SYNTHESIS, ANTIPLASMODIAL AND ADMET STUDIES OF 4-METHYLAMINO-2-PHENYLQUINOLINE ANALOGS
DOI:
https://doi.org/10.22159/ijpps.2016v8i11.14381Keywords:
Antimalarial, Chloroquine, RKL-2 strain, Pharmacokinetics, Pfitzinger reaction, Plasmodium falciparumAbstract
Objective: Synthesis, antiplasmodial and absorption, distribution, metabolism, excretion and toxicity (ADMET) studies of 4-methylamino-2-phenylquinoline analogs.
Methods: The synthesis of 4-methylamino-2-phenylquinoline analogs 7(a-j) by reacting substituted 4-(chloromethyl)-2-phenylquinoline 6(a-c) with secondary amines to explore their antimalarial property against P. falciparum RKL-2 strain and in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) properties using ACD/I-Lab 2.0. The synthesized structures were confirmed by IR, NMR and Mass spectral analysis.
Results: The results revealed that at 100 μg/ml, compounds 7a, 7d and 7i were found to be potent with percentage inhibition of 88.0±1.1, 79.1±1.1, 90.2±0.1, respectively. The compounds 7b, 7e, 7f and 7h were moderately active with 59.9±1.2, 48.5±2.0, 35.2±1.1 and 52.0±0.3 and the remaining compounds 7c, 7g and 7j exhibited mild activity 32.2±1.2, 36.8±3.0 and 28.7±2.0. The absorption, distribution, metabolism, excretion and toxicity (ADMET) studies of title compounds were analyzed and found to be obeying the Lipinski rule of five and are non-toxic.
Conclusion: The C4 of quinoline ring with morpholine 7a, piperidine 7d and imidazole 7i substitutions were promising enough to be taken as lead molecules in the drug discovery of new antimalarial. The in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) studies of the molecules were found to be obeying the Lipinski rule of five good drug likeliness.
Â
Downloads
References
Seenivasan KD, Devadasan V. Molecular docking, quantitative structure activity relationship and pharmacophore studies on antiviral, antimalarial and anti-inflammatory bioactive compounds from marine sources. Asian J Pharm Clin Res 2015;8 Suppl 3:36-43.
WHO report, Global Malaria Programme. World Health Organization, Geneva; 2014.
Talisuna AO, Bloland P, Alessandro UD. History, dynamics and public health importance of malaria parasite resistance. Clin Microbiol Rev 2004;17:235-54.
Sharma VP. Battling the malaria iceberg with chloroquine in India. Malaria J 2007;6:105.
Fidock DA, Nomura T, Talley AK, Cooper RA, Dzekunov SM, Ferdig MT, et al. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell 2000;6:861-71.
Roepe PD. PfCRT-mediated drug transport in malarial parasites. Biochemistry 2011;50:163-71.
Jambou R, Legrand E, Niang M, Khim N, Lim P, Volney B, et al. Resistance of Plasmodium falciparum field isolates to in vitro artemether and point mutations of the SERCA-type PfATPase6. Lancet 2005;366:1960-63.
Foley M, Tilley L. Quinoline antimalarials: mechanisms of action and resistance and prospects for new agents. Pharmacol Ther 1998;79:55-87.
Eicher T, Hauptmann S. The chemistry of heterocycles. 2nded. Weinheim; 2003. p. 316.
Baird JK, Fryauff DJ, Hoffman SL. Primaquine for prevention of malaria in travelers. Clin Infect Dis 2003;37:1659-67.
Baird JK, Reickmann KH. Can primaquine therapy for vivax malaria be improved? Trends Parasitol 2003;19:115-20.
Morimoto Y, Matsuda F, Shirahama H. Total synthesis of (±)-virantmycin and determination of its stereochemistry. Synlett 1991;3:202-03.
Woodward RB, Doering WV. The total synthesis of quinine. J Am Chem Soc 1945;67:860-74.
Alhaider AA, Abdelkader MA, Lien EJ. Synthesis and pharmacological activities of 2-substituted 4-phenylquinolines as potential antidepressant drugs. J Med Chem 1985;28:1394-8.
