Discovery of Host-Directed Small Molecules with Broad Anti-Leishmanial Efficacy.

Leishmaniasis, a neglected tropical disease affecting nearly 10% of the global population, suffers from limited therapeutic options and rising drug resistance. To address this, we developed 343 analogs of AR-12, a compound that has previously illustrated host-directed anti-leishmanial effects. Primary screening using a luminescence-based assay revealed 66 analogs with greater selectivity than the parent compound, AR-12. Sixteen promising candidates, selected for high potency (IC50 < 1 μM) or high selectivity (>15), underwent secondary screening via Giemsa staining. Four lead compounds (53, 134, 197, and 354) demonstrated therapeutic indices greater than 40. Tertiary assays confirmed their broad in vitro efficacy against both Leishmania donovani and L. mexicana. Notably, 197 exhibited potent host-directed activity and proteomic analysis identified lysozyme as a mechanistic target, implicating it in the host-mediated clearance of intracellular parasites. These findings highlight the dual host- and pathogen-directed mechanisms of these compounds and support their potential as the basis for new therapeutic strategies. Further optimization and clinical exploration of these leads are warranted to meet the urgent need for effective leishmaniasis treatments.