Novel 1,2,4-triazoles as selective carbonic anhydrase inhibitors showing ancillary anticathepsin B activity

<b>Background:</b> Exploration of the multi-target approach considering both human carbonic anhydrase (hCA) IX and XII and cathepsin B is a promising strategy to target cancer. <b>Methodology &amp; Results:</b> 22 novel 1,2,4-triazole derivatives were synthesized and evaluated for their inhibition efficacy against hCA I, II, IX, XII isoforms and cathepsin B. The compounds demonstrated effective inhibition against hCA IX and/or XII isoforms with considerable selectivity over off-target hCA I/II. All compounds presented significant anticathepsin B activities at a low concentration of 10^-7 M and <i>in vitro</i> results were also supported by the molecular modeling studies. <b>Conclusion:</b> Insights of present study can be utilized in the rational design of effective and selective hCA IX and XII inhibitors capable of inhibiting cathepsin B. This research comprises tail-approach synthesis and characterization of a library of 22 novel 1,2,4-triazoles. All novel compounds were evaluated <i>in vitro</i> as human carbonic anhydrase (hCA) I, II, IX and XII inhibitors and assayed <i>in vitro</i> as well as <i>in silico</i> for their inhibition potential against cathepsin B. The compounds showed poor inhibition against hCA I and effective inhibition against tumor-associated isoforms hCA IX and XII. Many compounds demonstrated selective inhibition toward hCA IX and/or XII isoforms over the off-targets hCA I and/or II isoforms. All compounds presented significant anticathepsin B activities at a low concentration of 10^-7 M.