Design, synthesis, and in vitro antiplasmodial activity of 4-aminoquinolines containing modified amino acid conjugates
A new series of side chain-modified 4-aminoquinolines were synthesized and screened for in vitro antiplasmodial activity against both chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. Among the series, compounds 30 and 31 showed significant inhibition of parasite growth against K1 strain of P. falciparum with IC50 values 0.28 and 0.31 µM, respectively, whereas compounds 34, 35, and 38 exhibited superior activity against K1 strain with IC50 values 0.18, 0.22, and 0.17 µM, respectively, as compared to 0.255 µM for chloroquine (CQ). All the compounds displayed good resistance factor between 1.54 and >34.48 as against 51.0 for CQ. All these analogues were found to form strong complex with hematin and inhibited the β-hematin formation in vitro, suggesting that this class of compounds act on a heme polymerization target. Overall results suggest that present series of compounds appear to be promising for further lead optimization to obtain compounds active against drug-resistant parasites.
KeywordsAntiplasmodial activity Heme binding Chloroquine Plasmodium falciparum β-Hematin Chloroquine-sensitive strain Chloroquine-resistant strain
One of the authors (K.S.R) thanks the CSIR, New Delhi, for Senior Research Fellowship. Authors thank the Director, CDRI, for the support, and the SAIF division for the spectral data. The CDRI Communication No is 9197.
Compliance with ethical standards
Conflicts of interest
The authors have no conflict of interest to declare.
- Cheruku SR, Maiti S, Dorn A, Scorneaux B, Bhattacharjee AK, Ellis WY, Vennerstrom JL (2003) Carbon isosteres of the 4-aminopyridine substructure of chloroquine: effects on pK(a), hematin binding, inhibition of hemozoin formation, and parasite growth. J Med Chem 46:3166–3169. doi: 10.1021/jm030038x CrossRefPubMedGoogle Scholar
- Dalal S, Ragheb DR, Klemba M (2012) Engagement of the S1, S1′ and S2′ subsites drives efficient catalysis of peptide bond hydrolysis by the M1-family aminopeptidase from Plasmodium falciparum. Mol Biochem Parasitol 183:70–77. doi: 10.1016/j.molbiopara.2012.02.003 CrossRefPubMedPubMedCentralGoogle Scholar
- Deshpande S (2010) Synthesis, biological evaluation and QSAR studies of novel antimalarial agents PhD Thesis, Jawaharlal Nehru University, New DelhiGoogle Scholar
- Egan TJ, Hunter R, Kaschula CH, Marques HM, Misplon A, Walden J (2000) Structure-function relationships in aminoquinolines: effect of amino and chloro groups on quinoline-hematin complex formation, inhibition of beta-hematin formation, and antiplasmodial activity. J Med Chem 43:283–291. doi: 10.1021/jm990437l CrossRefPubMedGoogle Scholar
- GraphPad Prism v3.0 (1999) GraphPad Software Inc., 10855 Sorrento Valley Rd. #203, San Diego. CA 92121Google Scholar
- Hocart SJ, Liu H, Deng H, De D, Krogstad FM, Krogstad DJ (2011) 4-aminoquinolines active against chloroquine-resistant Plasmodium falciparum: basis of antiparasite activity and quantitative structure-activity relationship analyses. Antimicrob Agents Chemother 55:2233–2244. doi: 10.1128/AAC.00675-10 CrossRefPubMedPubMedCentralGoogle Scholar
- Srivastava K, Puri S (2009) Recent Developments in Plasmodium falciparum in vitro model for Drug Discovery. Proc Natl Acad Sci, India 79:37–47Google Scholar
- Sunduru N, Sharma M, Srivastava K, Rajakumar S, Puri SK, Saxena JK, Chauhan PM (2009) Synthesis of oxalamide and triazine derivatives as a novel class of hybrid 4-aminoquinoline with potent antiplasmodial activity. Bioorg Med Chem 17:6451–6462. doi: 10.1016/j.bmc.2009.05.075 CrossRefPubMedGoogle Scholar
- Vasanth RD, Srinivasarao K, Katti SB (2014) Recent developments in the side chain modified 4-aminoquinolines as antimalarial agents. Chem Biol Interface 4:206–222Google Scholar
- World Malaria Report (WHO) (2014) http://www.who.int/malaria/publications/world_malaria_report_2014/en/