resumo
A series of cinnamic acid/4-aminoquinoline conjugates conceived to link, through a proper retro-enantio dipeptide, a heterocyclic core known to prevent hemozoin formation, to a trans-cinnamic acid motif capable of inhibiting enzyme catalytic Cys residues, were synthesized as potential dual-action antimalarials. The effect of amino acid configuration and the absence of the dipeptide spacer were also assessed. The replacement of the D-amino acids by their natural L counterparts led to a decrease in both anti-plasmodial and falcipain inhibitory activity, suggesting that the former are preferable. Molecules with such spacer were active against blood-stage Plasmodium falciparum, in vitro, and hemozoin formation, implying that the dipeptide has a key role in mediating these two activities. In turn, compounds without spacer were better falcipain-2 inhibitors, likely because these compounds are smaller and have their vinyl bonds in closer vicinity to the catalytic Cys, as suggested by molecular modeling calculations. These novel conjugates constitute promising leads for the development of new antiplasmodials targeted at blood-stage malaria parasites. (C) 2012 Elsevier Masson SAS. All rights reserved.
palavras-chave
CHLOROQUINE-RESISTANCE TRANSPORTER; FALCIPARUM CYSTEINE PROTEASES; MALARIA-INFECTED ERYTHROCYTE; LIGAND EFFICIENCY INDEXES; PEPTIDYL VINYL SULFONES; PLASMODIUM-FALCIPARUM; ANTIPLASMODIAL ACTIVITY; INHIBITORY-ACTIVITY; HYBRID MOLECULES; DRUG DISCOVERY
categoria
Pharmacology & Pharmacy
autores
Perez, BC; Teixeira, C; Figueiras, M; Gut, J; Rosenthal, PJ; Gomes, JRB; Gomes, P
nossos autores
Cátia Teixeira
Bolseiro de pós-Doutoramento
José R. B. Gomes
Investigador Principalagradecimentos
This work was mainly supported by Fundacao para a Ciencia e a Tecnologia (FCT, Portugal) through projects PTDC/QUI/65142/2006 and PTDC/QUI-QUI/116864/2010 coordinated by PG, and through strategic projects PEst-C/QUI/U10081/2011 and PEst-C/CTM/LA0011/2011 awarded to CIQUP and CICECO, respectively. Thanks are due to FCT also for both the LC-MS and NMR facilities, respectively funded through projects CONC-REEQ/275/QUI and REDE/1517/RMN/2005. CT thanks FCT for post-doctoral grant SFRH/BPD/62967/2009. JRBG is a holder of a Ciencia 2007 position of the Portuguese Ministry of Science. PJR is a Distinguished Clinical Scientist of the Doris Duke Charitable Foundation.