Novel isoxazole containing heteroretinoid (4) and its amide derivatives (5a-j) have been synthesized and evaluated for their in vivo antileishmanial activity against Leishmania donovani in hamsters. Compounds 3, 5a, 5d, 5k and 5l inhibited 70-76% parasite growth at 50 mg kg(-1) ×5 days. The present study has helped us in identifying a new lead that could be exploited as a potential antileishmanial agent.