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ISSN (Online): 2212-4071

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Research Article

4-Aminoquinoline-ferrocene Hybrids as Potential Antimalarials

Author(s): Xhamla Nqoro and Blessing A. Aderibigbe*

Volume 15, Issue 2, 2020

Page: [157 - 172] Pages: 16

DOI: 10.2174/1574891X15666200804160322

Price: $65

Abstract

Background: Malaria is a deadly disease. It is mostly treated using 4- aminoquinoline derivatives such as chloroquine etc. because it is well-tolerated, displays low toxicity, and after administration, it is rapidly absorbed. The combination of 4-aminoquinoline with other classes of antimalarial drugs has been reported to be an effective approach for the treatment of malaria. Furthermore, some patents reported hybrids 4-aminoquinolines containing ferrocene moiety with potent antimalarial activity.

Objective: The objective of the current study is to prepare 4-aminoquinoline-ferrocene hybrids via esterification and amidation reactions. The compounds were characterized via FTIR, LC-MS and NMR spectroscopy. In vitro screening against chloroquine-sensitive P. falciparum parasite (NF54) at concentrations (1 μM and 5 μM) and an inhibitory concentration (full dose-response) was studied.

Methods: The compounds were prepared via known reactions and monitored by Thin Layer Chromatography. The compounds were purified by column chromatography and characterized using FTIR, NMR and MS. In vitro antiplasmodial evaluation was performed against asexual parasite and chloroquine was used as a reference drug.

Results: The percentage inhibition effects of the hybrid compounds were in a range of 97.9-102% at 5 μM and 36-96% at 1 μM. Furthermore, the IC50 values of the compounds were in the range of 0.7-1.6 μM when compared to the parent drug, 4-ferrocenylketobutanoic acid.

Conclusion: The hybrid compounds displayed significant antimalarial activity when compared to the parent drug. However, they were not as effective as chloroquine on the drug-sensitive parasite. The findings revealed that 4-aminoquinolines and ferrocene are potential scaffolds for developing potent antimalarials.

Keywords: Ferrocene, Plasmodium falciparum, 4-aminoquinoline, esterification reaction, hybrid compound, malaria.

