired compound 333 in yields of 84% (method A) and 56% (method B). Biological screening of these macrocycles was conducted to evaluate their toxicity against larvae of Aphis craccivora Koch. Compound 328 was seen to exhibit the highest toxicity (93.33%) against the larvae, compound 326 showed prominent toxicity (83.33%), whereas compound 333 displayed 73.33% toxicity.

Zoom Image
Figure 3 Oligomeric triazolophanes 320, 321
Zoom Image
Scheme 39 Synthesis of macrocycles 346351 with anti-inflammatory activity
Zoom Image
Scheme 40 Synthesis of macrocycles 352357 with anti-inflammatory activity

# 6

Anti-inflammatory Derivatives

In order to reduce inflammation caused by various health issues, particularly arthritis, a focus of attention has been the development of few ‘clickable’ cyclophanes. In 2016, Anandhan et al. synthesized and screened the anti-inflammatory activity of certain triazole-based macrocycles (Scheme [39] and Scheme [40]).[8] The synthetic procedure commenced with propargylation of the amine 334 using KOH and TBAP in a toluene/H2O solvent system to afford the alkyne moiety 335. Compound 335 was subjected to three different reaction pathways to afford the macrocyclic precursors 339342, which were subsequently made to react with the azides 343345 by following the cycloaddition reaction methodology using copper sulfate and sodium ascorbate in THF/H2O medium at room temperature for 10 h in order to furnish a set of triazole-based macrocyclic compounds 346357 (55–77%). All the macrocycles exhibited good anti-inflammatory activity when compared to the reference prednisolone.

Zoom Image
Scheme 41 Synthesis of antiviral agent 364
Zoom Image
Scheme 42 Synthesis of antiviral agents 381, 383

# 7

Antiviral Derivatives

Viral infections have always been affecting the lives of people and are an important health concern. In order to combat with such infectious diseases, researchers have paid significant attention to the development of drugs required for treatment. In 2013, Mandadapu et al. reported the synthesis and bioevaluation of macrocyclic inhibitor 364 of 3C and 3C-like proteases of viral pathogens (Scheme [41]).[9] The synthetic procedure advanced with the development of the building block 359 from the (L) Boc-protected propargyl glycine 358 in four consecutive steps while the second building block 361 was synthesized from commercially available (L) Boc-Glu-OCH3 360 in two steps. These two were gradually coupled under standard conditions using HOBt and EDCI with DIPEA in DMF to graft the amide 362, which was further subjected to cycloaddition reaction conditions using CuBr, DBU in dichloromethane to afford the triazole-fused macrocycle 363 in 45% yield. Further treatment of 363 with lithium borohydride converted it into an alcohol, which subsequently formed the desired macrocycle 364 through Dess–Martin periodinane oxidation. Through biological assessment, compound 364 was noted to exhibit inhibition against novovirus 3CLpro, enterovirus 3Cpro and SARS-CoV 3CLpro.

Weerawarna et al., in 2016, developed a series of triazole-fused macrocycles 379390 and evaluated their antiviral properties (Scheme [42], Scheme [43] and Scheme [44]).[42] The synthesis progressed with the construction of the key intermediates 365ac, 368ae and 369a,b. Initially, the commercially available N-Boc-protected l-propargylglycine 358 was transformed into the intermediates 365ac in four consecutive steps. A subsequent coupling of N-Boc protected glutamic acid 366 and HCl salts of amino azides 367ae, under standard conditions involving EDCI and HOBt, proceeded to furnish the intermediates 368ae (Scheme [42]). Deprotection of the Boc-group in the presence of HCl yielded the azides 369a,b, which further underwent coupling with acid 365a in the presence of EDCI and HOBt to afford the macrocyclic precursors 370a,b, respectively. The crucial macrocyclization step was then undertaken via intramolecular CuAAC reaction in the presence of CuI with DBU in DCM solvent at room temperature for 24 h to achieve the macrocycles 371a,b in 45% and 50% yields. Sequential reduction with LiBH4 and oxidation through Dess–Martin periodinane afforded the desired triazole-based macrocycles 381 and 383 in good yields (Scheme [42]).

Zoom Image
Scheme 43 Synthesis of some antiviral agents
Zoom Image
Scheme 44 Synthesis of antiviral agent 390

In order to synthesize the other macrocycles 379, 380, 382, and 384389, the key intermediates 365ac and 368ae were coupled in the presence of copper sulfate and sodium ascorbate in THF/H2O at room temperature for 20 h to graft the triazole linked fragments 372ai (Scheme [43]). Subsequent amide bond formation through acid-amine coupling with a sequenced Boc-deprotection constructed the macrocycles 373ai in fair yields (ca. 60%). A similar reaction methodology of consecutive reduction-oxidation upon 373ai resulted in the formation of the desired macrocyclic compounds 379, 380, 382, and 384389.

The synthesis of the last macrocycle 390 commenced with the reaction of (Z)-l-ornithine with triflic azide solution in the presence of triethylamine and copper sulfate in acetonitrile medium to afford the acid 375. The N-Boc-protected amino acid was transformed into the azide moiety 376 in three consecutive steps and subsequent Boc-deprotection followed by coupling with 375 under standard conditions afforded the macrocyclic precursor 377. Intramolecular cycloaddition with CuI/DBU catalytic mixture in dichloromethane at room temperature for 12 h afforded macrocycle 378 in 48% yield. Finally, after two consecutive steps, the desired triazole-based macrocycle 390 was achieved (Scheme [44]). After investigating the biological properties of 379390, it was reported that these macrocycles showed inhibition against novovirus 3C-Like protease.

In 2019, the Groutas group extended their previous synthetic work[9] and established a few macrocyclic inhibitors of novovirus 3CLpro, 391393, utilizing similar multistep synthesis and click-methodology as described earlier (Figure [4]).[43] The FRET NV 3CL protease assay along with the examination of the effects of macrocycles on virus replication against NV or MNV gave results that were comparable to those of a few previously synthesized macrocycles.[9]

Zoom Image
Scheme 45 Synthesis of macrocycles 400403 with anti-trypanosomal activity

# 8

Anti-trypanosomal Derivatives

American trypanosomiasis, also known as Chagas disease, is a life-threatening condition caused by the parasite Trypanosoma cruzi transmitted through the faeces of triatomine bugs. Millions of people, especially in regions like Latin America, are affected every year with this fatal disease, and there is a desperate need for treatment.

Zoom Image
Figure 4 Antiviral agents 391393

Campo et al., in 2015, showed their interest in developing triazole-linked macrocyclic inhibitors of T. cruzi trans-sialidase (TcTS), which was found to be a potential drug target for the aforementioned disease (Scheme [45]).[44] In order to achieve the galactose monomer 399, O-propargyl-d-galactopyranose 394, was chosen as the starting material. With suitable benzoylation of 394 followed by exposure to ammonia in methanolic-THF medium, the hemiacetal 396 was synthesized. With further treatment with trichloroacetonitrile and DBU, compound 397 was formed and subsequently activated with trimethylsilyl trifluoromethanesulfonate and 2-(2-(2-chloroethoxy)ethoxy)ethanol to give the β-glycoside 398. Through two sequential reactions, the chlorinated fragment 398 was converted into the azide 399 and then tested under two different CuAAC reaction conditions. The first method (A) involved subjecting 399 to CuSO4/Cu turnings in DMF under microwave irradiation at 110 °C for 30 min, whereas the second reaction (B) was conducted at ambient temperature and continued for 2 days; both the reactions afforded linear as well as cyclic products. The cyclic oligomers of various ring sizes (monomer 400, dimer 401, trimer 402 and so on) were obtained by utilizing the 1,4-disubstituted triazole as connectors. When the component 399 was separately exposed to uncatalyzed microwave conditions for 30 min (Method C), the 1,4-disubstituted triazole based macrocycle 400 and the 1,5-disubstituted triazole based macrocycle 403 were obtained as products, along with their respective linear oligomers. Through biological investigation, it was reported that the macrocycles serve as acceptor substrates for the enzyme trans-sialidase related with host cell invasion by T. cruzi and were also noted to inhibit the invasion of T. cruzi into bovine macrophages.


