Design and synthesis of 2,6-di(substituted phenyl)thiazolo[3,2-b]-1,2,4-triazoles as α-glucosidase and α-amylase inhibitors, co-relative Pharmacokinetics and 3D QSAR and risk analysis

Abstract

Ten fused heterocyclic derivatives bearing the 2,6-di(subsituted phenyl)thiazolo[3,2-b]-1,2,4-triazoles as central rings were synthesized and structures of the compounds were established by analytical and spectral data using FTIR, EI-MS, ¹H NMR and ¹³C NMR techniques. In vitro inhibitory activities of synthesized compounds on α-amylase, α-glucosidase and α-burylcholinesterase (α-BuChE) were evaluated using a purified enzyme assays. Compound 5c demonstrated strong and selective α-amylase inhibitory activity (IC₅₀=1.1μmol/g). 5g exhibited excellent inhibition against α-glucosidase (IC₅₀=1.2μmol/g) when compared with acarbose (IC₅₀=4.7μmol/g) as a positive reference. Compound 5i was found to be most potent derivative against α-BuChE with the IC₅₀ of 1.5μmol/g which was comparable to the value obtained for (4.7μmol/g) positive control (i.e. galantamine hydrobromide). Molecular dockings of synthesized compounds into the binding sites of human pancreatic α-amylase, intestinal maltase-glucoamylase and neuronal α-butrylcholinesterase allowed to shed light on the affinity and binding mode of these novel inhibitors. Preliminary structure-activity relationship (SAR) studies were carried out to understand the relationship between molecular structural features and inhibition activities of synthesized derivatives. These data suggested that compounds 5c, 5g and 5i are promising candidates for hitto- lead follow-up in the drug-discovery process for the treatment of Alzheimer's disease and hyperinsulinamia.

Keywords: 3D QSAR; Anti-diabetic; Butyrylcholinesterase; Pharmacokinetics; Risk analysis; Thiazole; Triazolo; α-Glucosidase and α-amylase inhibitors.