Design, synthesis, characterization, molecular docking, MM-GBSA analysis, and molecular dynamics simulation of novel coumarin-hydrazone derivatives as potential carbonic anhydrase inhibitors

Abstract

Tumor-associated carbonic anhydrases (CAs), particularly CA IX and CA XII, are relevant molecular targets because of their role in pH regulation within the tumor microenvironment. In this study, six coumarin-based hydrazide-hydrazone derivatives (AT1–AT6) were designed and synthesized from 6-aminocoumarin through chloroacetamide, ester, and hydrazide intermediates followed by condensation with para -substituted benzaldehydes. The products were obtained in a yield range of 70–95% and characterized by Fourier-transform infrared (FT-IR) and proton nuclear magnetic resonance ( 1 H NMR) spectroscopy. Docking studies were performed against carbonic anhydrase models 2H4N and 7PP9, and the ranking was refined using Prime molecular mechanics/generalized Born surface area (MM-GBSA) analysis. The most favorable MM-GBSA values were observed for AT5 against 2H4N (–46.79 kcal/mol) and AT3 against 7PP9 (–50.56 kcal/mol). QikProp and SwissADME profiling suggested generally acceptable molecular weights, lipophilicity, solubility, and predicted oral absorption. A 200 ns Desmond molecular dynamics simulation of the AT3-2H4N complex showed retention of the modeled binding pose with ligand conformational fluctuations during the trajectory. Overall, these findings identify coumarin-hydrazide-hydrazone derivatives as computationally prioritized scaffolds that require biochemical CA inhibition and cellular validation before any anticancer conclusion can be drawn.