# 9

Derivatives with Miscellaneous Activities

The growth factor receptor-bound protein 2 (Grb2) is a favourable drug target for researchers, being a SH2 domain-containing signal transducer. In 2006, Choi et al. synthesized a series of SH2 domain-binding inhibitors 411414a,b via CuAAC reaction (Scheme [46]).[45] The synthetic procedure commenced with the preparation of key fragment 409a,b using the alkyne moiety 404 as the starting material. After heating at reflux in ethanol with hydrazine, the amine thus produced was further coupled with N-Boc l-Asn using HOBT and EDC to afford the Boc-protected amide 405. TFA-mediated deprotection of 405 formed 406, which was then subjected to two subsequent steps to synthesize the tripeptide 407. On attaining this compound in the form of an inseparable epimeric mixture, further N-Fmoc removal resulted in separation of the amines and production of the diastereomers 408a and 408b. The macrocyclic precursors 409a,b were prepared by treating 408a,b with bromoacetic anhydride and subsequent addition of sodium azide. Removal of the t-Bu group and exposure to copper sulfate, l-ascorbate and DIPEA in acetonitrile-t-BuOH/H2O solvent system at room temperature then afforded the monomeric macrocycles 411a,b along with the dimers 413a,b. The cycloaddition reaction produced the monomers as a majority at 1 μM substrate concentration, whereas the dimers were obtained predominantly at 2 μM substrate concentration. Finally, cleavage of the t-butyl esters produced the target monomeric (412a,b) and dimeric (414a,b) macrocycles. Surface plasmon resonance (SPR) was used to evaluate the Grb2 SH2 domain-binding affinities of the newly synthesized macrocycles. It was found that the (R)-isomeric-macrocycles 412b and 414b displayed binding constants above 1 μM. The monomeric (S)-macrocycle 412a bound with sub-micromolar affinity whereas its corresponding dimer 414a exhibited more than 50-fold higher binding affinity.

Zoom Image
Scheme 46 Synthesis of SH2 domain-binding inhibitors 411414a,b

A potent tyrosinase inhibitor cyclo-[Pro-Tyr-Pro-Val] (432), was isolated from the ‘good bacteria’ L. helveticus. Being interested in developing synthetic analogues of the natural cyclotetrapeptide, in 2007, the van Maarseveen group achieved two triazole analogues (425, 431) of the aforementioned compound (Scheme [47] and Scheme [48]).[11] The process began with the preparation of the linear precursor 423 through an initial coupling of the acid 415 and protected proline 416 to develop the azido-amide 417. Further deprotection of 417 led to the synthesis of a key fragment 418 (Scheme [47]). A similar EDC-HOBt-mediated coupling between alkyne 419 and protected valine 420 afforded 421, which, upon Boc deprotection, afforded the second key fragment 422. Subsequently, the macrocyclic precursor 423 was synthesized through peptide coupling of 418 and 422 in the presence of EDC, HOBt, DIPEA in dichloromethane and finally subjected to macrocyclization through CuBr-mediated CuAAC reaction with DBU in refluxing toluene to furnish the triazole-fused macrocycle 424 in 56% yield. Pd-catalyzed hydrogenation of 424 finally afforded the desired analogue 425 in 91% yield (Scheme [48]). In order to prepare the other triazole analogue 431, the alkyne moiety 426 was initially coupled with the azide moiety 427 to graft the triazole based key fragment 428. Compound 428 was further exposed to three consecutive reactions to obtain the linear macrocyclic precursor 429. A similar CuAAC methodology was applied to 429, which furnished the cyclotetrapeptide 430 in 36% yield. Benzyl group deprotection of 430 finally helped in grafting the desired analogue 431 in 90% yield (Scheme [48]). Biological investigation of the synthesized macrocycles 425 and 431 was carried out by comparison of their inhibitory activity with their parent compound 432. It was reported that the analogues exhibited three-fold increase in inhibition against mushroom tyrosinase.

Zoom Image
Scheme 47 Synthesis of tyrosinase inhibitor

In 2011, Ingale and Dawson described the synthesis of structurally constrained peptides through side-chain macrocyclization following CuAAC reaction (Scheme [49]).[46] Commercially available Tenta-gel resin was treated through Fmoc SPPS protocol to produce the protected resin-bound peptide 433. The key macrocyclization was conducted with CuBr, sodium ascorbate, 2,6-lutidine and DIPEA in DMSO for 16–18 h at room temperature to afford the triazole-based intermediate 434. Subsequent removal of protecting groups and resin cleavage provided the cyclized product 435 in 70% yield. In order to show the usefulness of this reaction in complex systems, full-length MPER epitope of gp41 668–683 was produced. The resin bound peptide 436 was exposed to similar macrocyclization conditions as stated earlier followed by deprotection and resin cleavage to afford the triazole-fused product 437 in 65% yield. Upon evaluating the binding of the triazole-constrained peptides to 4E10 and Z13e1, they were noted to alter the structure of helical peptides obtained from HIV gp41.

Zoom Image
Scheme 48 Synthesis of tyrosinase inhibitor
Zoom Image
Figure 5 A peptide variant of SFTI-1
Zoom Image
Scheme 49 Synthesis of peptide macrocycle 437

Sunflower trypsin inhibitor-1 (SFTI-1) is a cyclic peptide framework favoured by researchers synthesizing peptide-based pharmaceuticals as it acts a potent inhibitor of trypsin. With a wide range of applications in drug design, SFTI-1 is particularly targeted to serine proteases and GPCRs. The Kolmar group, in 2011, developed three triazole-based derivatives (440, 441 and 444) of a peptide variant of SFTI-1 (445; Figure [5]) by utilizing both CuAAC and RuAAC methodologies (Scheme [50]).[47] Commercially available SPPS building blocks Fmoc-l-propargylglycine (Fmoc-Pra-OH) and Fmoc-l-azidoalanine (Fmoc-Aza-OH) or Fmoc-l-azidohomoalanine (Fmoc-Aha-OH) were utilized to afford the macrocyclic precursors 438 and 439, respectively. Subsequent TFA-mediated cleavage with further macrocyclization undertaken in presence of copper sulfate, sodium ascorbate and DIPEA at room temperature resulted in the formation of the 1,4-disubstituted triazole-linked peptides 440 and 441, respectively. Application of RuAAC methodology to the unprotected peptide 439 led to a mixture of undesired products, thus prompting the researchers to develop a different linear precursor 442. The protected peptide 442 was subjected to [Cp*RuCl(cod)] catalyzed reaction under microwave irradiation at 60 °C for 5 h and the 1,5-disubstituted triazole-linked macrocycle 443 was obtained. The desired macrocycle 444 was obtained after the introduction of SPPS building block and consecutive acidic cleavage. Kinetic studies using active-site titrated trypsin made it clear that different modes of macrocyclization affected the inhibitory activity of the peptides significantly. The 1,5-disubstituted triazole-based macrocycle 444 was reported to retain inhibition in a range comparable to its parent peptide 445 (Figure [5]), whereas the 1,4-disubstituted triazole-based macrocycles 440 and 441 showed a decline in inhibition.

