Subscribe to RSS
Download PDF
DOI: 10.1055/a-2698-0616
Exploration of Oxetanes and Azetidines in Structure-Based Drug Design
Authors
This study received financial support from the Ministry of Human Resource Development. Govt. of India [grant number SB/2021/0792/CYMHRD/008189].
Abstract
Oxetane and azetidine motifs are widely used in medicinal chemistry to enhance various attributes such as hydrophilicity, metabolic stability, hydrophobicity, and conformational preference. These stable structures are present in numerous bioactive compounds, including FDA-validated therapeutic agents. This study aims to demonstrate the use of oxetane and azetidine ring systems as bioisosteric replacements for isopropyl groups in the development of novel lead candidates. The objective is to improve physicochemical and structural characteristics to facilitate effective molecular optimization, improve pharmacological activity, and simplify synthetic pathways. This can ultimately increase the chances of discovering medication that is more efficient and safer to use. We report the virtual screening of selected 14 approved drugs with a replacement of isopropyl to oxetane and azetidine group transformation, enabling optimization for receptor binding potential and absorption, distribution, metabolism, and excretion (ADME) properties. The results indicate that oxetane alectinib (−6.906 kcal/mol), azetidine procarbazine (−8.083 kcal/mol), azetidine erdafitinib (−7.677 kcal/mol), oxetane anastrozole (−7.454 kcal/mol), azetidine nateglinide (−6.686 kcal/mol), oxetane repaglinide (−7.831 kcal/mol), oxetane nilutamide (−9.649 kcal/mol), and oxetane proguanil (−8.555 kcal/mol) have excellent molecular affinity when compared to their parent molecule. This perspective aims to inspire medicinal chemists to explore the use of oxetane and azetidine moieties in the development of effective drug candidates.
Publication History
Received: 25 July 2025
Accepted after revision: 08 September 2025
Accepted Manuscript online:
08 September 2025
Article published online:
08 October 2025
© 2025. Thieme. All rights reserved.
Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
-
References
- 1 Amir M, Qureshi MA, Javed S. J Biomol Struct Dyn 2021; 39: 3934-3947
- 2 Anwer R, Ahmad N, Al Qumaizi KI, Al Khamees OA, Al Shaqha WM, Fatma T. J Mol Recognit 2017; 30 (1/6) e2599
- 3 Bachrach SM. J Org Chem 2008; 73: 2466-2468
- 4 Bauer MR, Di Fruscia P, Lucas SCC. et al. RSC Med Chem 2021; 12: 448-471
- 5 Brandi A, Cicchi S, Cordero FM. Chem Rev 2008; 108: 3988-4035
- 6 Bull JA, Croft RA, Davis OA, Doran R, Morgan KF. Chem Rev 2016; 116: 12150-12233
- 7 Litskan O, Semenchenko S, Lynnyk D. et al. Org Chem Front 2025; 12: 3775-3785
- 8 Candel FJ, Peñuelas M. Drug Des Dev Ther 2017; 11: 881-891
- 9 Albitz K, Tóth S, Csókás D. Angew Chem Int Ed 2025; 64: e202416441
