Abstract
Malaria is a life-threatening infectious disease caused by parasites of the genus Plasmodium, affecting more than 200 million people worldwide every year and leading to about a half million deaths. Malaria parasites of humans have evolved resistance to all current antimalarial drugs, urging for the discovery of new effective compounds. Given that the inhibition of deoxyuridine triphosphatase of Plasmodium falciparum (PfdUTPase) induces wrong insertions in plasmodial DNA and consequently leading the parasite to death, this enzyme is considered an attractive antimalarial drug target. Using a combi-QSAR (quantitative structure-activity relationship) approach followed by virtual screening and in vitro experimental evaluation, we report herein the discovery of novel chemical scaffolds with in vitro potency against asexual blood stages of both P. falciparum multidrug-resistant and sensitive strains and against sporogonic development of P. berghei. We developed 2D- and 3D-QSAR models using a series of nucleosides reported in the literature as PfdUTPase inhibitors. The best models were combined in a consensus approach and used for virtual screening of the ChemBridge database, leading to the identification of five new virtual PfdUTPase inhibitors. Further in vitro testing on P. falciparum multidrug-resistant (W2) and sensitive (3D7) parasites showed that compounds LabMol-144 and LabMol-146 demonstrated fair activity against both strains and presented good selectivity versus mammalian cells. In addition, LabMol-144 showed good in vitro inhibition of P. berghei ookinete formation, demonstrating that hit-to-lead optimization based on this compound may also lead to new antimalarials with transmission blocking activity.
Highlights
Malaria is an infectious disease caused by protozoans of the genus Plasmodium and transmitted through the bite of insect vectors of the genus Anopheles
The three best Hologram QSAR (HQSAR) models for Pf deoxyuridine -triphosphate nucleotide hydrolase (dUTPase) inhibition are shown in Supplementary Table S2
We developed robust and externally predictive consensus quantitative structure-activity relationships (QSARs) models, merging 2D- (HQSAR) and 3D-QSAR (CoMFA and Comparative Molecular Similarity Indices Analysis (CoMSIA)) models for prediction of inhibition and selectivity against Pf dUTPase
Summary
Plasmodium falciparum is the most prevalent and lethal species infecting humans in the African continent, being responsible for 99% of all malaria-attributed deaths (World Health Organization [WHO], 2016). Despite the fact that integrated control interventions have achieved significant progress in the reducing malaria cases and related mortality in recent years, malaria still causes 429,000 deaths every year, being endemic in 91 countries and territories of sub-Saharan Africa, South-East Asia, Latin America, and the Middle East (World Health Organization [WHO], 2016). Resistance to artemisinins has been detected in five countries in the Greater Mekong sub region of South-east Asia, endangering the future of P. falciparum elimination (Vogel, 2014; World Health Organization [WHO], 2016; Thu et al, 2017). There is an urgent need for the discovery and development of new antimalarial therapies
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