Zoom Image
Scheme 50 Synthesis of trypsin inhibitors 440, 441 and 444

In 2013, Pehere et al. designed triazole-fused macrocyclic protease inhibitors (Scheme [51] and Scheme [52]).[48] For the preparation of the macrocycle 450, initial coupling in between the dipeptide 446 with the azide moiety 447 under standard EDCI-HOBt conditions gave rise to the tripeptide 448, which further underwent macrocyclization in the presence of CuBr and DBU in dichloromethane for 7 h at room temperature to afford the macrocycle 449 (71%). Subsequently, 449 was reduced with lithium borohydride and the resultant alcohol was oxidized by DMP to provide the target compound 450 (52%) (Scheme [51]). The triazole-linked macrocyclic precursor 453 was next grafted in 60% yield by the intermolecular click reaction between alkyne 451 and azide 452 in the presence of copper sulfate and sodium ascorbate in dichloromethane/water medium at room temperature for 15 h. TFA-mediated Boc deprotection formed the moiety 454, which subsequently underwent HATU coupling to provide the triazole-fused macrocyclic ester 455 in 13% yield. Gradual reduction of 455 with lithium borohydride followed by oxidation with DMP helped achieve the target compound 456 (80%).

Zoom Image
Scheme 51 Synthesis of macrocyclic protease inhibitors 450 and 456
Zoom Image
Scheme 52 Synthesis of a series of macrocyclic protease inhibitors

In a similar manner, the alkyne fragment 457 was coupled with 452 under AAC reaction conditions using copper sulfate and sodium ascorbate to furnish the triazole-linked moiety 458 (63%). Further Boc deprotection followed by HATU/HOAt mediated amide formation resulted in the development of the triazole-fused macrocycle 460 in 48% yield (Scheme [52]). Two subsequent steps finally afforded the desired compound 461 in 80% yield. The macrocyclic precursor 462, constituting both the azide and alkyne parts, underwent intramolecular CuAAC reaction with CuBr under the aforementioned conditions to give 463 (70%), which, upon further oxidation with DMP, afforded macrocycle 465 in 73% yield. To the authors amazement, when compound 462 was left at room temperature for a few months, the 1,5-disubstituted triazole 464 (65%) was received. Upon further oxidation, the macrocycle 466 was obtained in 71% yield. Biological evaluation of the macrocycles showed all compounds displayed inhibition towards Cathepsin S (Cat S), a protease related to tumour growth, autoimmune diseases, and osteoporosis etc. Compound 466 was found to be on par with 465 when tested for inhibition towards the proteases calpain II (implicated in stroke, cataracts etc.), Cat S, and Chymotrypsin-like (CT-L) (anticancer therapeutic target). It was also found to exhibit a fourfold decrease in potency for Cathepsin L in comparison with 465.

Zoom Image
Scheme 53 Synthesis of Palmyrolide-A analogue 472

After isolation in 2010, the natural product Palmyrolide A had been identified as having neuroprotective activity as it suppressed neuronal spontaneous calcium ion oscillations through its voltage-gated sodium channel (VGSC) blocking ability. Thus, researchers have always considered Palmyrolide A to be a favourable target in CNS drug discovery. In 2016, Philkhana et al. synthesized two triazole based analogues (471, 472) of Palmyrolide A and investigated their bioactivities (Scheme [53]).[12] The process began by subjecting compound 467 to ozonolysis with subsequent Seyferth–Gilbert homologation using the Ohira Bestmann reagent to afford the alkyne 468. TCBC-mediated esterification of 468 with 6-azidohexanoic acid 469 produced the macrocyclic precursor 470, which was finally clicked intramolecularly with CuI in MeOH/PEG400 (1:2) medium at 80 °C under sealed conditions. The desired triazole-fused macrocycles 472 and 471 were obtained in a combined yield of 66% in a 2:1 ratio. Biological evaluation of the macrocycles was conducted to check their interaction with VGSC. Their inhibitory activity against the veratridine-stimulated Na+ influx in murine primary neuronal cultures proved that the triazole-containing moieties did not show much potency; instead, 472 exhibited a fivefold decrease in activity compared with its parent compound Palmyrolide A (Figure [6]).

Zoom Image
Figure 6 (–)-Palmyrolide A

Jogula et al., in 2017, synthesized some ‘Geldanamycin’ inspired triazole-based macrocycles by employing CuAAC reaction as the crucial macrocyclization step and evaluated their bioactivities (Scheme [54]).[49] The preparation of the target molecules was initiated from l-ascorbic acid (473) as it was converted into ester fragment 474 following a reported method. Several consecutive steps afforded the fragment 475, which was subsequently acidified to cleave the dioxolane moiety and treated with triisopropylsilyl chloride to achieve 476. The macrocyclic precursor 478 was next achieved through DCC/DMAP coupling of the separately synthesized azido-acid 477 and the alcohol 476. The final macrocyclization occurred via intramolecular cycloaddition reaction by utilizing CuI/DIPEA catalytic system in refluxing THF, and resulted in the desired product 479 in 63% yield. By following a similar methodology, ester 480 was converted into the TBS-protected alkyne fragment 481, which was further coupled with 477 to produce the macrocyclic precursor 482. This moiety was intramolecularly clicked using the aforementioned catalyst at 70 °C to graft the macrocycle 483 (70%). In order to assess these novel macrocycles biologically, initial molecular docking simulations of 479 and 483 were investigated with Hsp90. It was reported that 483 exhibited better binding with the ATP binding site of Hsp90 protein than geldanamycin. The synthesized macrocycles exhibited the ability to trans-differentiate human umbilical cord tissue-derived mesenchymal stem cells to neurons. By monitoring the phenotypic changes occurring within the cells, some selected biomarkers viz. nestin, agrin and RTN4 were identified to be present in the transformed neuronal cells with 483.

Zoom Image
Scheme 54 Synthesis of Geldanamycin inspired macrocycles 479, 483

The melanocortin system is known to be involved in the regulation of physiological functions like feeding behaviour, inflammation, pigmentation, exocrine gland function and more. In 2018, Tala et al. reported the synthesis of some triazole-bridged peptidomimetics and evaluated them as mouse melanocortin receptors (Scheme [55] and Scheme [56]).[50] Initially, the linear peptide 484 was synthesized by following the Fmoc/t-Bu SPPS method on Rink-amide MBHA resin. The solid-phase assembly in furnishing 484 had introduced both the alkyne and azide groups within the system by replacing the N α-Fmoc-Cys-OH residues with N α-Fmoc-l-Pra-OH and N α-Fmoc-l-Aza-OH amino acids within the peptide template 494 (Figure [7]). The macrocyclic precursor 484 favourably underwent intramolecular CuAAC reaction conducted overnight using copper sulfate-sodium ascorbate in H2O/tBuOH solvent system at room temperature and afforded the desired 1,4-disubstituted triazole-fused macrocyclic peptide 485 (Scheme [55]). In a similar manner, the linear peptide 486 was also prepared by coupling the amino acids on resin using the aforementioned strategy. Subsequently, macrocyclization was conducted with catalytic [Cp*RuCl(cod)] under microwave (30 W) at 60 °C for 3 h to graft the compound 487 on resin. After subjecting to further coupling of Tyr and subsequent TFA-mediated cleavage, the 1,5-substituted triazole-fused macrocyclic peptide 488 was obtained.

