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

Abstract

A new series of quinoline-based benzenesulfonamides (<b>QBS</b>) were developed as potential carbonic anhydrase inhibitors (CAIs). The target <b>QBS</b> 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 (<b>QBS</b>&nbsp;<b>13a</b>-<b>c</b>); thereafter, the sulphonamide group was switched to <i>ortho</i>- and <i>meta</i>-positions to afford regioisomers <b>9a</b>-<b>d</b> and <b>11a</b>-<b>g</b>. Moreover, a linker elongation approach was adopted where the amino linker was replaced by a hydrazide one to afford <b>QBS</b>&nbsp;<b>16</b>. All the described <b>QBS</b> have been synthesized and investigated for their CA inhibitory action against <i>h</i>CA I, II, IX and XII. In general, <i>para</i>-sulphonamide derivatives <b>13a</b>-<b>c</b> displayed the best inhibitory activity against both cancer-related isoforms <i>h</i>CA IX (<i>K</i>_Is = 25.8, 5.5 and 18.6 nM, respectively) and <i>h</i>CA XII (<i>K</i>_Is = 9.8, 13.2 and 8.7 nM, respectively), beside the excellent <i>h</i>CA IX inhibitory activity exerted by <i>meta</i>-sulphonamide derivative <b>11c</b> (<i>K</i>_I = 8.4 nM). The most promising <b>QBS</b> 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.