Synthesis and in vitro antiplasmodial activityof quinoline-ferrocene esters

David D N-Da; Jaco C Breytenbach; Peter J Smith; Carmen Lategan

doi:10.1055/s-0031-1296211

Arzneimittelforschung, Table of Contents

Arzneimittelforschung 2011; 61(6): 358-365
DOI: 10.1055/s-0031-1296211

Antibiotics · Antimycotics · Antiparasitics · Antiviral Drugs · Chemotherapeutics · Cytostatic

Editio Cantor Verlag Aulendorf (Germany)

Synthesis and in vitro antiplasmodial activityof quinoline-ferrocene esters

David D N-Da

¹Department of Pharmaceutical Chemistry, North-West University, Potchefstroom, South Africa

,

Jaco C Breytenbach

¹Department of Pharmaceutical Chemistry, North-West University, Potchefstroom, South Africa

,

Peter J Smith

²Department of Pharmacology, University of Cape Town, Groote Schuur Hospital, South Africa

,

Carmen Lategan

²Department of Pharmacology, University of Cape Town, Groote Schuur Hospital, South Africa

› Author Affiliations

Abstract

New 4-aminoquinoline-derived esterscontaining the redox-active ferrocenegroup brought in by either ferrocenyfor-mic or 4-ferrocenylbutanoic acids weresynthesized and tested in vitro for theirantiplasmodial activity. The results re-vealed that only esters derived from fer-rocenylformic acid were active againstboth chloroquine (CQ)-resistant Dd2 andCQ-sensitive D10 strains of Plasmodium falciparum. However, none of theseshowed higher actvity than CQ against the sensitive strain. Ester 16, which pos-sesses a butyl branch in the structure,was the most active of all. With an IC₅₀ of0.13 mM on the resistant strain, this esterpossessed 2.5-fold higher activity than CQ(IC₅₀ = 0.34 mM). All tested esters showedgood selectivity towards P. falciparum with indexes higher than 60.

Key words

Antiplasmodial activity - Chloroquine - Cytotoxicity - Ferrocene - Plasmodium falciparum