Zoom Image
Scheme 55 Synthesis of macrocyclic peptides 485, 488

The effects of ring size on macrocyclization were further investigated by the team and, henceforth, the N α-Fmoc-l-Aza-OH residues in 494 were replaced with N α-FmocL-Orn(N3)-OH amino acids to develop the linear peptide 489 through the Fmoc/tBu SPPS method. Subsequently, 489 was coupled with 1,3-diethynylbenzene 490 by following the intermolecular copper sulfate-sodium ascorbate catalyzed reaction in the presence of tris(3-hydroxylpropyltriazolylmethyl)amine in a similar manner to that described earlier. This yielded the target macrocyclic 1,4-disubstituted bis-triazole-fused peptide 491 predominantly (Scheme [56]). The peptide resin 492, afforded in a way same as the linear precursors, was coupled with 490 through intermolecular RuAAC reaction using [Cp*RuCl(cod)] under microwave conditions as stated earlier. Through subsequent deprotection, resin-cleavage and purification, the 1,5-disubstituted bis-triazole-macrocyclic peptide 493 was obtained as the major product. With the generated macrocycles in hand, the pharmacological assessment with mouse melanocortin receptors mMC1R, mMC3R, mMC4R, and mMC5R was conducted. Their ability to stimulate intracellular cAMP signalling was tested in HEK293 cells. The macrocyclic peptide 485 showed 41-, 13-, 14-, and 7-fold decrease in potency at the mMC1R, mMC3R, mMC4R, and mMC5R, respectively, in comparison to the template peptide 494. The peptide 488 was noted to exhibit an increase in potency at the mMC3R and mMC5R, while maintaining potent nanomolar agonist activity with mMC1R and mMC4R in contrast with the potency of 488. Compound 488 was also found to show a fivefold decrease in potency at mMC4R in comparison with 494 and a 29-fold reduced potency at mMC1R. Peptides 491 and 493 were seen to display modest selectivity for mMC5R.

Zoom Image
Scheme 56 Synthesis of macrocyclic peptides 491, 493
Zoom Image
Figure 7 A peptide template

White et al., in 2020, established a series of triazole-linked cyclic peptides using the SFTI-1 framework and assayed them against serine protease inhibitors (Scheme [57]).[51] Commercially available β-azidoalanine (Aza) or γ- azidohomoalanine (hAza) and propargylglycine (Prg) were assembled by Fmoc SPPS on 2-chlorotrityl chloride resin 495. Subsequent resin cleavage and backbone cyclization brought the azide and alkyne groups close to each other. Further TFA-cleavage was followed by CuAAC reaction with copper sulfate, THPTA and sodium ascorbate at 37 °C for 3 h resulted in the formation of 1,4-disubstituted triazole-linked peptide macrocycles 500df and 501df. On exposing the protected peptide to RuAAC reaction with [Cp*RuCl(cod)] catalyst in DMF at 80 °C for 18 h, the 1,5-disubstituted triazole-linked peptide was obtained. Final deprotection led to the production of the target compounds 500b,c, 502b, 501b,c and 503b. The inhibitory activities of triazoles 500bf were evaluated against trypsin using SFTI-1 as a reference. Compounds 500b,c were found to be more potent compared with the others, whereas 500b was reported to retain maximum inhibition when compared with SFTI-1. The other triazole-based peptide analogues 502b, 501b and 503b were screened for inhibition against kallikrein-related peptidase 7 (KLK7), plasmin and matriptase. Compound 502b exhibited a sevenfold lower inhibitory activity than its parent 502a when assayed upon KLK7 protease involved in skin disorders. Compound 501b showed 62-fold less inhibition compared with 501a after being evaluated against plasmin, a protease related to fibrinolysis. Furthermore, the analogues 501cf exhibited extreme loss in potency (>6300-fold) when assayed against the same, confirming that 501b remained the most favourable disulfide mimetic. The other analogue 503b was noted to display 120-fold less inhibition than 503a after being screened against matriptase, a membrane-anchored protease involved in epithelial tumours. The triazole-linked peptides 500b503b were tested against human serum and were found to resist degradation. On being investigated against liver S9 assays, 500b503b were reported to be stable with half-lives greater than 200 min.

Zoom Image
Scheme 57 Synthesis of macrocyclic peptides 500bf, 501bf, 502b and 503b

Kulsi et al., in 2020, designed an amide-based triazole-fused macrocycle 511 through cyclo-oligomerization (Scheme [58]).[52] The synthetic route progressed with the azide-alkyne cycloaddition between O-phthalimide-protected propargyl alcohol 504 and azido-glucose 505 using copper sulfate and sodium ascorbate in t-BuOH/H2O medium to afford the triazole 506 in 88% yield. Five consecutive steps led to the production of the intermediate 507, which was further subjected to sequential protection–deprotection to furnish 509. Subsequently, the fragments 507 and 509 were coupled together to form amide 510 under EDC/HOBt conditions. The final macrocyclization to yield the cyclic peptide 511 (55%) took place via hydrolysis and activation with penta-fluorophenyl ester (PFP) with gradual peptide coupling. Through several assessments, macrocycle 511 was found to be an electroneutral and anion receptor. With an incredible ability to distinguish in between ions, the macrocycle exhibited a preference towards Cl ion and served as a scaffold for ion transportation, thus imposing cancer cell death by disruption of ionic homeostasis.

Zoom Image
Scheme 58 Synthesis of triazole-fused macrocycle 511

In 2022, Cheekatla et al. developed a aza-oxa based macrocycles by employing CuAAC reaction and evaluated their biological properties (Scheme [59]).[53] The synthetic procedure commenced by subjecting the amine-hydroxyl derivatives 512ad to O-propargylation with propargyl bromide by using NaH in DMF at 0 °C and subsequent N-propargylation in the presence of DIPEA in refluxing chloroform to afford the alkyne moieties 513ad. These alkynes underwent intermolecular CuAAC reaction with bis(2-azidoethyl)amine 514 using catalytic CuI and DIPEA in acetonitrile medium at room temperature for 12–24 h to afford the triazole-fused macrocycles 515ad. For the other macrocycle 518, diol 516 was initially converted into its corresponding di-propargylated moiety 517 by the action of propargyl bromide and NaH in DMF at 0 °C and was further treated under similar click-conditions as described earlier. By studying the fluorescence properties for the interaction between the macrocycles with bovine serum albumin (BSA) and human serum albumin (HSA), it was reported that all the compounds exhibited a varied range of interactions. The macrocycles that interacted well with the proteins showed fluorescence quenching. Upon calculating the binding constants for the interaction of macrocycles and BSA, 518 was noted to have the highest binding while the other macrocycles 515ad exhibited moderate binding. Furthermore, the fluorescence studies of 518 with HSA showed that it had the highest interaction and quenching while the other macrocycles displayed moderate results.

Zoom Image
Scheme 59 Synthesis of aza-oxa macrocycles

Thurakkal et al. synthesized a triazole-based macrocyclic fluorescence sensor in 2023 for the detection of antibiotics containing nitro groups (Scheme [60]).[54] The envisioned procedure commenced with the reaction of dansyl chloride 519 with diethanolamine 520 in the presence of triethylamine to afford 521. After subsequent exposure to proparyl bromide, 521 was converted into the dialkyne-moiety 522. The final macrocyclization was conducted in the presence of the azide moiety 514 through CuAAC reaction with copper sulfate and sodium ascorbate in MeOH/H2O medium at room temperature for 30 min to furnish the macrocycle 523. The photophysical studies of 523 along with its interaction with several antibiotic drugs such as dimetridazole (DMI), nitrofurantoin (NFT), and nitrofurazone (NFZ) were conducted. Fluorescence spectroscopy and molecular docking showed that DTMC sensed the nitro-containing compounds and also showed favourable interaction with proteins.

