Design, Nonlinear Optical Response, And Molecular Docking Of Donor–π–Acceptor Benzenesulfonamide–Benzothiazole Hybrids As Potential Carbonic Anhydrase Ix-Targeted Anticancer Agents

Abstract

Tumor hypoxia is a hallmark of solid malignancies, driving metabolic reprogramming, extracellular acidification, invasion, therapeutic resistance, and poor clinical prognosis. Carbonic anhydrase IX (CA IX), a hypoxia-inducible zinc metalloenzyme localized on the tumor cell surface, plays a pivotal role in regulating tumor pH homeostasis and has therefore emerged as a promising target for anticancer therapy and imaging. In parallel, benzothiazole scaffolds are well-established privileged structures in anticancer drug discovery, while sulfonamide-based compounds remain dominant inhibitors of carbonic anhydrases due to their strong affinity for the catalytic zinc ion. Donor–π–acceptor (D–π–A) systems further offer enhanced intramolecular charge transfer properties, contributing to improved nonlinear optical (NLO) responses and functional versatility.In this study, a computational medicinal chemistry approach was employed to design and evaluate benzenesulfonamide–benzothiazole hybrids incorporating a D–π–A framework, using 6-hydroxy-1,3-benzothiazole-2-sulfonamide as a lead motif against human CA IX (PDB ID: 6FE2). A comprehensive workflow integrating Avogadro, Open Babel, ORCA, Multiwfn, AutoDockTools, AutoDock Vina, SwissADME, and pkCSM was utilized for geometry optimization, electronic property analysis, molecular docking, and pharmacokinetic prediction. Structural examination of the 6FE2 crystal structure confirmed the presence of the catalytic zinc ion without a co-crystallized inhibitor, necessitating an active-site-directed docking strategy.Key electronic descriptors, including frontier molecular orbitals, dipole moment, polarizability, and first hyperpolarizability, were calculated to assess NLO behavior and correlated with binding affinity and molecular recognition. The findings highlight the dual potential of these hybrids as CA IX-targeted anticancer agents and promising NLO materials, offering valuable insights for future rational drug design.