Design, DFT, molecular Docking and ADMET evaluation of novel imine-sulphonamide analogues as carbonic anhydrase II inhibitors

Purpose: Carbonic anhydrases (CAs) are zinc containing metalloenzymes distributed in human tissues, helps to regulate ion and pH cellular homeostasis. Statement of Problem : Discovery of carbonic anhydrase II (CA II) inhibitor is essential to minimize off-target effects and related complications including oxidative stress, cancer, glaucoma, and obesity. However, current therapeutic efficacy and safety profiles are still below ideal, which leads to more potent and specific CA II inhibitors discovery. In this work, new non-heterocyclic imine compounds with sulfonamide groups that were specially designed to inhibit CA II are designed. Methods: Based on structure-activity relationship (SAR) insights, twelve novel non-heterocyclic imine derivatives were designed by incorporating sulfonamide moieties and aromatic rings to enhance CA II binding affinity and inhibitory activity. Molegro Virtual Docker, SwissADME were utilized computational analysis. Furthermore, to evaluate molecular stability and reactivity, frontier molecular orbitals and chemical reactivity descriptors were analyzed using Density Functional Theory (DFT) computations. Result: Docking scores demonstrated significant binding affinities for compounds C-1, C-2, C-4, E-1, E-2, E-4, P-1, P-2, and P-4 (scores ranging from − 63.58 to -73.23). ADMET analysis confirmed favorable drug-likeness, with compounds C-2, C-4, E-2, E-4, P-2, and P-4 exhibiting good oral bioavailability and minimal toxicity.DFT study supported the compounds' possible reactivity and binding efficiency by revealing favorable HOMO-LUMO energy gaps and high electrophilicity indices. Conclusion: The designed imine sulphonamido derivatives showed promising potential as safe CA II inhibitors in silico. These findings permit further in vivo validation and toxicity studies. This work contributes in the advancement of targeted therapies for CA-related disorders.