Theoretical and experimental studies of new modified isoflavonoids as potential inhibitors of topoisomerase I from Plasmodium falciparum.

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

doi:10.1371/journal.pone.0091191

Abstract

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.

Highlights

Malaria is the most lethal parasitic disease, causing 219 million cases and 660,000 deaths annually, mainly in African sub-Saharan countries [1]
The selectivity index (SI) is a ratio between toxicity and activity. *IC50 #10 mg/mL are considered as active; 11–20 mg/mL as partially active (PA) and . 20 mg/mL as inactive. **SI based in results from three experiments; values bellow 10 are indicative of drug toxicity
The results suggest that LQB223 may establish better interactions with P. falciparum Topo I (PfTopoI) (2187.5 cal mol21) than with HssTopoI (2171.2 Kcal mol21)

Summary

Introduction

Malaria is the most lethal parasitic disease, causing 219 million cases and 660,000 deaths annually, mainly in African sub-Saharan countries [1]. Brazil registered 306,000 cases of malaria in 2009, most of which were in the Amazon Region and caused by Plasmodium vivax followed by P. falciparum [2]. This species may cause severe malaria and death in untreated individuals, especially children under five [3], in addition, it quickly develops resistance under selective drug pressure [4]. P. falciparum is resistant to most available drugs; its low susceptibility to artemisinincombined therapy (ACT) is registered, especially in Southeast Asia countries [5]. The search for better treatments based on new molecular targets should broaden the therapeutic arsenal and allow strategies to fight drug resistance in human malaria [9,10,11]

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Results

Conclusion