Design and synthesis of benzothiazole-based SLC-0111 analogues as new inhibitors for the cancer-associated carbonic anhydrase isoforms IX and XII

Abstract

In this work, different series of benzothiazole-based sulphonamides <b>8a-c, 10, 12, 16a-b</b> and carboxylic acids <b>14a-c</b> were developed as novel SLC-0111 analogues with the goal of generating potent carbonic anhydrase (CA) inhibitors. The adopted strategy involved replacing the 4-fluorophenyl tail in SLC-0111 with a benzothiazole motif that attached to the ureido linker to produce compounds <b>8c</b> and its regioisomers <b>8a-b</b>. In addition, the ureido spacer was elongated by methylene or ethylene groups to afford the counterparts <b>10</b> and <b>12</b>. In turn, the primary sulfamoyl zinc binding group (ZBG) was either substituted or replaced by carboxylic acid functionality in order to provide the secondary sulphonamide-based SLC-0111 analogues <b>16a-b</b>, and the carboxylic acid derivatives <b>14a-c</b>, respectively. All compounds (<b>8a-c, 10, 12, 14a-c</b> and <b>16a-b</b>) were tested for their ability to inhibit CA isoforms CA I, II, IX and XII. Additionally, the <i>in vitro</i> anticancer properties of the developed CAIs were evaluated.