Bicyclic Lactams From Chiral Imines: Synthesis, Structural Optimization, and Biological Evaluation of Promising Antileishmanial Agents

In this study, a bicyclic lactam derived from piperidine was synthesized via an asymmetric Michael reaction using a chiral imine 3 . In addition, twenty‐four nitrogen‐modulated analogues were synthesized, including 20 benzylated ( 9a–k( S ) and ent‐9a–j( R ) ) and 4 acylated ( 12( S ) and 13a–c( S ) ) derivatives. All compounds were evaluated for their antileishmanial activity against axenic and intramacrophage amastigotes of Leishmania major (cutaneous leishmaniasis) and L. donovani (visceral leishmaniasis). Several derivatives displayed potent activity with low toxicity toward macrophages and MRC‐5 cell lines. Notably, compounds ent‐9b (IC 50 values of 0.33 and 0.78 μM against intramacrophage amastigote forms of L. major and L. donovani , respectively), ent‐9d (IC 50 = 0.69 and 1.12 μM), ent‐9e (IC 50 = 0.21 and 0.43 μM), ent‐9h (IC 50 = 0.68 and 1.54 μM), and 13b (IC 50 = 0.97 and 0.88 μM) exhibited remarkable activity and favorable selectivity indices compared with the reference drug miltefosine (IC 50 = 2.74 and 1.03 μM). Pharmacokinetic (ADME) analyses were conducted to assess their drug‐likeness and identify promising candidates for further development. Ligand‐based inverse virtual screening suggested L. major phosphodiesterase B1 and L. donovani cAMP‐specific phosphodiesterase as potential molecular targets. These compounds represent promising leads for further development in the fight against leishmaniasis.