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

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 = 1.1 μmol/g). 5 g exhibited excellent inhibition against α-glucosidase (IC50 = 1.2 μmol/g) when compared with acarbose (IC50 = 4.7 μmol/g) as a positive reference. Compound 5i was found to be most potent derivative against α-BuChE with the IC50 of 1.5 μmol/g which was comparable to the value obtained for (4.7 μmol/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, 5 g and 5i are promising candidates for hitto- lead follow-up in the drug-discovery process for the treatment of Alzheimer's disease and hyperinsulinamia.

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