Exploring the Carbonic Anhydrase II Inhibition, Molecular Docking and DFT Analysis of <i>Bis</i> ‐Schiff Bases of 4‐Nitroacetophenone

Abstract This study presents the carbonic anhydrase II (CA II) inhibition and computational studies of azines bearing 4‐nitroacetophenone. Amongst them, four compounds 2o, 2a, 2j and 2 g demonstrated excellent inhibitory potential with IC50 values (IC50 = 4.35 ± 0.35 µM) to (IC50 = 12.63 ± 0.66 µM), while the remaining derivatives exhibited good to less inhibition. The frontier molecular orbital (FMO) analysis was determined by Density Functional Theory (DFT) calculations provides significant insights into their chemical properties and interactions. The high energy gap values for 2o and 2a correlate with CA II inhibitory activity, suggesting a strong interaction between the inhibitor and enzyme. The molecular docking, molecular electrostatic potential (MEP), and molecular dynamic (MD) analyses underscore the importance of the nitro group's high negative potential in targeting the catalytic zinc metal ion in CA II. This interaction is crucial for the formation of a tetrahedral geometry around the zinc ion, involving histidine residues like His119, which is essential for the correct orientation. The comparative analysis reveals that active compounds exhibit superior physicochemical and ADMET profiles compared to acetazolamide. Their high GI absorption, moderate BBB permeability, and favorable toxicity profiles make them promising candidates for further development as CA II inhibitors.