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[1]
Ashley EA, Pyae Phyo A, Woodrow CJ. Malaria. Lancet 2018; 391(10130): 1608-21.
[http://dx.doi.org/10.1016/S0140-6736(18)30324-6] [PMID: 29631781]
[2]
World Malaria Report 2020. Available at:. https://www.who.int/news-room/fact-sheets/detail/malaria (Accessed on: March 29, 2020).
[3]
Kumar S, Bhardwaj TR, Prasad DN, Singh RK. Drug targets for resistant malaria: historic to future perspectives. Biomed Pharmacother 2018; 104: 8-27.
[http://dx.doi.org/10.1016/j.biopha.2018.05.009] [PMID: 29758416]
[4]
Chopra R, Chibale K, Singh K. Pyrimidine-chloroquinoline hybrids: synthesis and antiplasmodial activity. Eur J Med Chem 2018; 148: 39-53.
[http://dx.doi.org/10.1016/j.ejmech.2018.02.021] [PMID: 29454189]
[5]
Lynch D, Sophister J. 4-aminoquinolines as Antimalarial Drugs. Trinity Student Scientific Review; 2: 196-211. Available at:. https://pdfs.semanticscholar.org/7497/4e1412022fc96801d3dbaf41183761b0a2f8.pdf(Accessed on: March 30,2020.
[6]
Vandekerckhove S, D’hooghe M. Quinoline-based antimalarial hybrid compounds. Bioorg Med Chem 2015; 23(16): 5098-119.
[http://dx.doi.org/10.1016/j.bmc.2014.12.018] [PMID: 25593097]
[7]
Sinha M, Dola VR, Agarwal P, Srivastava K, Haq W, Puri SK, et al. Antiplasmodial activity of new 4-aminoquinoline derivatives against chloroquine resistant strain. Bioorg Med Chem 2014; 22(14): 3573-86.
[http://dx.doi.org/10.1016/j.bmc.2014.05.024] [PMID: 24906512]
[8]
Luzzatto L. G6PD deficiency: a polymorphism balanced by heterozygote advantage against malaria. Lancet Haematol 2015; 2(10): e400-1.
[http://dx.doi.org/10.1016/S2352-3026(15)00191-X] [PMID: 26686037]
[9]
Nqoro X, Tobeka N, Aderibigbe BA. Quinoline-based hybrid compounds with antimalarial activity. Molecules 2017; 22(12): 2268.
[http://dx.doi.org/10.3390/molecules22122268]
[10]
Kondratskyi A, Kondratska K, Abeele FV, Gordienko D, Dubois C, Toillon RA, et al. Ferroquine, the next generation antimalarial drug, has antitumor activity. Sci Rep 2017; 7(1): 15896.
[http://dx.doi.org/10.1038/s41598-017-16154-2] [PMID: 29162859]
[11]
Barends M, Jaidee A, Khaohirun N, Singhasivanon P, Nosten F. In vitro activity of ferroquine (SSR 97193) against Plasmodium falciparum isolates from the Thai-Burmese border. Malar J 2007; 6: 81.
[http://dx.doi.org/10.1186/1475-2875-6-81] [PMID: 17597537]
[12]
Biot C, Taramelli D, Forfar-Bares I, Maciejewski LA, Boyce M, Nowogrocki G, et al. Insights into the mechanism of action of ferroquine. Relationship between physicochemical properties and antiplasmodial activity. Mol Pharm 2005; 2(3): 185-93.
[http://dx.doi.org/10.1021/mp0500061] [PMID: 15934779]
[13]
N’Da DD, Smith PJ. Synthesis, In vitro antiplasmodial and antiproliferative activities of a series of quinoline–ferrocene hybrids. Med Chem Res 2014; 23: 1214-24.
[http://dx.doi.org/10.1007/s00044-013-0748-4]
[14]
Biot C, Dessolin J, Ricard I, Dive D. Easily synthesized antimalarial ferrocene triazacyclononane quinoline conjugates. J Organomet Chem 2004; 689: 4678-82.
[http://dx.doi.org/10.1016/j.jorganchem.2004.04.036]
[15]
Bellot F, Coslédan F, Vendier L, Brocard J, Meunier B, Robert A. Trioxaferroquines as new hybrid antimalarial drugs. J Med Chem 2010; 53(10): 4103-9.
[http://dx.doi.org/10.1021/jm100117e] [PMID: 20443628]
[16]
Yong J, Lu C. Ferrocene derivative, preparation method and use thereof. US9738673B1. 2017.
[17]
Ferey V, Mateos-Caro J, Mondiere R, Vayron P, Vigne S. Method of synthesis of ferroquine by convergent reductive amination. US8497375B2. 2013.
[18]
Brocard J, Lebibi J, Maciejewski L. Antimalarial organometallic iron complexes. US6127543A. 2013.
[19]
Pretorius SI, Breytenbach WJ, de Kock C, Smith PJ, N’Da DD. Synthesis, characterization and antimalarial activity of quinoline-pyrimidine hybrids. Bioorg Med Chem 2013; 21(1): 269-77.
[http://dx.doi.org/10.1016/j.bmc.2012.10.019] [PMID: 23168082]
[20]
Smit F. Synthesis and In vitro antimalarial activity of novel chalcone derivatives PhD Thesis, The North West University, South Africa. 2014.
[21]
Davis WL, Shago RF, Langner EH, Swarts JC. Synthesis and electrochemical properties of a series of ferrocene-containing alcohols. Polyhedron 2005; 24: 1611-6.
[http://dx.doi.org/10.1016/j.poly.2005.04.022]
[22]
Mukaya HE, Neuse EW, Van Zyl RL, Chen CT. Synthesis and preliminary bio-evaluation of polyaspartamide Co-conjugates of p-amino-salicylic acid chelated platinum (II) and ferrocene complexes. J Inorg Organomet Polym Mater 2015; 25(3): 367-75.
[http://dx.doi.org/10.1007/s10904-015-0174-9]
[23]
Verlinden BK, Niemand J, Snyman J, Sharma SK, Beattie RJ, Woster PM, et al. Discovery of novel alkylated (bis)urea and (bis)thiourea polyamine analogues with potent antimalarial activities. J Med Chem 2011; 54(19): 6624-33.
