A series of twenty six structurally diverse a-aminophosphonates have been synthesized and evaluated for in vitro anti-leishmanial activity and cytotoxicity using the MTT assay. Among them, seven compounds (1–7) exhibited anti-leishmanial potency against the L. donovani promastigote with IC50 values in the low micromolar range. The structure–activity relationships were quantitatively evaluated by a statistically reliable CoMFA model with high predictive abilities (r²pred ¼ 0.87, r²ncv ¼ 0.985).