Synthesis and biological evaluation of 4,7,9-trisubstituted benzoxazepines as antileishmanial agents

[Display omitted] •New anti-leishmanial chemotypes.•Leishmania lead validation.•Leishmania structure–activity relationships.•Leishmania pharmacophore. Herein we report a series of antileishmanial analogues derived from 4-[(3,5-dimethyl-4-isoxazolyl)acetyl]-9-[(1-methyl-3-piperidinyl)methoxy]-7-(5-methyl-2-thienyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (1), which was identified through a previously reported high-throughput phenotypic screen. The analogue series was designed, synthesized, and evaluated for antileishmanial activity to establish pharmacophore elements and preliminary structure–activity relationships as key steps in validating the series for further optimization. This study led to identification of the early lead compound 46, which exhibited sub-micromolar proliferation inhibitory activity against intra-macrophage L. mexicana amastigotes, modest selectivity towards host macrophages (J774A.1 line), and good aqueous solubility.