Design, Synthesis, and Evaluation of Novel Quinazolin-4(3H)-One Derivatives: Anti-Leishmanial Activity, Selectivity, and Molecular Docking Insights.

In this study, 16 novel quinazolin-4(3H)-one derivatives were synthesized and evaluated for their antileishmanial activity against Leishmania major and Leishmania donovani. Among them, compounds 2 (4-hydroxy substituted) and 9 (4-morpholino substituted) exhibited the highest efficacy, with compound 2 showing IC50 values of 23.94 μM for L. major and 90.80 μM for L. donovani, while compound 9 demonstrated IC50 values of 23.05 μM for L. major and 56.30 μM for L. donovani. Miltefosine, the reference drug, showed IC50 values of 32.89 μM for L. major, 4.78 μM for L. donovani, and 7.53 μM for HUVEC cells. Compound 2 showed superior selectivity (SI = 15.2 for L. major and 4.0 for L. donovani) compared to miltefosine (SI = 4.4 for L. major and 0.6 for L. donovani). Molecular docking studies identified phosphodiesterase B1 (PDEB1) as a key target, with compound 2 showing the strongest binding affinity. The docking score of compound 2 was calculated as -11.909 kcal/mol for PDEB1. ADME predictions indicated compound 2's favorable pharmacokinetic profile, including good solubility, permeability, and adherence to Lipinski's Rule of Five. Overall, compound 2 exhibited the most promising therapeutic profile, highlighting its potential as a lead compound for antileishmanial drug development.