Abstract

The current study outlines the synthesis of 28 new heterocyclic compounds derived from mefenamic acid, as well as an investigation of their therapeutic potential beyond traditional NSAID prescriptions. These derivatives were explored in relation to important health concern such as diabetes, which remains a global concern due to its rising prevalence and associated mortality rates. These newly synthesized derivatives were structurally validated using spectroscopic techniques including 1H-NMR, 13C-NMR, and HRMS (EI) and then biologically studied for in vitro inhibition against yeast α-glucosidase enzyme. Interestingly, in vitro ă–glucosidase inhibitory results indicated that all derivatives displayed potent inhibitory potential when compared to the standard drug acarbose (IC50 375.82 ± 1.76 µM). The most active derivatives throughout the series were 6b (IC50 9.7 ± 1.21 µM), 4f (IC50 38.8 ± 2.11 µM) 4e (IC50 54.2 ± 3.12 µM) and 8j (IC50 54.4 ± 1.21µM) with significant inhibitory activity against α-glucosidase. Limited SAR studies indicated that the inhibitory potential of these derivatives is varied according to various substituents on the benzene and azole rings. In silico studies have also supported the in vitro findings about search for inhibitors of the aforementioned enzyme, providing insight into the binding interactions of the majority of active compounds with the active site of α-glucosidase enzyme. The findings of this study may pave the way for the development of more effective and selective α-glucosidase inhibitors, thereby advancing the field of antidiabetic drug discovery while also uncovering new facets of mefenamic acid's pharmacological versatility.