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

Abstract

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.

GRAPHICAL ABSTRACT

Summary points

• 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.

Keywords: :

• 1,2,4-triazole
• benzenesulfonamide
• cancer
• carbonic anhydrase inhibitors
• cathepsin B inhibitors
• tail-approach

Financial disclosure

Authors A Kumar and P Arya are thankful to the Council of Scientific and Industrial Research, New Delhi, India, for the award of Senior Research Fellowship. The authors are also grateful to DST-FIST for providing financial assistance to set up an NMR instrument in the Department of Chemistry, Kurukshetra University, Kurukshetra, under the FIST program no. SR/FST/CS-I/2017/12(C). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Acknowledgments

The authors are grateful to Central Instrumentation Laboratory, GJUS&T Hisar for providing an HRMS facility.

Additional information

Funding

Authors A Kumar and P Arya are thankful to the Council of Scientific and Industrial Research, New Delhi, India, for the award of Senior Research Fellowship. The authors are also grateful to DST-FIST for providing financial assistance to set up an NMR instrument in the Department of Chemistry, Kurukshetra University, Kurukshetra, under the FIST program no. SR/FST/CS-I/2017/12(C).