Zoom Image
Scheme 60 Synthesis of macrocyclic fluorescence sensor

# 10

Conclusion

We have reported several synthetic methodologies for the preparation of biologically active 1,2,3-triazole-fused macrocyclic compounds having ring sizes of 12 to 60 members. Many of them have been constructed through peptide linkages. In most of the cases, the renowned Cu-catalyzed azide-alkyne cycloaddition reaction led to the 1,4-disubstituted 1,2,3-triazoles, whereas the 1,5-disubstituted 1,2,3-triazole-fused macrocycles were obtained via Ru-catalyzed cycloaddition. The thorough literature survey demonstrates that the azide-alkyne cycloaddition is a versatile method that does not require drastic reaction conditions. It was observed that even when further functionalization of the triazole-linked scaffolds was conducted, in order to obtain the target bioactive compounds, the triazole moieties remained unaffected. Researchers also synthesized analogues of a few naturally occurring bioactive macrocycles involving azide-alkyne cycloaddition strategies.[4] [17] [21] [24] The macrocycles described herein hold promising biological properties viz. anticancer, antibacterial, antiviral, anti-trypanosomal, antilarval, anti-inflammatory etc. The bioactivities of these triazole-based analogues were retained, which showed the nitrogen-rich triazole moiety to be an extremely useful moiety in drug discovery. We anticipate that this review article will pique the curiosity of various researchers in establishing several methodologies to graft biologically relevant triazole-fused macrocycles.


#
#

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors acknowledge the Department of Science and Technology, Ministry of Science and Technology (New Delhi) for providing the HRMS instrument (Thermo Scientific) under the FIST programme.

  • References

  • 1 Liang Y, Fang R, Rao Q. Molecules 2022; 27: 2837
    • 2a Marsault E, Peterson ML. J. Med. Chem. 2011; 54: 1961
    • 2b Cheekatla SR, Barik D, Anand G, Mol KM. R, Porel M. Organics 2023; 4: 333
    • 2c Medved’ko AV, Gaisen SV, Kalinin MA, Vatsadze SZ. Organics 2023; 4: 417
    • 2d Begnini F, Poongavanam V, Over B, Castaldo M, Geschwindner S, Johansson P, Tyagi M, Tyrchan C, Wissler L, Sjö P, Schiesser S, Kihlberg J. J. Med. Chem. 2021; 64: 1054
  • 3 Jahan N, Ansary I. SynOpen 2023; 7: 209
  • 4 Horne WS, Olsen CA, Beierle JM, Montero A, Ghadiri MR. Angew. Chem. Int. Ed. 2009; 48: 4718
  • 5 Day JE. H, Sharp SY, Rowlands MG, Aherne W, Workman P, Moody CJ. Chem. Eur. J. 2010; 16: 2758
  • 6 Duan X, Zhang Y, Ding Y, Lin J, Kong X, Zhang Q, Dong C, Luo G, Chen Y. Eur. J. Org. Chem. 2012; 500
  • 7 Prabhakaran P, Subaraja M, Rajakumar P. ChemistrySelect 2018; 3: 4687
  • 8 Anandhan R, Kannan A, Rajakumar P. Synth. Commun. 2017; 47: 671
  • 9 Mandadapu SR, Weerawarna PM, Prior AM, Uy RA. Z, Aravapalli S, Alliston KR, Lushington GH, Kim Y, Hua DH, Chang K, Groutas WC. Bioorg. Med. Chem. Lett. 2013; 23: 3709
  • 10 Rana R, Dolma SK, Maurya SK, Reddy SG. E. Toxin Rev. 2020; 39 (02) 197
  • 11 Bock VD, Speijer D, Hiemstra H, van Maarseveen JH. Org. Biomol. Chem. 2007; 5: 971
  • 12 Philkhana SC, Mehrotra S, Murray TF, Reddy DS. Org. Biomol. Chem. 2016; 14: 8457
    • 13a Ansary I, Roy H, Das A, Mitra D, Bandyopadhyay AK. ChemistrySelect 2019; 4: 3486
    • 13b Silvestri IP, Andemarian F, Khairallah GN, Yap SW, Quach T, Tsegay S, Williams CM, O’Hair RA. R, Donnelly PS, Williams SJ. Org. Biomol. Chem. 2011; 9: 6082
    • 13c Johansson JR, Beke-Somfai T, Stålsmeden AS, Kann N. Chem. Rev. 2016; 116: 14726
    • 13d Roshandel S, Suri SC, Marcischak JC, Rasul G, Surya Prakash GK. Green Chem. 2018; 20: 3700
    • 13e Dar BA, Bhowmik A, Sharma A, Sharma PR, Lazar A, Singh AP, Sharma M, Singh B. Appl. Clay Sci. 2013; 80–81: 351
  • 14 Jahan N, Das A, Ansary I. ChemistrySelect 2022; 7: e202201831
  • 15 Chen J, Nikolovska-Coleska Z, Yang C, Gomez C, Gao W, Krajewski K, Jiang S, Roller P, Wang S. Bioorg. Med. Chem. Lett. 2007; 17: 3939
  • 16 Singh EK, Nazarova LA, Lapera SA, Alexander LD, McAlpine SR. Tetrahedron Lett. 2010; 51: 4357
  • 17 Nahrwold M, Bogner T, Eissler S, Verma S, Sewald N. Org. Lett. 2010; 12: 1064
  • 18 Pirali T, Faccio V, Mossetti R, Grolla AA, Micco SD, Bifulco G, Genazzani AA, Tron GC. Mol. Diversity 2010; 14: 109
