Background: This research project is designed to identify the anti-diabetic effects of thenewly synthesized compounds to conclude the perspective of consuming one or more of these newsynthetic compounds for diabetes management.Introduction: A series of dihydropyrimidine (DHPM) derivative bearing electron releasing andelectron-withdrawing substituents on phenyl ring (a-j) were synthesized and screened for antihyperglycemic(anti-diabetic) activity on streptozotocin (STZ) induced diabetic rat model. Thenewly synthesized compounds were characterized by using FT-IR, melting point, 1H and 13C NMRanalysis. The crystal structure and supramolecular features were analyzed through single-crystalX-ray study. Anti-diabetic activity testing of newly prepared DHPM scaffolds was mainly basedon their relative substituent on the phenyl ring along with urea and thiourea. Among the synthesizedDHPM scaffold, the test compound c having chlorine group on phenyl ring at the ortho positionto the hydropyrimidine ring with urea and methyl acetoacetate derivative shows moderatelowering of glucose level. However, the title compounds methyl 4-(4-hydroxy-3-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(g) and ethyl 4-(3-ethoxy-4-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(h) having methoxyand ethoxy substituents on phenyl ring show significant hypoglycemic activity compared to theremaining compounds from the Scheme 1.Methods: The experimental rat models for the study were divided into 13 groups (n = 10); group 1animals were treated with 0.5% CMC (0.5mL) (vehicle); group 2 were considered the streptozotocin(STZ)/nicotinamide diabetic control group (DC) and untreated, group 3 diabetic animals wereadministered with gliclazide 50 mg/kg and act as a reference drug group. The remaining groups ofthe diabetic animals were administered with the newly synthesized dihydropyrimidine compoundsin a single dose of 50 mg/kg orally using the oral gavage, daily for 7 days continuously. Theblood glucose level was measured before and 72 hrs after nicotinamide-STZ injection, for confirmationof hyperglycemia and type 2 diabetes development.Results: Blood glucose levels were significantly (p<0.05) reduced after treatment with these derivatives.The mean percentage reduction for gliclazide was 50%, while that of synthesized compoundswere approximately 36%.Conclusion: Our result suggests that the synthesized new DHPM derivative containing alkoxygroup on the phenyl ring shows a significant lowering of glucose level compared to other derivatives.