Synthesis of chiral chloroquine and its analogues as antimalarial agents |
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| Institution: | 1. Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India;2. Parasitology Division, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India;1. Syngene International Ltd, Biocon Park, Plot Nos. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560 099, India;2. Department of P.G. Studies and Research in Chemistry, Sahyadri Science College (Autonomous), Shimoga 577 203, India;1. Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave, Lawrence, KS 66045, United States;2. Department of Chemistry, University of Kansas, 1251 Wescoe Hall Dr, Lawrence, KS 66045, United States;3. High Throughput Screening Facility, University of Kansas, 2034 Becker Dr, Lawrence, KS 66047, United States;4. Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Dr, Lawrence, KS 66045, United States;1. Faculty of Pharmacy, Apotex Centre, University of Manitoba, 750 McDermot Ave, Winnipeg, Manitoba R3E 0T5, Canada;2. College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA;1. Université de Toulouse, UPS, UMR 152 Pharma-DEV, Université Toulouse 3, Faculté des sciences pharmaceutiques, 35 Chemin des maraîchers, F-31062 Toulouse Cedex 9, France;2. Institut de Recherche pour le Développement, IRD, UMR 152 Pharma-DEV, F-31062 Toulouse Cedex 9, France;3. CNRS, LCC (Laboratoire de Chimie de Coordination), 205 Route de Narbonne, BP 44099, F-31077 Toulouse Cedex 4, France;4. Université de Toulouse, UPS, INPT, F-31077 Toulouse Cedex 4, France |
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| Abstract: | In this investigation, we describe a new approach to chiral synthesis of chloroquine and its analogues. All tested compounds displayed potent activity against chloroquine sensitive as well as chloroquine resistant strains of Plasmodium falciparum in vitro and Plasmodium yoelii in vivo. Compounds S-13b, S-13c, S-13d and S-13i displayed excellent in vitro antimalarial activity with an IC50 value of 56.82, 60.41, 21.82 and 7.94 nM, respectively, in the case of resistant strain. Furthermore, compounds S-13a, S-13c and S-13d showed in vivo suppression of 100% parasitaemia on day 4 in the mouse model against Plasmodium yoelii when administered orally. These results underscore the application of synthetic methodology and need for further lead optimization. |
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| Keywords: | 4-Aminoquinolines Chiral chloroquine analogues Chloroquine resistant stain |
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