Hydrazinyl arylthiazole based pyridine scaffolds: Synthesis, structural characterization, in vitro α-glucosidase inhibitory activity, and in silico studies

Abstract

Acarbose, miglitol, and voglibose are the inhibitors of α-glucosidase enzyme and being clinically used for the management of type-II diabetes mellitus. However, many adverse effects are also associated with them. So, the development of new therapeutic agents is an utmost interest in medicinal chemistry research. Current study is based on the identification of new α-glucosidase inhibitors. For that purpose, hydrazinyl arylthiazole based pyridine derivatives 1-39 were synthesized via two step reaction and fully characterized by spectroscopic techniques EI-MS, HREI-MS, ¹H-, and ¹³C NMR. However, stereochemistry of the iminic bond was confirmed by NOESY. All compounds were subjected to in vitro α-glucosidase inhibitory activity and found many folds active (IC₅₀ = 1.40 ± 0.01-236.10 ± 2.20 μM) as compared to the standard acarbose having IC₅₀ value of 856.45 ± 5.60 μM. A limited structure-activity relationship was carried out in order to make a presumption about the substituent's effect on inhibitory activity which predicted that substituents of more negative inductive effect played important role in the activity as compared to the substituents of less negative inductive effect. However, in order to have a good understanding of ligand enzyme interactions, molecular docking study was also conducted. In silico study was confirmed that substituents like halogens (Cl) and nitro (NO₂) which have negative inductive effect were found to make important interactions with active site residues.

Keywords: Hydrazinyl arylthiazole; In vitro; Molecular docking; Pyridine; Structure-activity relationship; Synthesis; α-Glucosidase.