ABSTRACT
A library of imidazole-thiadiazole compounds (1-24) was synthesized to explore their therapeutic applications. The compounds were subjected to meticulous in vitro evaluation against α-glucosidase, α-amylase, acetylcholinesterase (AChE), and butylcholinesterase (BChE) enzymes. Compounds were also investigated for antioxidant activities using cupric reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays. Derivatives 5-7, 9-11, 18, and 19 displayed potent inhibitory activities with IC50 values of 1.4 ± 0.01 to 13.6 ± 0.01 and 0.9 ± 0.01 to 12.8 ± 0.02 µM against α-glucosidase, and α-amylase enzymes, respectively, compared to the standard acarbose (IC50 = 14.8 ± 0.01 µM). Compounds 11-13, 16, 20, and 21 exhibited potent activity IC50 = 8.6 ± 0.02 to 34.7 ± 0.03 µM against AChE enzyme, compared to donepezil chloride (IC50 = 39.2 ± 0.05 µM). Compound 21 demonstrated comparable inhibition IC50 = 45.1 ± 0.09 µM against BChE, compared to donepezil chloride (IC50 = 44.2 ± 0.05 µM). All compounds also demonstrated excellent antioxidant activities via CUPRAC, FRAP, and DPPH methods. Complementing the experimental studies, extensive kinetics, ADME/T, and molecular docking analysis were also conducted to unravel the pharmacokinetics and safety profiles of the designed compounds. These studies supported the experimental findings and facilitated the prioritization of hit candidates for subsequent stages of drug development.
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.
