Cheminformatics-driven identification of new antiplasmodial hits effective against asexual and sexual stages

Due to the emergence of resistance from artemisinin in Africa1, it is urgent the search for new antimalarials with new mechanisms of action, including transmission-blocking activity. This study aims to discover new antiplasmodial compounds for asexual and sexual stages. Initially, were generated and validated shape-based models for aurora kinase-2 from P. falciparum (PfArk-2) and QSAR models for ookinete formation inhibition . These models were employed in a virtual screening to find putative inhibitors of PfArk-2, with activity in 3D7 and W2 strains (in house models) and ookinete formation inhibition. Using these models, we prioritized ten compounds for experimental validation against asexual (3D7, Dd2) and transmission-blocking stages. Among them, four compounds showed antiplasmodial activity against 3D7 and Dd2 at low micromolar concentrations with selectivity indexes between 17-66. In addition, three compounds inhibited ookinete formation at 10 μM. In conclusion, these compounds represent new chemical scaffolds for prospective hit-to-lead optimization.