Unveiling potent anti-leishmanial agents: a QSAR exploration of diverse chemical scaffolds targeting Leishmania donovani amastigotes.

Leishmaniasis, caused by Leishmania spp. remains a major global health concern due to drug resistance, toxicity, non-specificity, and prolonged treatments. Addressing the need for new therapeutics, we investigated a range of bioactive compounds, including chalcones, pyrimidines, quinolines, azoles, sulphonamides, flavonoids, and quinazoline derivatives, targeting Leishmania donovani amastigotes. Key molecular descriptors influencing anti-leishmanial activity were identified using LASSO and multiple linear regression (MLR), yielding robust QSAR models (r2 > 0.84) validated through rigorous statistical analysis. Virtual screening and scaffold-hopping strategies led to the design of 12 novel compounds, among which six; mainly benzothiazole and benzoxazole derivatives exhibited clear predicted pIC₅₀ values and promising ADMET profiles. Quinoline-based compounds showed moderate activity, consistent with prior experimental data. Structural analysis revealed the significance of quinoline rings linked to thiazole or benzoxazole moieties, with modifications like alkyl halides and methyl groups enhancing bioactivity. Further molecular docking against Leishmania donovani N-myristoyltransferase (Ld-NMT) and sterol 14-α demethylase CYP51 demonstrated strong binding affinities with compounds N8, N9, and N11. Structure-based similarity searches using ChEMBL confirmed selective bioactivity and low predicted cytotoxicity, supporting minimal off-target interactions. These findings present a computationally guided framework for developing effective, targeted anti-leishmanial agents.