Design, Synthesis, Molecular Dynamics, and In Vitro Evaluation of Isatin-Based Quinazoline Derivatives as Potential...

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.