In vitro alpha amylase and protein denaturation inhibitory activity of newer generation Schiff base Oxazolone derivatives: Synthesis, chemical characterization, molecular docking, MD simulation, DFT, ADMET, and bioactivity

Chronic inflammation and diabetes mellitus are closely linked diseases and involved in metabolic dysfunction and disease pathogenesis. So, three new Oxazolone Schiff base derivatives (JS1A, JS2A and JS3A) were synthesized by a multi-step procedure, and then characterized by FTIR, ¹H NMR, ¹³C NMR, mass spectrometry and elemental analysis. A series of synthetic compounds was screened by integrated computational and experimental studies to assess their antidiabetic and anti-inflammatory properties. Molecular docking studies with pancreatic α-amylase (4GQR) and cyclooxygenase-2 (6COX) revealed good binding interactions with the highest docking affinity of JS2A with both targets. Furthermore, the 100 ns molecular dynamics simulations showed that the protein-ligand complexes were stable, especially for JS2A. The synthesized derivatives have been analyzed using frontier molecular orbital and molecular electrostatic potential to identify suitable electronic properties, reactive sites, and interaction potentials. The drug-likeness, pharmacokinetic behavior, and low predicted toxicity were deemed acceptable based on ADMET prediction studies; improvements in solubility and permeability may be needed. All synthesized compounds showed α-amylase inhibitory and protein-denaturation inhibitory activities in vitro in a dose-dependent manner. Among the synthesized compounds, JS2A showed strong in vitro inhibitory activities against α-amylase and protein denaturation. Overall, these results indicate that Schiff base Oxazolone derivatives can be considered as multifunctional scaffolds with prospective antidiabetic and anti-inflammatory properties.