Insights into the inhibitory potential of novel hydrazinyl thiazole-linked indenoquinoxaline against alpha-amylase: a comprehensive QSAR, pharmacokinetic, and molecular modeling study

Abstract

The rising prevalence of diabetes necessitates the development of novel drugs, especially given the side effects associated with current medications like Acarbose and Voglibose. A series of 36 Hydrazinyl thiazole-linked indenoquinoxaline derivatives with notable activity against alpha-amylase were studied. To create a molecular model predicting alpha-amylase activity, a QSAR study was performed on these compounds. Molecular descriptors were calculated using Chem3D and Gaussian software and then correlated with their IC₅₀ biological activities to form a dataset. This model data was refined using PCA and modeled with MLR. The model's performance was statistically verified (R² =0.800; $R_{\text{adj}}^2$ = 0.767; $R_{\text{cv}}^2$ = 0.651) and its applicability domain was defined. It was predicted to possess high predictive power ($R_{\text{test}}^2$ = 0.872). Based on this, new compounds were proposed, and their activities were predicted using the developed model. Additionally, their binding ability to the biological target was studied through molecular docking and dynamics. Their pharmacokinetics were also evaluated using ADMET predictions. Two designed compounds named AE and AB emerged as particularly promising, displaying properties that suggest substantial therapeutic potential and they can form stable complexes into the binding pocket of alpha-amylase enzyme.Communicated by Ramaswamy H. Sarma.

Keywords: Diabetes mellitus; QSAR; alpha-amylase; docking; molecular dynamics.