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

Abstract

A library of 22 derivatives of 1,3,4‐oxadiazole‐2‐thiol was synthesized, structurally characterized, and assessed for its potential to inhibit α‐amylase, α‐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 α‐glucosidase and α‐amylase enzymes, with IC50 values of 18.52 ± 0.09 and 20.25 ± 1.05 µM, respectively, in comparison to the standard acarbose (12.29 ± 0.26; 15.98 ± 0.14 µM). Compounds also demonstrated varying degrees of inhibitory potential against AChE (IC50 = 9.25 ± 0.19 to 36.15 ± 0.12 µM) and BChE (IC50 = 10.06 ± 0.43 to 35.13 ± 0.12 µM) enzymes compared to the standard donepezil (IC50 = 2.01 ± 0.12; 3.12 ± 0.06 µM), as well as DPPH (IC50 = 20.98 ± 0.06 to 52.83 ± 0.12 µM) and ABTS radical scavenging activities (IC50 = 22.29 ± 0.18 to 47.98 ± 0.03 µM) 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 α‐amylase, noncompetitive‐type inhibition for α‐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.

4‐Furfuryloxymethyl‐1,2,3‐triazol‐1‐yl‐acetohydrazide Hybrids as Cholinesterase and Carbonic Anhydrase Inhibitors: Synthesis, Characterization and Comprehensive Biological Activity Studies

“…[26][27][28] Therefore, the current efforts are to find new cholinesterase inhibitors for more effective AD treatment. [29] Carbonic anhydrase I and II are two isoforms of the enzyme carbonic anhydrase. Both CA I and CA II are zinc-containing metalloenzymes, and their activity is crucial for maintaining proper physiological pH levels and efficient transport of carbon dioxide within the body.…”

“…Accordingly, inhibiting these cholinesterases can play a key role in the treatment of AD by blocking ACh hydrolysis [26–28] . Therefore, the current efforts are to find new cholinesterase inhibitors for more effective AD treatment [29] …”