Structure-guided design of COX-2-based sulfonamides as carbonic anhydrase II inhibitors: an integrated docking, ADMET, and DFT study

Carbonic anhydrases (CAs) are zinc containing metalloenzymes distributed in human tissues, regulating ion and pH cellular homeostasis. 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 CA II inhibitors discovery. In this work, new non-heterocyclic imine compounds with sulfonamide groups that were specially designed to inhibit CA II. Based on structure-activity relationship (SAR) insights, 12 novel non-heterocyclic imine derivatives were designed by incorporating sulfonamide moieties and aromatic rings to enhance CA II binding affinity and inhibitory activity. In silico molecular analysis were performed for designed compounds with ADMET analysis. Furthermore, to evaluate molecular stability and reactivity, frontier molecular orbitals and chemical reactivity descriptors were analyzed using Density Functional Theory (DFT) computations. 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 possible reactivity and binding efficiency by revealing favorable HOMO-LUMO energy gaps and high electrophilicity indices. The designed screened imine-sulphonamide derivatives showed promising computational profiles warranting experimental validation as potential CA II inhibitors. These findings need further in vivo validation and toxicity studies. This work contributes to the advancement of targeted therapies for CA-related disorders.