Yu XY, Hill JM, Yu G, Yang Y, Kluge AF, Keith D, et al. A series of quinoline analogues as potent inhibitors of C-albicansprolyl tRNA synthetase. Bioorg Med Chem Lett 2001;11:541-4.
Madrid PB, Sherrill J, Liou AP, Weisman JL, DeRisib JL, Guy RK. Synthesis of ring-substituted 4-aminoquinolines and evaluation of their antimalarial activities. Bioorg Med Chem Lett 2005;15:1015-8.
O’Neill PM, Mukhtar A, Stocks PA, Randle LE, Hindley S, Ward SA, et al. Isoquine and related amodiaquine analogs: a new generation of improved 4-aminoquinoline antimalarials. J Med Chem 2003;46:4933-45.
Ridley RG, Hofheinz W, Matile H, Jaquet C, Dorn A, Masciadri R, et al. 4-aminoquinoline analogs of chloroquine with shortened side chains retain activity against chloroquine-resistant plasmodium falciparum. Antimicrob Agents Chemother 1996;40:1846-54.
Stocks PA, Raynes KJ, Bray PG, Park BK, O’Neill PM, Ward SA. Novel short chain chloroquine analogs retain activity against chloroquine-resistant K1 Plasmodium falciparum. J Med Chem 2002;45:4975-83.
Crumplin GC. The 4-Quinolones: antibacterial agents in vitro. Springer-Verlag London; 1990.
Gutzwiller J, Uskokovic M. Total synthesis of quinine and quinidine II. J Am Chem Soc 1970;92:204-5.
Madrid PB, Wilson NT, DeRisi JL, Guy RK. Parallel synthesis and antimalarial screening of 4-aminoquinoline library. J Comb Chem 2004;6:437-42.
David PH. 2-phenyl-4-quinoline carboxylic acid and pharmaceutical compositions thereof. U S Pat 1987;4 Suppl 680:299.
Dubroeucq MC, Lefur G, Renault C. Eur Pat; 1984. p. 112776.
Atwell GJ, Bos CD, Baguley BC, Denny WA. Potential antitumor agents. 56. "Minimal" DNA-intercalating ligands as antitumor drugs: phenylquinoline-8-carboxamides. J Med Chem 1988; 31:1048-52.
Molyneaux CA, Krugliak M, Ginsburg H, Chibale K. Arylpiperazines displaying preferential potency against chloroquine-resistant strains of the malaria parasite Plasmodium falciparum. Biochem Pharmacol 2005;71:61-8.
Jain M, Vangapandu S, Sachdeva S, Singh S, Singh PP, Gena GB, et al. Discovery of a bulky 2-tert-butyl group containing primaquine analogue that exhibits potent blood-schizonticidal antimalarial activities and complete elimination of methemoglobin toxicity. J Med Chem 2004;47:285-7.
Govind Nayak, Birendra Shrivastava, Akhlesh Kumar Singhai. Azetidin-2-one fused quinoline analogues: synthesis and biological evaluation of some novel 2-chloro-3-formyl quinoline derivatives. Int J Curr Pharm Res 2016;8:64-7.
Sheelavanth S, Yadav DB, Harishkumar HN, Kiran KB, Satyanarayan ND. Synthesis and biological evaluation of cinchophen analogs containing benzofuran nucleus. Inventi Impact: Med Chem 2011;2:4.
Sheelavanth S, Yadav DB, Anand U, Nagaraja KL, Kiran JR, Satyanarayan ND. Facile synthesis of phenyl esters and amides of Cinchophen using EDC. HCl and antibacterial activity. OCAIJ 2012;8:24-8.
Satyanarayan ND, Santoshkumar S, Sheelavanth S, Yadav DB, Anantacharya R, Sandeep T. Antitubercular, antibacterial and molecular docking studies of new 2-(naphtha[2,1-] furan-2-yl quinoline-4-carboxylic acids and their esters. Inventi Rapid Med Chem 2016;3:19343.
