Work

Development of thiazole-based α-amylase inhibitors: synthesis, in vitro evaluation, and computational insights via DFT and molecular docking

Year: 2026

Type: article

Abstract: In this research, a new series of thiazole-based hydrazone derivatives (9–14) was designed, synthesized, and evaluated for α-amylase inhibitory activity as a strategy to manage postprandial hyperglycemia in type 2 diabetes (T2DM). The target compounds were obtained via a two-step procedure: condensation of thiosemicarbazide with substituted aromatic aldehydes to form hydrazones, followed by cyclization with phenacyl bromide. All derivatives exhibited potent inhibition against porcine pancreatic α-amylase, with IC 50 ranging from 1.04 ± 0.08 µM to 4.47 ± 0.08 µM, outperforming the clinical standard acarbose (IC 50 = 4.30 ± 0.04 µM) in most cases. Compound 10 , bearing an ortho -nitro substituent, was the most active (IC 50 = 1.04 µM), while the dimethoxy analogue 14 showed the weakest activity. Structure–activity relationship (SAR) analysis indicated that electron-withdrawing groups (-NO 2 , -Cl) enhance inhibition, whereas electron-donating groups (-OCH 3 ) are detrimental. Density functional theory (DFT) calculations at the B3PW91/D3/6 31G** level revealed that the high potency of 10 correlates with the highest electrophilicity index (ω = 4.04 eV) and the most negative chemical potential (μ = –3.816 eV). Molecular docking against human pancreatic α-amylase (PDB ID: 3BAJ) demonstrated that compound 10 establishes favorable binding interactions through hydrogen bonds with Asp197 and Tyr62, and electrostatic contacts with Glu233. The combined experimental and computational approach identifies the ortho -nitro-substituted thiazole scaffold as a promising preliminary hit for further development as α-amylase inhibitors.

Source: Scientific Reports

DOI: 10.1038/s41598-026-77430-8