High-throughput screening identifies novel chemical scaffolds targeting Leishmania donovani parasites.

High-throughput screening (HTS) is one of the critical strategies that can accelerate the process of drug discovery by exploring small drug-like molecule libraries. HTS noticeably contributes to the identification of potential hits using various automation tools and biological assays. Leishmaniasis, a neglected tropical disease, is one of the most deadly protozoan parasitic infections causing significant global burden in certain poverty-stricken countries. Given the paucity of effective chemotherapeutic agents available for the treatment of this life-threatening infection, the discovery of novel leishmanicidal scaffolds through innovative strategies is pivotal to combating this parasitic disease. In the present study, we have employed the HTS strategy to scrutinize 10,000 drug-like molecules from the in-house ChemDiv library to identify potent hits against Leishmania donovani. Noticeably, 99 molecules showed > 80% inhibitory effect against the L. donovani parasites at 50 µM concentration, and among them, four molecules displayed a 50% inhibitory concentration (IC) value < 10 µM along with a favorable selectivity index (> 10). Scanning electron microscopy analysis suggests that these potent hits cause considerable morphological alterations. The predicted ADME or pharmacokinetics study of these potent hit molecules indicates that all the hits have considerable drug-likeness properties and showed a low risk of adverse effects, along with a predicted high level of oral bioavailability. Thus, these promising hits identified by the HTS strategy can serve as an initial basis for consequent medicinal chemistry endeavors aimed at unraveling a new series of anti-leishmanial agents.