Incorporation of Basic Side Chains into Cryptolepine Scaffold: Structure−Antimalarial Activity Relationships and Mechanistic Studies

The synthesis of cryptolepine derivatives containing basic side-chains at the C-11 position and their evaluations for antiplasmodial and cytotoxicity properties are reported. Propyl, butyl, and cycloalkyl diamine side chains significantly increased activity against chloroquine-resistant Plasmodium falciparum strains while reducing cytotoxicity when compared with the parent compound. Localization studies inside parasite blood stages by fluorescence microscopy showed that these derivatives accumulate inside the nucleus, indicating that the incorporation of a basic side chain is not sufficient enough to promote selective accumulation in the acidic digestive vacuole of the parasite. Most of the compounds within this series showed the ability to bind to a double-stranded DNA duplex as well to monomeric hematin, suggesting that these are possible targets associated with the observed antimalarial activity. Overall, these novel cryptolepine analogues with substantially improved antiplasmodial activity and selectivity index provide a promising starting point for development of potent and highly selective agents against drug-resistant malaria parasites.

João Lavrado, Ghislain G. Cabal, Miguel Prudêncio, Maria M. Mota, Jiri Gut§, Philip J. Rosenthal§, Cecília Díaz, Rita C. Guedes, Daniel J. V. A. dos Santos, Elena Bichenkova, Kenneth T. Douglas, Rui Moreira*, and Alexandra Paulo

Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon. Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal
Unidade de Malária, Instituto de Medicina Molecular, Universidade de Lisboa, 1649-028 Lisboa, Portugal
§ Department of Medicine, San Francisco General Hospital, University of California, San Francisco, Box 0811, San Francisco, California 94143, United States
Departamento de Bioquímica, Escuela de Medicina and Instituto Clodomiro Picado, Universidad de Costa Rica, 2060 San José, Costa Rica
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom

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