Maqbool_2024_Arch.Pharm.(Weinheim)__e2400325

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 alpha-glucosidase, alpha-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 IC(50) values of 1.4+/-0.01 to 13.6+/-0.01 and 0.9+/-0.01 to 12.8+/-0.02microM against alpha-glucosidase, and alpha-amylase enzymes, respectively, compared to the standard acarbose (IC(50)=14.8+/-0.01microM). Compounds 11-13, 16, 20, and 21 exhibited potent activity IC(50)=8.6+/-0.02 to 34.7+/-0.03microM against AChE enzyme, compared to donepezil chloride (IC(50)=39.2+/-0.05microM). Compound 21 demonstrated comparable inhibition IC(50)=45.1+/-0.09microM against BChE, compared to donepezil chloride (IC(50)=44.2+/-0.05microM). 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.