  • 19 Sun H, Liu L, Lu J, Qiu S, Yang C, Yi H, Wang S. Bioorg. Med. Chem. Lett. 2010; 20: 3043
  • 20 Ajay A, Sharma S, Gupt MP, Bajpai V, Hamidullah, Kumar B, Kaushik MP, Konwar R, Ampapathi RS, Tripathi RP. Org. Lett. 2012; 14: 4306
  • 21 Davis MR, Singh EK, Wahyudi H, Alexander LD, Kunicki JB, Nazarova LA, Fairweather KA, Giltrap AM, Jolliffe KA, McAlpine SR. Tetrahedron 2012; 68: 1029
  • 22 Neilsen PM, Pehere AD, Pishas KI, Callen DF, Abell AD. ACS Chem. Biol. 2013; 8: 353
  • 23 Tahoori F, Balalaie S, Sheikhnejad R, Sadjadi M, Boloori P. Amino Acids 2014; 46: 1033
  • 24 Goh WY. L, Chai CL. L, Chen A. Eur. J. Org. Chem. 2014; 7239
  • 25 Zhang Y, Seigal BA, Terrett NK, Talbott RL, Fargnoli J, Naglich JG, Chaudhry C, Posy SL, Vuppugalla R, Cornelius G, Lei M, Wang C, Zhang Y, Schmidt RJ, Wei DD, Miller MM, Allen MP, Li L, Carter PH, Vite GD, Borzilleri RM. ACS Med. Chem. Lett. 2015; 6: 770
  • 26 Seigal BA, Connors WH, Fraley A, Borzilleri RM, Carter PH, Emanuel SL, Fargnoli J, Kim K, Lei M, Naglich JG, Pokross ME, Posy SL, Shen H, Surti N, Talbott R, Zhang Y, Terrett NK. J. Med. Chem. 2015; 58: 2855
  • 27 Cao G, Yang K, Li Y, Huang L, Teng D. Molecules 2016; 21: 212
  • 28 Gabba A, Robakiewicz S, Taciak B, Ulewicz K, Broggoni G, Rastelli G, Krol M, Murphy P, Passarella D. Eur. J. Org. Chem. 2017; 60
  • 29 Raj PJ, Bahulayan D. Tetrahedron Lett. 2017; 58: 2122
  • 30 Hernandez-Vazquez E, Chvez-Riveros A, Romo-Perez A, Ramirez-Apan MT, Blanco AD. C, Morales-Barcenas R, Duenas-Gonzalez A, Miranda LD. ChemMedChem 2018; 13: 1193
  • 31 Cruz-Lopez O, Temps C, Longo B, Myers SH, Franco-Montalban F, Unciti-Broceta A. ACS Omega 2019; 4: 21620
  • 32 Rahman A, Sharma P, Kaur N, Shanavas AK, Neelakandan PP. ChemistrySelect 2020; 5: 5473
  • 33 Srinivas A, Rao EK. Acta Chim. Slov. 2021; 68: 404
  • 34 Hernandez-Vazquez E, Amador-Sanchez YA, Cruz-Mendoza MA, Ramírez-Apan MT, Miranda LD. Bioorg. Med. Chem. Lett. 2021; 40: 127899
  • 35 Isidro-Llobet A, Murillo T, Bello P, Cilibrizzi A, Hodgkinson JT, Galloway WR. J. D, Bender A, Welch M, Spring DR. Proc. Natl. Acad. Sci. USA 2011; 108: 6793
  • 36 Noor A, Huff GS, Kumar SV, Lewis JE. M, Paterson BM, Schieber C, Donnelly PS, Brooks HJ. L, Gordon KC, Moratti SC, Crowley JD. Organometallics 2014; 33: 7031
  • 37 Guo Y, Liu C, Song H, Wang F, Zou Y, Wu Q, Hu H. RSC Adv. 2017; 7: 2110
  • 38 Singh K, Sharma G, Shukla M, Kant R, Chopra S, Shukla SK, Tripathi RP. J. Org. Chem. 2018; 83: 14882
  • 39 Yang X, Kemmink J, Rijkers DT. S, Liskamp RM. J. Bioorg. Med. Chem. Lett. 2022; 73: 128887
  • 40 Selvarani S, Rajakumar P, Nagaraj S, Choudhury M, Velmurugan D. New J. Chem. 2018; 42: 12684
  • 41 Maurya SK, Rana R. Beilstein J. Org. Chem. 2017; 13: 1106
  • 42 Weerawarna PM, Kim Y, Kankanamalage AC. G, Damalanka VC, Lushington GH, Alliston KR, Mehzabeen N, Battaile KP, Lovell S, Chang K, Groutas WC. Eur. J. Med. Chem. 2016; 119: 300
  • 43 Kankanamalage AC. G, Weerawarna PM, Rathnayake AD, Kim Y, Mehzabeen N, Battaile KP, Lovell S, Chang K, Groutas WC. Proteins Struct. Funct. Bioinform. 2019; 87: 579
  • 44 Campo VL, Ivanova IM, Carvalho I, Lopes CD, Carneiro ZA, Saalbach G, Schenkman S, da Silva JS, Nepogodiev SA, Field RA. Tetrahedron 2015; 71: 7344
  • 45 Choi WJ, Shi Z, Worthy KM, Bindu L, Karki RG, Nicklaus MC, Fisher RJ, Burke TR. Jr. Bioorg. Med. Chem. Lett. 2006; 16: 5265
  • 46 Ingale S, Dawson PE. Org. Lett. 2011; 13: 2822
  • 47 Empting M, Avrutina O, Meusinger R, Fabritz S, Reinwarth M, Biesalski M, Voigt S, Buntkowsky G, Kolmar H. Angew. Chem. Int. Ed. 2011; 50: 5207
  • 48 Pehere AD, Pietsch M, Gütschow M, Neilsen PM, Pedersen DS, Nguyen S, Zvarec O, Sykes MJ, Callen DF, Abell AD. Chem. Eur. J. 2013; 19: 7975
  • 49 Jogula S, Soorneedi AR, Gaddam J, Chamakuri S, Deora GS, Indarapu RK, Ramgopal MK, Dravida S, Arya P. Eur. J. Med. Chem. 2017; 135: 110
  • 50 Tala SR, Singh A, Lensing CJ, Schnell SM, Freeman KT, Rocca JR, Haskell-Luevano C. ACS Chem. Neurosci. 2017; 9: 1001
  • 51 White AM, De Veer SJ, Wu G, Harvey PJ, Yap K, King GJ, Swedberg JE, Wang CK, Law RH. P, Durek T, Craik DJ. Angew. Chem. Int. Ed. 2020; 59: 11273
  • 52 Kulsi G, Sannigrahi A, Mishra S, Saha KD, Datta S, Chattopadhyay P, Chattopadhyay K. ACS Omega 2020; 5: 16395
  • 53 Cheekatla SR, Thurakkal L, Jose A, Barik D, Porel M. Molecules 2022; 27: 3409
  • 54 Thurakkal L, Mol R, Porel M. Chem. Commun. 2023; 59: 7399

