Novel hit of DPP-4Is as promising antihyperglycemic agents with dual antioxidant/anti-inflammatory effects for type 2 diabetes with/without COVID-19

•Novel pyrimidinone and thio-pyrimidinone derivatives were synthesized and screened for their antidiabetic and DPP-4 inhibition potential.•Most of the synthesized compound showed antihyperglycemic activity.•Five derivatives showed antidiabetic efficacy with plasma DPP-4 reducing effect.•The active derivatives were evaluated for their antioxidant and anti-inflammatory activities.•8b offered the highest activity as DPP-4I, with promising anti-inflammatory/antioxidant effects and may be able to mitigate COVID-19 in type 2 diabetic patients. DPP-4Is are well recognized therapy for type 2 diabetes. In spite of sharing a common mode of action, the chemical diversity among members of DPP‐4Is raised the question whether structural differences may result in distinguished activities. DPP-4Is were recently explored as drug repurposing means for treatment of SARS-CoV-2 due to the urgent need for small molecule drugs for controlling infections. The use of DPP-4Is was not correlated with adverse COVID-19-related consequences among patients with type 2 diabetes. Inspired by these reasons and the importance of pyrimidinone ring as DPP-4I with both antioxidant and anti-inflammatory activities, we succeeded to prepare some novel pyrimidinone and thio-pyrimidinone derivatives, which were then screened for their antidiabetic activity and DPP-4 inhibition. In addition, their anti‐inflammatory effect on LPS-stimulated RAW 264.7 cells were evaluated. Furthermore, their antioxidant activities were also tested.