[http://dx.doi.org/10.1021/jm200463z] [PMID: 21882831]
[24]
Njogu PM, Gut J, Rosenthal PJ, Chibale K. Design, synthesis, and antiplasmodial activity of hybrid compounds based on (2 R, 3 S)-N-benzoyl-3-phenylisoserine. ACS Med Chem Lett 2013; 4(7): 637-41.
[http://dx.doi.org/10.1021/ml400164t] [PMID: 24900723]
[25]
Çapcı A, Lorion MM, Wang H, Simon N, Leidenberger M, Borges Silva MC, et al. Artemisinin-(Iso)quinoline hybrids by C-H activation and click chemistry: combating multidrug-resistant malaria. Angew Chem Int Ed Engl 2019; 58(37): 13066-79.
[http://dx.doi.org/10.1002/anie.201907224] [PMID: 31290221]
[26]
García G, Serrano I, Sánchez-Alonso P, Rodríguez-Puyol M, Alajarín R, Griera M, et al. New losartan-hydrocaffeic acid hybrids as antihypertensive-antioxidant dual drugs: ester, amide and amine linkers. Eur J Med Chem 2012; 50: 90-101.
[http://dx.doi.org/10.1016/j.ejmech.2012.01.043] [PMID: 22336384]
[27]
Capela R, Magalhaes J, Miranda D, Machado M, Sanches-Vaz M, Albuquerque IS, et al. Endoperoxide-8-aminoquinoline hybrids as dual-stage antimalarial agents with enhanced metabolic stability. Eur J Med Chem 2018; 149: 69-78.
[http://dx.doi.org/10.1016/j.ejmech.2018.02.048] [PMID: 29499488]
[28]
Di L, Kerns EH. Prodrugs.In: Drug-Like Properties (Concepts, Structure Design and Methods from ADME to Toxicity Optimization). 2nd ed. UK: Academic Press, Elsevier 2016.471-485.
[29]
Lieberman H, Vemuri NM. Chemical and Physicochemical Approaches to Solve Formulation Problems.In: Wermuth, C.G.; Aldous D, Raboisson P, Rognan D, Eds. ; The Practice of Medicinal Chemistry. 4th ed. UK: Academic Press, Elsevier 2015.767-791.
[http://dx.doi.org/10.1016/B978-0-12-417205-0.00032-8]
[30]
Miranda D, Capela R, Albuquerque IS, Meireles P, Paiva I, Nogueira F, et al. Novel endoperoxide-based transmission-blocking antimalarials with liver-and blood-schizontocidal activities. ACS Med Chem Lett 2013; 5(2): 108-12.
[http://dx.doi.org/10.1021/ml4002985] [PMID: 24900781]
[31]
Walsh JJ, Coughlan D, Heneghan N, Gaynor C, Bell A. A novel artemisinin-quinine hybrid with potent antimalarial activity. Bioorg Med Chem Lett 2007; 17(13): 3599-602.
[http://dx.doi.org/10.1016/j.bmcl.2007.04.054] [PMID: 17482816]
[32]
Njogu EM, Omondi B, Nyamori VO. Synthesis, physical and antimicrobial studies of Ferrocenyl-N-(pyridinylmethylene) anilines and Ferrocenyl-N-(pyridinylmethyl) anilines. S Afr J Chem 2016; 69: 51-66.
[http://dx.doi.org/10.17159/0379-4350/2016/v69a7]
[33]
Yong J, Jiang X, Wu X, Huang S, Zhang Q, Lu C. Synthesis and characterization of Ferrocene Derivatives and preliminarily electrocatalytic oxidation of L-Cysteine at Nafion-Ferrocene Derivatives modified glassy carbon electrode. Adv Chem 2014; 2014: 1-7.
[http://dx.doi.org/10.1155/2014/987481]
[34]
Singh A, Gut J, Rosenthal PJ, Kumar V. 4-Aminoquinoline-ferrocenyl-chalcone conjugates: synthesis and anti-plasmodial evaluation. Eur J Med Chem 2017; 125: 269-77.
[http://dx.doi.org/10.1016/j.ejmech.2016.09.044] [PMID: 27688182]
[35]
Wani WA, Jameel E, Baig U, Mumtazuddin S, Hun LT. Ferroquine and its derivatives: new generation of antimalarial agents. Eur J Med Chem 2015; 101: 534-51.
[http://dx.doi.org/10.1016/j.ejmech.2015.07.009] [PMID: 26188909]
[36]
Hu YQ, Gao C, Zhang S, Xu L, Xu Z, Feng LS, et al. Quinoline hybrids and their antiplasmodial and antimalarial activities. Eur J Med Chem 2017; 139: 22-47.
[http://dx.doi.org/10.1016/j.ejmech.2017.07.061] [PMID: 28800458]
[37]
Biot C, Pradines B, Sergeant MH, Gut J, Rosenthal PJ, Chibale K. Design, synthesis, and antimalarial activity of structural chimeras of thiosemicarbazone and ferroquine analogues. Bioorg Med Chem Lett 2007; 17(23): 6434-8.
[http://dx.doi.org/10.1016/j.bmcl.2007.10.003] [PMID: 17949976]
[38]
Salas PF, Herrmann C, Cawthray JF, Nimphius C, Kenkel A, Chen J, et al. Structural characteristics of chloroquine-bridged ferrocenophane analogues of ferroquine may obviate malaria drug-resistance mechanisms. J Med Chem 2013; 56(4): 1596-613.
[http://dx.doi.org/10.1021/jm301422h] [PMID: 23327489]
[39]
Biot C, Nosten F, Fraisse L, Ter-Minassian D, Khalife J, Dive D. The antimalarial ferroquine: from bench to clinic. Parasite 2011; 18(3): 207-14.
[http://dx.doi.org/10.1051/parasite/2011183207] [PMID: 21894260]
[40]
Kublin JG, Cortese JF, Njunju EM, G. Mukadam RA, Wirima JJ, Kazembe PN, et al. Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi. J Infect Dis 2003; 187(12): 1870-5.
[http://dx.doi.org/10.1086/375419] [PMID: 12792863]

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