resumo
In a follow-up study to our reports of N-cinnamoylated chloroquine and quinacrine analogues as promising dual-stage antimalarial leads with high in vitro potency against both blood-stage Plasmodium falciparum and liver-stage Plasmodium berghei, we decided to investigate the effect of replacing the cinnamoyl moiety with other acyl groups. Thus, a series of N-acylated analogues were synthesized, and their activities against blood- and liver-stage Plasmodiumspp. were assessed along with their in vitro cytotoxicities. Although the new N-acylated analogues were found to be somewhat less active and more cytotoxic than their N-cinnamoylated counterparts, they equally displayed nanomolar activities in vitro against blood-stage drug-sensitive and drug-resistant P.falciparum, and significant in vitro liver-stage activity against P.berghei. Therefore, it is demonstrated that simple N-acylated surrogates of classical antimalarial drugs are promising dual-stage antimalarial leads.
palavras-chave
MALARIA-INFECTED ERYTHROCYTES; PLASMODIUM-FALCIPARUM; CHLOROQUINE; ANALOGS; PERMEABILITY; DERIVATIVES; INHIBITORS; PARASITES; GROWTH; AGENTS
categoria
Pharmacology & Pharmacy
autores
Gomes, A; Machado, M; Lobo, L; Nogueira, F; Prudencio, M; Teixeira, C; Gomes, P
nossos autores
Ana Sofia Martins Gomes
Bolseiro de investigação
Cátia Teixeira
Bolseiro de pós-DoutoramentoGrupos
agradecimentos
This work was co-funded by Fundacao para a Ciencia e Tecnologia (FCT) refs. UID/Multi/04378/2013, PTDC/QUI-QUI/116864/2010, EXPL/QEQ-COM/0927/2013, and PTDC/SAU-MIC/117060/2010) and by FEDER (European Union), within the frame of the COMPETE programme (refs. FCOMP-01-0124-FEDER-020963 and FCOMP-01-0124-FEDER-041066). C.T. thanks the FCT for funding through strategic project PEst-C/CTM/LA0011/2013 and for the postdoctoral fellowship SFRH/BPD/62967/2009. 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.