Multitargeted inhibition of key enzymes associated with diabetes and Alzheimer's disease by 1,3,4-oxadiazole derivatives: Synthesis, in vitro screening, and computational studies

A library of 22 derivatives of 1,3,4-oxadiazole-2-thiol was synthesized, structurally characterized, and assessed for its potential to inhibit alpha-amylase, alpha-glucosidase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and antioxidant activities. Most of the tested compounds demonstrated good to moderate inhibition potential; however, their activity was lower than that of the standard acarbose. Significantly, compound 3f exhibited the highest inhibition potential against alpha-glucosidase and alpha-amylase enzymes, with IC50 values of 18.52 +/- 0.09 and 20.25 +/- 1.05 mu M, respectively, in comparison to the standard acarbose (12.29 +/- 0.26; 15.98 +/- 0.14 mu M). Compounds also demonstrated varying degrees of inhibitory potential against AChE (IC50 = 9.25 +/- 0.19 to 36.15 +/- 0.12 mu M) and BChE (IC50 = 10.06 +/- 0.43 to 35.13 +/- 0.12 mu M) enzymes compared to the standard donepezil (IC50 = 2.01 +/- 0.12; 3.12 +/- 0.06 mu M), as well as DPPH (IC50 = 20.98 +/- 0.06 to 52.83 +/- 0.12 mu M) and ABTS radical scavenging activities (IC50 = 22.29 +/- 0.18 to 47.98 +/- 0.03 mu M) in comparison to the standard ascorbic acid (IC50 = 18.12 +/- 0.15; 19.19 +/- 0.72). The kinetic investigations have demonstrated that the compounds exhibit competitive-type inhibition for alpha-amylase, noncompetitive-type inhibition for alpha-glucosidase and AChE, and mixed-type inhibition for BChE. Additionally, a molecular docking study was performed on all synthetic oxadiazoles to explore the interaction details of these compounds with the active sites of the enzymes.

Automated summary

A library of 22 derivatives of 1,3,4-oxadiazole-2-thiol was synthesized and evaluated for its inhibitory potential against various enzymes and antioxidant activities. Most of the compounds showed good to moderate inhibition potential, with compound 3f exhibiting the highest inhibition against alpha-glucosidase and alpha-amylase enzymes.