- 10 Das T, Mukhopadhyay C. J Biomol Struct Dyn 2023; 41: 3368-3381
- 11 Delaney JS. J Chem Inf Comput Sci 2004; 44: 1000-1005
- 12 Delaney JS. J Chem Inf Comput Sci 2004; 44: 1000-1005
- 13 Dey S, Basak S, De A. et al. J Chromatogr Sci 2020; 58: 309-322
- 14 Ding D, Wang M, Wu J-X, Kang Y, Chen L. Cell Rep 2019; 27: 1848-1857
- 15 Dubois MAJ, Croft RA, Ding Y. et al. RSC Med Chem 2021; 12: 2045-2052
- 16 Dubois MAJ, Smith MA, White AJP. et al. Org Lett 2020; 22: 5279-5283
- 17 Evans GB, Furneaux RH, Greatrex B, Murkin AS, Schramm VL, Tyler PC. J Med Chem 2008; 51: 948-956
- 18 Madhav H, Reddy GS. RSC Med Chem 2024; 15: 1022-1037
- 19 Ikee Y, Hashimoto K, Kamino M. et al. Chem Pharm Bull 2008; 56: 346-356
- 20 Mughal H, Szostak M. Org Biomol Chem 2021; 19: 3274-3286
- 21 Johnson TW, Gallego RA, Edwards MP. J Med Chem 2018; 61: 6401-6420
- 22 Khan MF, Nahar N, Rashid RB, Chowdhury A, Rashid MA. BMC Complement Altern Med 2018; 18: 48
- 23 Kumari S, Maurya J, Ramamoorthy A, Sundarrajan S, Lulu S, Arumugam M. Int J Pharm Pharm Sci 2014; 6: 66-69
- 24 Lonikar N, Choudhari P, Bhusnuare O. J Biomol Struct Dyn 2021; 39: 3515-3522
- 25 Venkitasamy KJ. J Biomol Struct Dyn 2023; 41: 14638-14650
- 26 Maetani M, Kato N, Jabor VAP. et al. ACS Med Chem Lett 2017; 8: 438-442
- 27 Manish M, Mishra S, Anand A, Subbarao N. Comput Biol Med 2022; 150: 106125
- 28 Moriguchi I, Hirono S, Liu Q, Nakagome I, Matsushita Y. Chem Pharm Bull 1992; 40: 127-130
- 29 Mugumbate G, Abrahams KA, Cox JAG. et al. PLoS One 2015; 10: 1-10
- 30 Ono F, Chiba S, Isaka Y. et al. Sci Rep 2020; 10: 1-10
- 31 Jeffries B, Wang Z, Troup RI. et al. Beilstein J Org Chem 2020; 16: 2141-2150
- 32 Leelavathi PT, Shankar M, Pasha TY, Ramesh B, Sekar M. Pharm Res 2023; 7: 000282
- 33 Parsy C, Alexandre FR, Brandt G. et al. Bioorg Med Chem Lett 2014; 24: 4444-4449
- 34 Pastewska M, Bednarczyk-Cwynar B, Kovačević S. et al. J Chromatogr A 2021; 1656: 462552
- 35 Pletsa V, Valavanis C, van Delft JH, Steenwinkel MJ, Kyrtopoulos SA. Carcinogenesis 1997; 18: 2191-2196
- 36 Raffa RB, Pergolizzi JV. Pharmacol Pharm 2019; 10: 465-473
- 37 Girdhar N, Yadav V, Kumari N, Subbarao N, Krishnamachari A. Biomol Struct Dyn. 2024
- 38 Rogers-Evans M, Knust H, Plancher JM. et al. Chimia 2014; 68: 492-499
- 39 Ryckmans T, Edwards MP, Horne VA. et al. Bioorg Med Chem Lett 2009; 19: 4406-4409
- 40 Sachdeva H, Khaturia S, Saquib M. et al. Appl Biochem Biotechnol 2022; 194: 6438-6467
- 41 Shaker B, Yu MS, Lee J, Lee Y, Jung C, Na D. J Microbiol 2020; 58: 235-244
- 42 Raturi A, Yadav V, Hoda N, Subbarao N, Chaudhry SA. J Biomol Struct Dyn 2023; 42: 585-611
- 43 Dubois MAJ, Smith MA, White AJP. et al. Org Lett 2020; 22: 5279-5283
- 44 Shweta M, Rashmi D. J Drug Delivery Ther 2019; 9: 266-369
- 45 Skinner-Adams TS, Fisher GM, Riches AG. et al. Commun Biol 2019; 2: 1-7
