Coumarin derivatives as new chemotype targeting leishmanial sterol biosynthesis pathway proteins: an integrated in vitro, mechanistic, and in silico evaluation.

Leishmaniasis is a devastating neglected tropical disease (NTD) that has affected millions of vulnerable populations globally. Despite incredible pharmaceutical innovations, the existing anti-leishmanial therapy faces several pitfalls, such as drug resistance, toxicity, selectivity, cost concerns, etc. In our efforts to identify new chemical scaffolds, the present investigation scrutinizes the anti-leishmanial potency of the synthesized coumarin-oxime ether derivatives against Leishmania donovani parasites. The primary screening shortlisted six potential molecules (5a, 5d, 5i, 5j, 5k, and 5n) with IC50 values in the range of 4.97 to 28.72 µM. Among them, two potent hits (5j and 5k) demonstrated a promising cytocompatibility profile coupled with significant effectiveness in clearing the intracellular amastigote burden. Mechanistic insights elucidated that the potent hits (5j and 5k) orchestrated significant cell membrane disruption, escalated cellular ROS, alteration in mitochondrial membrane potential (ΔΨm), ATP depletion, lipid accumulation, and cell cycle disruption culminating in parasitic mortality. Furthermore, computational analysis revealed a dual-targeting strategy wherein the identified molecules (5j and 5k) inhibit the Sterol C-24 methyl transferase (SMT) and Sterol 14-α demethylase (SDM) protein of the ergosterol biosynthesis pathway in Leishmania parasites. Altogether, the present research work highlighted coumarin derivatives as a promising scaffold for developing new, safe, and effective chemotherapeutics to cure leishmaniasis.