Corresponding Author

Inul Ansary
Department of Chemistry, The University of Burdwan
Burdwan 713104
India   

Publication History

Received: 17 October 2023

Accepted after revision: 15 November 2023

Accepted Manuscript online:
16 November 2023

Article published online:
04 January 2024

© 2023. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References

  • 1 Liang Y, Fang R, Rao Q. Molecules 2022; 27: 2837
    • 2a Marsault E, Peterson ML. J. Med. Chem. 2011; 54: 1961
    • 2b Cheekatla SR, Barik D, Anand G, Mol KM. R, Porel M. Organics 2023; 4: 333
    • 2c Medved’ko AV, Gaisen SV, Kalinin MA, Vatsadze SZ. Organics 2023; 4: 417
    • 2d Begnini F, Poongavanam V, Over B, Castaldo M, Geschwindner S, Johansson P, Tyagi M, Tyrchan C, Wissler L, Sjö P, Schiesser S, Kihlberg J. J. Med. Chem. 2021; 64: 1054
  • 3 Jahan N, Ansary I. SynOpen 2023; 7: 209
  • 4 Horne WS, Olsen CA, Beierle JM, Montero A, Ghadiri MR. Angew. Chem. Int. Ed. 2009; 48: 4718
  • 5 Day JE. H, Sharp SY, Rowlands MG, Aherne W, Workman P, Moody CJ. Chem. Eur. J. 2010; 16: 2758
  • 6 Duan X, Zhang Y, Ding Y, Lin J, Kong X, Zhang Q, Dong C, Luo G, Chen Y. Eur. J. Org. Chem. 2012; 500
  • 7 Prabhakaran P, Subaraja M, Rajakumar P. ChemistrySelect 2018; 3: 4687
  • 8 Anandhan R, Kannan A, Rajakumar P. Synth. Commun. 2017; 47: 671
  • 9 Mandadapu SR, Weerawarna PM, Prior AM, Uy RA. Z, Aravapalli S, Alliston KR, Lushington GH, Kim Y, Hua DH, Chang K, Groutas WC. Bioorg. Med. Chem. Lett. 2013; 23: 3709
  • 10 Rana R, Dolma SK, Maurya SK, Reddy SG. E. Toxin Rev. 2020; 39 (02) 197
  • 11 Bock VD, Speijer D, Hiemstra H, van Maarseveen JH. Org. Biomol. Chem. 2007; 5: 971
  • 12 Philkhana SC, Mehrotra S, Murray TF, Reddy DS. Org. Biomol. Chem. 2016; 14: 8457
    • 13a Ansary I, Roy H, Das A, Mitra D, Bandyopadhyay AK. ChemistrySelect 2019; 4: 3486
    • 13b Silvestri IP, Andemarian F, Khairallah GN, Yap SW, Quach T, Tsegay S, Williams CM, O’Hair RA. R, Donnelly PS, Williams SJ. Org. Biomol. Chem. 2011; 9: 6082
    • 13c Johansson JR, Beke-Somfai T, Stålsmeden AS, Kann N. Chem. Rev. 2016; 116: 14726
    • 13d Roshandel S, Suri SC, Marcischak JC, Rasul G, Surya Prakash GK. Green Chem. 2018; 20: 3700
    • 13e Dar BA, Bhowmik A, Sharma A, Sharma PR, Lazar A, Singh AP, Sharma M, Singh B. Appl. Clay Sci. 2013; 80–81: 351
  • 14 Jahan N, Das A, Ansary I. ChemistrySelect 2022; 7: e202201831
  • 15 Chen J, Nikolovska-Coleska Z, Yang C, Gomez C, Gao W, Krajewski K, Jiang S, Roller P, Wang S. Bioorg. Med. Chem. Lett. 2007; 17: 3939
  • 16 Singh EK, Nazarova LA, Lapera SA, Alexander LD, McAlpine SR. Tetrahedron Lett. 2010; 51: 4357
  • 17 Nahrwold M, Bogner T, Eissler S, Verma S, Sewald N. Org. Lett. 2010; 12: 1064
  • 18 Pirali T, Faccio V, Mossetti R, Grolla AA, Micco SD, Bifulco G, Genazzani AA, Tron GC. Mol. Diversity 2010; 14: 109
  • 19 Sun H, Liu L, Lu J, Qiu S, Yang C, Yi H, Wang S. Bioorg. Med. Chem. Lett. 2010; 20: 3043
  • 20 Ajay A, Sharma S, Gupt MP, Bajpai V, Hamidullah, Kumar B, Kaushik MP, Konwar R, Ampapathi RS, Tripathi RP. Org. Lett. 2012; 14: 4306
  • 21 Davis MR, Singh EK, Wahyudi H, Alexander LD, Kunicki JB, Nazarova LA, Fairweather KA, Giltrap AM, Jolliffe KA, McAlpine SR. Tetrahedron 2012; 68: 1029
  • 22 Neilsen PM, Pehere AD, Pishas KI, Callen DF, Abell AD. ACS Chem. Biol. 2013; 8: 353
  • 23 Tahoori F, Balalaie S, Sheikhnejad R, Sadjadi M, Boloori P. Amino Acids 2014; 46: 1033
  • 24 Goh WY. L, Chai CL. L, Chen A. Eur. J. Org. Chem. 2014; 7239
  • 25 Zhang Y, Seigal BA, Terrett NK, Talbott RL, Fargnoli J, Naglich JG, Chaudhry C, Posy SL, Vuppugalla R, Cornelius G, Lei M, Wang C, Zhang Y, Schmidt RJ, Wei DD, Miller MM, Allen MP, Li L, Carter PH, Vite GD, Borzilleri RM. ACS Med. Chem. Lett. 2015; 6: 770
  • 26 Seigal BA, Connors WH, Fraley A, Borzilleri RM, Carter PH, Emanuel SL, Fargnoli J, Kim K, Lei M, Naglich JG, Pokross ME, Posy SL, Shen H, Surti N, Talbott R, Zhang Y, Terrett NK. J. Med. Chem. 2015; 58: 2855
  • 27 Cao G, Yang K, Li Y, Huang L, Teng D. Molecules 2016; 21: 212
  • 28 Gabba A, Robakiewicz S, Taciak B, Ulewicz K, Broggoni G, Rastelli G, Krol M, Murphy P, Passarella D. Eur. J. Org. Chem. 2017; 60
  • 29 Raj PJ, Bahulayan D. Tetrahedron Lett. 2017; 58: 2122
  • 30 Hernandez-Vazquez E, Chvez-Riveros A, Romo-Perez A, Ramirez-Apan MT, Blanco AD. C, Morales-Barcenas R, Duenas-Gonzalez A, Miranda LD. ChemMedChem 2018; 13: 1193
  • 31 Cruz-Lopez O, Temps C, Longo B, Myers SH, Franco-Montalban F, Unciti-Broceta A. ACS Omega 2019; 4: 21620
  • 32 Rahman A, Sharma P, Kaur N, Shanavas AK, Neelakandan PP. ChemistrySelect 2020; 5: 5473
  • 33 Srinivas A, Rao EK. Acta Chim. Slov. 2021; 68: 404
  • 34 Hernandez-Vazquez E, Amador-Sanchez YA, Cruz-Mendoza MA, Ramírez-Apan MT, Miranda LD. Bioorg. Med. Chem. Lett. 2021; 40: 127899
  • 35 Isidro-Llobet A, Murillo T, Bello P, Cilibrizzi A, Hodgkinson JT, Galloway WR. J. D, Bender A, Welch M, Spring DR. Proc. Natl. Acad. Sci. USA 2011; 108: 6793
  • 36 Noor A, Huff GS, Kumar SV, Lewis JE. M, Paterson BM, Schieber C, Donnelly PS, Brooks HJ. L, Gordon KC, Moratti SC, Crowley JD. Organometallics 2014; 33: 7031
  • 37 Guo Y, Liu C, Song H, Wang F, Zou Y, Wu Q, Hu H. RSC Adv. 2017; 7: 2110
  • 38 Singh K, Sharma G, Shukla M, Kant R, Chopra S, Shukla SK, Tripathi RP. J. Org. Chem. 2018; 83: 14882
  • 39 Yang X, Kemmink J, Rijkers DT. S, Liskamp RM. J. Bioorg. Med. Chem. Lett. 2022; 73: 128887
  • 40 Selvarani S, Rajakumar P, Nagaraj S, Choudhury M, Velmurugan D. New J. Chem. 2018; 42: 12684
  • 41 Maurya SK, Rana R. Beilstein J. Org. Chem. 2017; 13: 1106
  • 42 Weerawarna PM, Kim Y, Kankanamalage AC. G, Damalanka VC, Lushington GH, Alliston KR, Mehzabeen N, Battaile KP, Lovell S, Chang K, Groutas WC. Eur. J. Med. Chem. 2016; 119: 300
  • 43 Kankanamalage AC. G, Weerawarna PM, Rathnayake AD, Kim Y, Mehzabeen N, Battaile KP, Lovell S, Chang K, Groutas WC. Proteins Struct. Funct. Bioinform. 2019; 87: 579
  • 44 Campo VL, Ivanova IM, Carvalho I, Lopes CD, Carneiro ZA, Saalbach G, Schenkman S, da Silva JS, Nepogodiev SA, Field RA. Tetrahedron 2015; 71: 7344
  • 45 Choi WJ, Shi Z, Worthy KM, Bindu L, Karki RG, Nicklaus MC, Fisher RJ, Burke TR. Jr. Bioorg. Med. Chem. Lett. 2006; 16: 5265
  • 46 Ingale S, Dawson PE. Org. Lett. 2011; 13: 2822
  • 47 Empting M, Avrutina O, Meusinger R, Fabritz S, Reinwarth M, Biesalski M, Voigt S, Buntkowsky G, Kolmar H. Angew. Chem. Int. Ed. 2011; 50: 5207
  • 48 Pehere AD, Pietsch M, Gütschow M, Neilsen PM, Pedersen DS, Nguyen S, Zvarec O, Sykes MJ, Callen DF, Abell AD. Chem. Eur. J. 2013; 19: 7975
  • 49 Jogula S, Soorneedi AR, Gaddam J, Chamakuri S, Deora GS, Indarapu RK, Ramgopal MK, Dravida S, Arya P. Eur. J. Med. Chem. 2017; 135: 110
  • 50 Tala SR, Singh A, Lensing CJ, Schnell SM, Freeman KT, Rocca JR, Haskell-Luevano C. ACS Chem. Neurosci. 2017; 9: 1001
  • 51 White AM, De Veer SJ, Wu G, Harvey PJ, Yap K, King GJ, Swedberg JE, Wang CK, Law RH. P, Durek T, Craik DJ. Angew. Chem. Int. Ed. 2020; 59: 11273
  • 52 Kulsi G, Sannigrahi A, Mishra S, Saha KD, Datta S, Chattopadhyay P, Chattopadhyay K. ACS Omega 2020; 5: 16395
  • 53 Cheekatla SR, Thurakkal L, Jose A, Barik D, Porel M. Molecules 2022; 27: 3409
  • 54 Thurakkal L, Mol R, Porel M. Chem. Commun. 2023; 59: 7399