- 46 Stepan AF, Karki K, McDonald WS. et al. J Med Chem 2011; 54: 7772-7783
- 47 Su M, Yang Q, Du Y. et al. J Chem Inf Model 2019; 59: 895-913
- 48 Verma J, Subbarao N. J Biomol Struct Dyn 2022; 30: 127457
- 49 Surleraux DLNG, Tahri A, Verschueren WG. et al. J Med Chem 2005; 48: 1813-1822
- 50 Suvannang N, Nantasenamat C, Isarankura-Na-Ayudhya C, Prachayasittikul V. Molecules 2011; 16: 3597-3617
- 51 Butler MS. J Nat Prod 2004; 67: 2141-2153
- 52 Tian X, He Y, Zhou J. Front Pharmacol 2015; 6: 57
- 53 Wuitschik G, Carreira EM, Wagner B. et al. J Med Chem 2010; 53: 3227-3246
- 54 Zheng X, Gao L, Wang L. et al. J Med Chem 2019; 62: 6315-6329
- 55 Zheng X, Liang C, Wang L. et al. J Med Chem 2018; 61: 10228-10241
- 56 Daina A, Michielin O, Zoete V. Sci Rep 2017; 7: 42717
- 57 Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W. J Comput Aided Mol Des 2013; 27: 221-234
- 58 Agrawal A, Chanana P. J Biomol Struct Dyn 2023; 20: 1201-1214
- 59 Chen P, Lee NV, Hu W. et al. Mol Cancer Ther 2016; 15: 2273-2281
- 60 Sakamoto H, Tsukaguchi T, Hiroshima S. et al. Cancer Cell 2011; 19: 679-690
- 61 Boerma LJ, Xia G, Qui C. et al. J Biol Chem 2014; 289: 814-826
- 62 Raies AB, Bajic VB. WIREs Comput Mol Sci 2016; 6: 147-172
- 63 Banerjee P, Eckert AO, Schrey AK, Preissner R. Nucleic Acids Res 2018; 46: W257-W263
- 64 Martin TM, Harten P, Venkatapathy R, Das S, Young DM. Toxicol Mech Methods 2008; 18: 251-266
- 65 Banks JL, Beard HS, Cao Y. et al. J Comput Chem 2005; 26: 1752-1780
- 66 Abraham MJ, Murtola T, Schulz R. et al. SoftwareX 2015; 1–2: 19-25
- 67 Hornak V, Abel R, Okur A, Strockbine B, Roitberg A, Simmerling C. Proteins: Struct, Funct, Bioinf 2006; 65: 712-725
- 68 Sousa da Silva AW, Vranken WFACPYPE. Notes 2012; 5: 367
- 69 Mark P, Nilsson L. J Phys Chem A 2001; 105: 9954-9960
- 70 Mahoney MW, Jorgensen WL. J Chem Phys 2000; 112: 8910-8922
- 71 Kashif M, Subbarao N. J Biomol Struct Dyn 2023; 41: 13914-13922
- 72 Kollman PA, Massova I, Reyes C. et al. Acc Chem Res 2000; 33: 889-897
- 73 Kumari R, Kumar R, Lynn A. J Chem Inf Model 2014; 54: 1951-1962
- 74 Richmond TJ. J Mol Biol 1984; 178: 63-89
- 75 Kirchmair J, Williamson MJ, Tyzack JD. et al. J Chem Inf Model 2012; 52: 617-648
- 76 Wang Y, Xing J, Xu Y. et al. Quart Rev Biophys 2015; 48: 488-515
- 77 Duchowicz PR, Talevi A, Bellera C, Bruno-Blanch LE, Castro EA. Bioorg Med Chem 2007; 15: 3711-3719
- 78 Leeson P, Springthorpe B. Nat Rev Drug Discovery 2007; 6: 881-890
- 79 Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Adv Drug Delivery Rev 1997; 23: 3-25
- 80 Coates JT, Lindsley CW, McKinney D, Rhodes GR. US Patent Application US 2010/0160340 A1 2010
- 81 Chen S, Liu Z, Xu B, Gao Y. WO 2017/114512 A1 2017 https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017114512
- 82 Yadav V, Kashif M, Kamali Z, Gourinath S, Subbarao N. Molr Inf 2025; 44: 1-13