Design, Synthesis, Molecular Dynamics, and In Vitro Evaluation of Isatin‐Based Quinazoline Derivatives as Potential Antidiabetic Agents

Abstract

A series of substituted indolo[2,1‐b]quinazoline‐6,12‐diones (SJ1‐SJ8), which consist of already published derivatives (SJ1‐SJ5) and newly synthesized derivatives (SJ6‐SJ8), has been studied for their possible α‐amylase inhibition property as an antidiabetic lead compound. The synthesized derivatives have been identified by spectroscopy and analysis methods and tested for their in vitro α‐amylase inhibitory activity. The most potent inhibitory activity among the tested derivatives was showed by SJ2 (IC50 = 18.49 ± 0.06 µM), similar to the reference drug acarbose (IC50 = 16.26 ± 0.02 µM). The second‐best activity was observed for the newly identified derivative SJ8 (IC50 = 19.67 ± 0.19 µM). Molecular docking and 100 ns molecular dynamics simulations supported favorable and stable interactions of SJ2 in the α‐amylase active site, while MM‐PBSA analysis showed favorable binding energetics. The electronic properties of SJ2 were also clarified by DFT and molecular electrostatic potential analyzes, and in silico ADMET profiling indicated promising predicted drug‐like and pharmacokinetic properties. To summarize, SJ2 is a promising lead for α‐amylase inhibition, which needs further optimization and biological validation. Future evaluation against α‐glucosidase and relevant in vivo models will be essential to determine the more general antidiabetic potential of this scaffold.