Pharmacophore-guided computational profiling of thiadiazole-based therapeutic addressing flap necrosis: Molecular simulation, DFT mapping, pharmacokinetic and kinetic evaluation.

Flap necrosis is a major complication in reconstructive surgery, mainly caused by reduced blood supply leading to partial or complete tissue damage. In this study, a new series of N-(5-(1-hydroxyethyl)-1,3,4-thiadiazol-2-yl) aryl sulfonamide derivatives was designed, synthesized, and evaluated for anti-necrotic activity. The compounds showed significant inhibition at 10, 25, and 50 µM, with compound 4 exhibiting the highest activity (89.7%, 92.1%, and 96.8%), outperforming the standard antioxidant, ascorbic acid (79.4%, 84.2%, and 87.3%). Molecular docking studies indicated strong binding interactions within the target protein through hydrogen bonding and hydrophobic contacts. Molecular dynamics simulations confirmed the stability of these interactions over time. DFT analysis provided insights into electronic properties, while ADMET profiling suggested favorable pharmacokinetic and safety characteristics. Enzyme kinetics clarified the inhibition mechanism, and pharmacophore modeling identified key features responsible for activity. Overall, compound 4 emerges as a promising candidate for further development as an anti-necrosis agent.