Antiplasmodial activity of hydroxyethylamine analogs: Synthesis,biological activity and structure activity relationship of plasmepsin inhibitors |
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| Authors: | Amit Kumar Singh Vinoth Rajendran Snigdha Singh Prashant Kumar Yogesh Kumar Archana Singh Whelton Miller Vladimir Potemkin Maria Grishina Nikesh Gupta Prakasha Kempaiah Ravi Durvasula Brajendra K. Singh Ben M. Dunn Brijesh Rathi |
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| Affiliation: | 1. Department of Chemistry, University of Delhi, Delhi 110007, India;2. Department of Biochemistry, University of Delhi South Campus, New Delhi 110021, India;3. Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College, University of Delhi, Delhi 110007, India;4. Department of Botany, Hansraj College University Enclave, University of Delhi, Delhi 110007, India;5. Department of Chemistry & Physics, Lincoln University, Lincoln University, PA 19352, USA;6. Department of Chemical & Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA;g. South Ural State University, Laboratory of Computational Modeling of Drugs, 454080, Russia;h. Department of Chemistry, Miranda House University Enclave, University of Delhi, Delhi 110007 India;i. Special Centre for Nanosciences, Jawaharlal Nehru University, New Delhi 110067, India;j. Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA;k. Department of Medicine, Loyola University Stritch School of Medicine, Maywood, IL 60153, USA;l. Department of Biochemistry & Molecular Biology, University of Florida College of Medicine, P.O. Box 100245, Gainesville, FL, USA |
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| Abstract: | Malaria, particularly in endemic countries remains a threat to the human health and is the leading the cause of mortality in the tropical and sub-tropical areas. Herein, we explored new C2 symmetric hydroxyethylamine analogs as the potential inhibitors of Plasmodium falciparum (P. falciparum; 3D7) in in-vitro cultures. All the listed compounds were also evaluated against crucial drug targets, plasmepsin II (Plm II) and IV (Plm IV), enzymes found in the digestive vacuole of the P. falciparum. Analog 10f showed inhibitory activities against both the enzymes Plm II and Plm IV (Ki, 1.93?±?0.29?µM for Plm II; Ki, 1.99?±?0.05?µM for Plm IV). Among all these analogs, compounds 10g selectively inhibited the activity of Plm IV (Ki, 0.84?±?0.08?µM). In the in vitro screening assay, the growth inhibition of P. falciparum by both the analogs (IC50, 2.27?±?0.95?µM for 10f; IC50, 3.11?±?0.65?µM for 10g) displayed marked killing effect. A significant growth inhibition of the P. falciparum was displayed by analog 12c with IC50 value of 1.35?±?0.85?µM, however, it did not show inhibitory activity against either Plms. The hemolytic assay suggested that the active compounds selectively inhibit the growth of the parasite. Further, potent analogs (10f and 12c) were evaluated for their cytotoxicity towards mammalian HepG2 and vero cells. The selectivity index (SI) values were noticed greater than 10 for both the analogs that suggested their poor toxicity. The present study indicates these analogs as putative lead structures and could serve as crucial for the development of new drug molecules. |
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| Keywords: | Phthalimide Hydroxyethylamine Antimalarial Drug resistance Plasmepsins |
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