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BIBTEX RIS

Theoretical and Experimental Studies of New Modified Isoflavonoids as Potential Inhibitors of Topoisomerase I from Plasmodium falciparum

2014; Public Library of Science; Volume: 9; Issue: 3 Linguagem: Inglês

10.1371/journal.pone.0091191

1932-6203

Wilian A. Cortopassi, Julia Penna-Coutinho, Anna Caroline Campos Aguiar, André Silva Pimentel, Camilla D. Buarque, Paulo R. R. Costa, Bruna R. M. Alves, Tanos C. C. França, Antoniana U. Krettli,

Synthesis and Biological Evaluation

DNA topoisomerase I from Plasmodium falciparum (PfTopoI), a potential selective target for chemotherapy and drug development against malaria, is used here, together with human Topo I (HssTopoI), for docking, molecular dynamics (MD) studies and experimental assays. Six synthetic isoflavonoid derivatives and the known PfTopoI inhibitors camptothecin and topotecan were evaluated in parallel. Theoretical results suggest that these compounds dock in the binding site of camptothecin and topotecan inside both enzymes and that LQB223 binds selectively in PfTopoI. In vitro tests against P. falciparum blood parasites corroborated the theoretical findings. The selectivity index (SI) of LQB223 ≥ 98 suggests that this molecule is the most promising in the group of compounds tested. In vivo experiments in mice infected with P. berghei showed that LQB223 has an antimalarial activity similar to that of chloroquine.