Full Text

References

References
1 Marsh K. Malaria disaster in Africa. Lancet 1998; 352: 924-5
2 White NJ. Antimalarial drug resistance. J Clin Invest. 2004; 113: 1084-92
3 von Seidlein L, Greenwood BM. Mass administrations of antimalarial drugs. Trends Parasitol. 2003; 19: 452-60
4 Wasi N, Singh HB, Gajanana M, Raichowdhary N. Synthesis of metal complexes of antimalarial drugs and in vitro evaluation of their activity against plasmodium falciparum. Inorg Chim Acta. 1987; 135: 133-7
5 Navarro M, Perez H, Sanchez-Delgado RA. Toward a novel metal-based chemotherapy against tropical diseases. 2.Synthesis and antimalarial activity in vitro and in vivo ofnew ruthenium- and rhodium-chloroquine complexes. J Med Chem. 1996; 39: 1095-9
6 Navarro M, Perez H, Sanchez-Delgado RA. Toward a novelmetal-based chemotherapy against tropical diseases. 3.Synthesis and antimalarial activity in vitro and in vivo ofnew gold-chloroquine complex [Au (PPh₃) (CQ)] Pf6. J Med Chem. 1997; 40: 1937-9
7 Farrell NP, Williamson J, McLaren DJM. Trypanocidal andantitumor activity of platinum-metal and platinum-metaldrug dual-function complexes. Biochem Pharmacol. 1984; 33: 961-71
8 Sanchez-Delgado RA, Lazardi K, Rincon L, Urbina JA, Hubert AJ, Noels AN. Toward a novel metal-based chemotherapy against tropical diseases. 1. Enhancement of the effi-cacy of clotrimazole against Trypanosoma cruzi bycomplexation to ruthenium in RuCl₂ (clotrimazol)₂ . J Med Chem. 1993; 36: 2041-3
9 Köpf-Maier H, Köpf-Maier P. Titanocene dichloride-thefirst metallocene with cancerostatic activity. Angew Chem Int Ed. 1979; 18: 477-8
10 Jaouen G Bioorganometallics: Biomolecules, labelling, medicine. Jaouen G. editor. Weinheim: Wiley-VCH; 2006
11 Köpf-Maier P, Köpf-Maier H, Neuse EW. Ferroceniumcomplexes: a new type of water-soluble antitumor agent. J Cancer Res Clin Oncol. 1984; 108: 336-40
12 van Staveren DR, Metzler-Nolte N. Bioorganometallicchemistry of ferrocene. Chem Rev. 2004; 104: 5931-85
13 Fouda MFR, Abd-Elzaher MM, Abdelsamaia RA, Labib AA. On the medicinal chemistry of ferrocene. Appl Organomet Chem. 2007; 21: 613-25
14 Tabbi G, Cassino C, Cavigiolio G, Colangelo D, Ghiglia A, Viano I et al. Water stability and cytotoxic activity relation-ship of a series of ferrocenium derivatives. ESR insights onthe radical production during the degradation process. J Med Chem. 2002; 45: 5786-96
15 Osella D, Mahboobi H, Colangelo D, Cavigiolio G, Vessières A, Jaouen G. FACS analysis of oxidative stress induced ontumor cells by SERMs. Inorg Chim Acta. 2005; 358: 1993-8
16 Tamura H, Miwa M. DNA cleaving activity and cytotoxicactivity of ferrocenium cations. Chem Lett. 1997; 26: 1177-8
17 Kovjazin R, Eldar T, Patya M, Vanichkin A, Lander HM, Novogrodsky A. Ferrocene-induced lymphocyte activationand antitumor activity is mediated by redox-sensitive sig-naling. The FASEB J. 2003; 17: 467-9
18 Top S, Vessières A, Cabestaing C, Laios I, Leclercq G, Provot C et al. Studies on organometallic selective receptormodulators (SERMs). Dual activity in the hydroxy-ferrocifen series. J Organomet Chem. 2001; 637 (639) 500-6
19 Biot C, Glorian G, Maciejewski LA, Brocard JS, Domarle O, Blampain G et al. Synthesis and antimalarial activity in vi-tro and in vivo of a new ferrocene-chloroquine analogue. J Med Chem. 1997; 40: 3715-8
20 Biot C, Daher W, Ndiaye CM, Melnyk P, Pradines B, Chavain N et al. Probing the role of the covalent linkage of fer-rocene into a chloroquine template. J Med Chem. 2006; 49: 4707-17
21 Biot C, Delhaes L, N’Diaye CM, Maciejewski LA, Camus D, Dive D et al. Synthesis and antimalarial activity in vitro ofpotential metabolites of ferrochloroquine and related com-pounds. Biorg Med Chem. 1999; 7: 2843-7
22 Chavain N, Vezin H, Dive D, Touati N, Paul J-P, Buisine E et al. Investigation of the redox behavior of ferroquine, anew antimalarial. Mol Pharm. 2008; 5: 710-716
23 Biot C, Daher W, Chavain N, Fandeur T, Khalife J, Dive D et al. Design and synthesis of hydroxyferroquine deriva-tives with antimalarial and antiviral activities. J Med Chem. 2006; 49: 2845-9
24 Biot C, Delhaes L, Maciejewski LA, Mortuaire M, Camus D, Dive D et al. Synthetic ferrocenic mefloquine and quinineanalogues as potential antimalarial agents. Eur J Med Chem. 2000; 5: 707-14
25 Delhaes L, Biot C, Berry L, Maciejewski LA, Camus D, Brocard JS et al. Novel ferrocenic artemisinin derivatives:synthesis, in vitro antimalarial activity and affinity of bind-ing with ferroprotoporphyrin. Biorg Med Chem. 2000; 8: 2739-45
26 Burgess SJ, Selzer A, Kelly JX, Smilkstein MJ, Riscoe MK, Peyton DH. A chloroquine-like molecule designed to re-verse resistance in Plasmodium falciparum. J Med Chem. 2006; 49: 5623-5
27 N’Da DD, Breytenbach JC, Smith P, Lategan C. Synthesis,cytotoxicity and antimalarial activity of ferrocenyl amidesof 4-aminoquinolines. Arzneimittelforschung 2010; 60 (10) 627-35
28 Trager W, Jensen JB. Human malaria parasites in continu-ous culture. Science 1976; 193: 673-6
29 Makler MT, Ries JM, Banroft WJE, Piper RC, Gibbins BL, Hinrichs DJ. Parasite lactate dehydrogenase as an assayfor plasmodium falciparum drug sensitivity. Am J Trop Med Hyg. 1993; 48: 739-42
30 Mosmann T. Rapid colorimetric assay for cellular growthand survival: Application to proliferation and cytotoxicityassays. J Immunol Methods. 1983; 65: 55-63
31 Rubinstein LV, Schoemaker RH, Paul KD, Simon RM, Tosini S, Skehan P et al. Comparison of in vitro anticancer-drug-screening data generated with a tetrazolium assayversus a protein assay against a diverse panel of human tu-mor cell lines. J Natl Cancer Inst. 1990; 82: 1113-7
32 Cooke MW, Cameron TS, Robertson KN, Swarts JC Aquino MAS. Structure and electrochemistry of various diruthe-nium (II, III) tetrametallocenecarboxylates. Organometallics. 2002; 21: 5962-71
33 Zhang E, Hou H, Meang X, Liu Y, Liu Y, Fan Y. Ferrocenylfunctional coordination polymers based on mono-, bi-,and heterotrinuclear organometallic building blocks:syntheses, structures, and properties. Crystal Growth Design. 2009; 9: 903-13
34 Wilson R, Schiffrin DJ. Chemiluminescence of luminol cat-alyzed by electrochemically oxidized ferrocenes. Anal Chem. 1996; 68: 1254-7
35 Ekoue-Kovi K, Yearick K, Iwaniuk DP, Natarajan JK, Alumasa J, de Dios AC et al. Synthesis and antimalarial activ-ity of new 4-amino-7-chloroquinolyl amides, sulfon-amides, ureas and thioureas. Biorg Med Chem. 2009; 17: 270-83
36 Bigucci F, Kamsu-Kom T, Cholet C, Besnard M, Bonnet-Delpon D, Ponchel G. Transport of fluoroalkyl dihydroarte-misinin derivatives across rat intestinal tissue. J Pharm Pharmacol. 2008; 60: 163-9