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

Background: 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. Methodology & Results: 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 in vitro results were also supported by the molecular modeling studies. Conclusion: 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 in vitro as human carbonic anhydrase (hCA) I, II, IX and XII inhibitors and assayed in vitro as well as in silico 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.