Exploring the potential of new mefenamic acid derivatives as α-glucosidase inhibitors: Structure-activity relationship, in-vitro and in-silico studies

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 1 H NMR, 13 C NMR, and HRMS (EI) and then biologically studied for in vitro inhibition against yeast α-glucosidase enzyme. Interestingly, in vitro α–glucosidase inhibitory results indicated that all derivatives displayed potent inhibitory potential when compared to the standard drug acarbose (IC 50 375.82 ± 1.76 µM). The most active derivatives throughout the series were 6b (IC 50 9.7 ± 1.21 µM), 4f (IC 50 38.8 ± 2.11 µM) 4e (IC 50 54.2 ± 3.12 µM) and 8j (IC 50 54.4 ± 1.21 µM) 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.