Development of 4-((3-oxo-3-phenylpropyl)amino)benzenesulfonamide derivatives utilizing tail/dual-tail approaches as novel carbonic anhydrase inhibitors

In the current work, we adopted the tail/dual tail approaches to design and synthesize the benzenesulfonamide derivatives 6a-b, 8, 10a-b, 12a-b, 14, and 16 as new SLC-0111 analogs endowed with carbonic anhydrase (CA) inhibitory activity. All the prepared benzenesulfonamide derivatives were tested for their inhibitory action towards hCA isoforms; hCA I, II, IX, and XII. The results revealed their ability to affect the examined isoforms in variable degrees with KI ranges: 49.3–6459 nM for CA I, 5.1–4171 nM for CA II, 9.4–945.1 nM for CA IX, and 5.2–1159 nM for CA XII. As expected, appending a second hydrophilic tail (ethanolamine) in compound 16 significantly enhanced the inhibitory activities towards hCA IX and hCA XII isoforms by about 5-fold in comparison to its single tail analogue 6c (KI = 51.5 and 28.2 nM for 6c vs. 10.2 and 5.2 nM for 16, respectively). Moreover, SAR analysis pointed out the significance of grafting the sulfamoyl functionality at para-position, as well as the incorporation of a bulky hydrophobic tail for CA inhibitory activity. The most potent hCA IX inhibitors (6f and 16) displayed efficient cell growth inhibitory activity against breast cancer cell lines; T-47D (IC50 = 19 and 10.9 μM, respectively) and MCF-7 (IC50 = 7.5 and 5.7 μM, respectively).