Zoom Image
Zoom Image
Zoom Image
Zoom Image
Scheme 1 Synthesis of STAT3 inhibitor 7
Zoom Image
Scheme 2 Synthesis of apicidin analogues 16a,b and 17
Zoom Image
Scheme 3 Synthesis of Apicidin analogues 25ac
Zoom Image
Scheme 4 Synthesis of anticancer agents 33
Zoom Image
Scheme 5 Synthesis of cryptophycin-52 analogue 44
Zoom Image
Scheme 6 Synthesis of fragment 42 for the development of analogue 44
Zoom Image
Scheme 7 Synthesis of macrocyclic peptide mimetics 56a,b
Zoom Image
Scheme 8 Synthesis of macrocyclic peptide mimetics 61a,b
Zoom Image
Scheme 9 Synthesis of cyclopeptidic Smac mimetics 70a,b
Zoom Image
Scheme 10 Synthesis of radicicol analogues 82ae
Zoom Image
Scheme 11 Synthesis of epothilone analogue 92 and its dimer 94
Zoom Image
Scheme 12 Synthesis of macrocyclic glycoconjugates 113c, 114c and 115c
Zoom Image
Scheme 13 Synthesis of sansalvamide-A analogue 126
Zoom Image
Scheme 14 Synthesis of macrocyclic inhibitors of CT-L protease 138, 139
Zoom Image
Scheme 15 Synthesis of macrocyclic heptapeptide 145
Zoom Image
Scheme 16 Synthesis of triazole analogue 157 of natural product LL-Z1640-2
Zoom Image
Scheme 17 Synthesis of apoptosis protein inhibitor 169
Zoom Image
Scheme 18 Synthesis of a few macrocyclic anticancer agents
Zoom Image
Scheme 19 Synthesis of antitumor agents 186193
Zoom Image
Scheme 20 Synthesis of migrastatin analogues 201 and 204
Zoom Image
Scheme 21 Synthesis of coumarin-tagged macrocycles 211
Zoom Image
Scheme 22 Synthesis of triazole fused macrocycles 219
Zoom Image
Scheme 23 Synthesis of triazole-fused macrocycle 223
Zoom Image
Scheme 24 Synthesis of triazole-fused macrocycle 231
Zoom Image
Scheme 25 Synthesis of thymidine analogue 235
Zoom Image
Scheme 26 Synthesis of anticancer agents 241243
Zoom Image
Scheme 27 Synthesis of anticancer agents 250252
Zoom Image
Scheme 28 Synthesis of anticancer agents 258
Zoom Image
Figure 1 Macrocycle 259 for potency comparison of 258
Zoom Image
Scheme 29 Synthesis of macrocyclic peptidometric framework 264
Zoom Image
Scheme 30 Synthesis of antibacterial agents of Re-complexes 271a,b
Zoom Image
Scheme 31 Synthesis of triazole fragments 276, 279 required for 285, 286
Zoom Image
Scheme 32 Synthesis of antibacterial peptide macrocycles 285, 286
Zoom Image
Scheme 33 Synthesis of antibacterial agents 291aj
Zoom Image
Scheme 34 Synthesis of antibacterial agent 294a
Zoom Image
Scheme 35 Synthesis of antibacterial agents 294a,b
Zoom Image
Scheme 36 Synthesis of tricyclic hexapeptide 306
Zoom Image
Scheme 37 Synthesis of oligomeric triazolophanes 312321
Zoom Image
Figure 2 Oligomeric triazolophanes 312319
Zoom Image
Scheme 38 Synthesis of antilarval sugar-embedded macrocycles 326, 329 and 333
Zoom Image
Figure 3 Oligomeric triazolophanes 320, 321
Zoom Image
Scheme 39 Synthesis of macrocycles 346351 with anti-inflammatory activity
Zoom Image
Scheme 40 Synthesis of macrocycles 352357 with anti-inflammatory activity
Zoom Image
Scheme 41 Synthesis of antiviral agent 364
Zoom Image
Scheme 42 Synthesis of antiviral agents 381, 383
Zoom Image
Scheme 43 Synthesis of some antiviral agents
Zoom Image
Scheme 44 Synthesis of antiviral agent 390
Zoom Image
Scheme 45 Synthesis of macrocycles 400403 with anti-trypanosomal activity
Zoom Image
Figure 4 Antiviral agents 391393
Zoom Image
Scheme 46 Synthesis of SH2 domain-binding inhibitors 411414a,b
Zoom Image
Scheme 47 Synthesis of tyrosinase inhibitor
Zoom Image
Scheme 48 Synthesis of tyrosinase inhibitor
Zoom Image
Figure 5 A peptide variant of SFTI-1
Zoom Image
Scheme 49 Synthesis of peptide macrocycle 437
Zoom Image
Scheme 50 Synthesis of trypsin inhibitors 440, 441 and 444
Zoom Image
Scheme 51 Synthesis of macrocyclic protease inhibitors 450 and 456
Zoom Image
Scheme 52 Synthesis of a series of macrocyclic protease inhibitors
Zoom Image
Scheme 53 Synthesis of Palmyrolide-A analogue 472
Zoom Image
Figure 6 (–)-Palmyrolide A
Zoom Image
Scheme 54 Synthesis of Geldanamycin inspired macrocycles 479, 483
Zoom Image
Scheme 55 Synthesis of macrocyclic peptides 485, 488
Zoom Image
Scheme 56 Synthesis of macrocyclic peptides 491, 493
Zoom Image
Figure 7 A peptide template
Zoom Image
Scheme 57 Synthesis of macrocyclic peptides 500bf, 501bf, 502b and 503b
Zoom Image
Scheme 58 Synthesis of triazole-fused macrocycle 511
Zoom Image
Scheme 59 Synthesis of aza-oxa macrocycles
Zoom Image
Scheme 60 Synthesis of macrocyclic fluorescence sensor