In this study, we presented rational designing and synthesis of coumarin-dihydroquinazolinone conjugates to evaluate their agonist activity at GPR109a receptor. Among the synthesized small molecule library, compound 10c displayed robust agonist action at GPR109a with EC50 < 11 nM. Homology model of human GPR109a protein was generated to realize the binding interaction of the active molecule with the active site of GPR109a. Further, the efficacy of active compound 10c was supported by in-vivo experiments which showed reduced body weight in diet induced obese mice model. Interestingly, compound 10c reduced leptin in blood plasma and total serum cholesterol. These results suggest that the coumarin-dihydroquinazolinone conjugate is a suitable scaffold to further expand the chemical diversity and make them potential niacin receptor 1 agonist.