Anantacharya R, Manjulatha K, Satyanarayan ND, Santoshkumar S, Kaviraj MY. Antiproliferative, DNA cleavage and ADMET study of substituted 2-(1-benzofuran-2-yl) quinoline-4-carboxylic acid and its esters. Cogent Chem 2016;2. https://doi.org/10.1080/23312009.2016.1158382
Milner E, McCalmont W, Bhonsle J, Caridha D, Carroll D, Gardner S, Gerena L, Gettayacamin M, et al. Structure-activity relationships amongst 4-position quinoline methanol antimalarials that inhibit the growth of drug sensitive and resistant strains of Plasmodium falciparum. Bioorg Med Chem Lett 2010;20:1347-51.
O’Hagan D, Rzepa HS. Some influences of fluorine in bioorganic chemistry. Chem Commun 1997;7:645-52.
Kirk KL, Cantacuzene D, Collins B, Chen GT, Nimit Y, Creveling CR. Syntheses and adrenergic agonist properties of ring-fluorinated isoproterenols. J Med Chem 1982;25:680-4.
Morgan P, Maggs JL, Page PCB, Parks BK. Oxidative dehalogenation of 2-fluoro-17α-ethynyloestradiol in vivo: a distal structure-metabolism relationship of 17α-ethynylation. Biochem Pharmacol 1992;44:1717-24.
Rieckmann KH, Campbell GH, Sax LJ, Mrema JE. Drug sensitivity of Plasmodium falciparum, an in vitro microtechnique. Lancet 1978;1:22-3.
Desjardins RE, Peters W, Richards. In vitro techniques for antimalarial development and evaluation. In: W. H. G. editors. Handbook of experimental pharmacology. Springer-Verlag, Germany; 1984. p. 179-200.
Trager W, Jensen JB. Human malaria parasites in continuous culture. Science 1976;193:673-5.
Lambros C, Vanderberg JP. Synchronization of plasmodium falciparum intraerythrocytic stages in culture. J Parasitol 1979;65:418-20.
Singh J, Misra BG. J.S.B. stain; simplified method of preparation. Indian J Malariol 1956;10:117-29.
El-Behery M, El-Twigry H. Synthesis, magnetic, spectral, and antimicrobial studies of Cu(II), Ni(II) Co(II), Fe(III), and UO2(II) complexes of a new Schiff base hydrazone derived from 7-chloro-4-hydrazinoquinoline. Spectrochim Acta Part A 2007;66:28–36.
Gemma S, Kukreja G, Fattorusso C, Persico M, Romano MP, Altarelli M, et al. Synthesis of N1-arylidene-N2-quinolyl-and N2-acrydinylhydrazones as potent antimalarial agents active against CQ-resistant P. falciparum strains. Bioorg Med Chem Lett 2006;16:5384–8.
Ginsburg H, Famin O, Zhang J, Krugliak M. Inhibition of glutathione-dependent degradation of heme by chloroquine and amodiaquine as a possible basis for their antimalarial mode of action. Biochem Pharmacol 1998;56:1305–13.
Sanchez CP, Lanzer M. Changing ideas on chloroquine in Plasmodium falciparum. Curr Opin Infect Dis 2000;13:653–8.
Panjarathinam R. Textbook of medical parasitology. 2nd Ed. Orient Longman Pvt. Ltd. Chennai; 2007. p. 329.
Sahu R, Thakur DS, Kashyap P. Schiff base: an overview of its medicinal chemistry potential of new drug molecules. Int J Pharm Sci Nanotechnol 2012;5:1757-64.
Feixiong C, Weihua L, Yadi Z, Jie S, Zengrui W, Guixia L, et al. Admetsar: a comprehensive source and free tool for assessment of chemical ADMET properties. J Chem Inf Model 2012;52:3099-105.
Lin JH, Yamazaki M. Role of P-glycoprotein in pharma-cokinetics: clinical implications. Clin Pharmacokinet 2003; 42:59-98.
Published
How to Cite
Issue
Section
