The inhibition of α-amylase (α-Amy) and α-glucosidase (α-Gls) plays a central role in attenuation of postprandial hyperglycemia in diabetic patients. In continuation of our previous studies, new derivatives of pyrimidine-fused heterocycle (PFH) compounds were synthesized and their inhibitory activities examined against mouse/yeast α-Gls and pancreatic α-Amy. Since oxidative stress is known as a pathogenic link between hyperglycemia and development of various diabetic complications, in this study, antioxidant activity of the synthetic compounds was assessed. This class of compounds can be synthesized, using a multi-component reaction of barbituric acid, aldehyde and amine in a single-step process. The synthetic procedure provides an easy access to the compounds and also provides the possibility of synthesis a highly diversified chemical bank of PFH derivatives. Comparing the results obtained herein with those in our previous studies, both PFH ring and the substituents on substructures 1 and 3 of the heterocyclic ring play a significant role in the enzyme inhibitory activity of the synthetic compounds. Moreover, it seems that PFH ring plays a central role in low-to-moderate inhibitory properties of these potentially anti-diabetic drugs against α-Amy which is desirable on the basis of their lower susceptibility for possible development of the gastrointestinal side effects. Therefore, considering inhibitory properties of the synthetic compounds against these carbohydrate-hydrolyzing enzymes and simplicity of their preparation procedures, one can synthesis potent and selective enzyme inhibitors by selection of appreciate starting materials in the multi-component reaction.