Development of Novel Quinoline-Based Sulfonamides as Selective Cancer-Associated Carbonic Anhydrase Isoform IX Inhibitors.

A new series of quinoline-based benzenesulfonamides ( QBS ) were developed as potential carbonic anhydrase inhibitors (CAIs). The target QBS CAIs is based on the 4-anilinoquinoline scaffold where the primary sulphonamide functionality was grafted at C4 of the anilino moiety as a zinc anchoring group ( QBS   13a - c ); thereafter, the sulphonamide group was switched to ortho - and meta -positions to afford regioisomers 9a - d and 11a - g . Moreover, a linker elongation approach was adopted where the amino linker was replaced by a hydrazide one to afford QBS   16 . All the described QBS have been synthesized and investigated for their CA inhibitory action against h CA I, II, IX and XII. In general, para -sulphonamide derivatives 13a - c displayed the best inhibitory activity against both cancer-related isoforms h CA IX ( K _I s = 25.8, 5.5 and 18.6 nM, respectively) and h CA XII ( K _I s = 9.8, 13.2 and 8.7 nM, respectively), beside the excellent h CA IX inhibitory activity exerted by meta -sulphonamide derivative 11c ( K _I = 8.4 nM). The most promising QBS were further evaluated for their anticancer and pro-apoptotic activities on two cancer cell lines (MDA-MB-231 and MCF-7). In addition, molecular docking simulation studies were applied to justify the acquired CA inhibitory action of the target QBS.