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  3. Triazinyl-benzenesulfonamide derivatives as hCA IX inhibitors: Design, synthesis, and activity determination using an optimized stop-flow methodology

Triazinyl-benzenesulfonamide derivatives as hCA IX inhibitors: Design, synthesis, and activity determination using an optimized stop-flow methodology

  • Bioorg Chem. 2026 Mar:170:109524. doi: 10.1016/j.bioorg.2026.109524.
Vojtech Varecka 1,  Karolina Seligova 2,  Alena Hofrova 3,  Karin Ravaszova 1,  Petr Mokry 2,  Miroslava Bittova 1,  Jozef Hritz 4,  Eva Havrankova 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Faculty of Science, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic.
  • 2 Department of Chemical Drugs, Faculty of Pharmacy, Masaryk University of Brno, Palackeho trida 1946/1, 612 00 Brno, Czech Republic.
  • 3 Department of Chemistry, Faculty of Science, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic; National Centre for Biomolecular Research (NCBR), Faculty of Science, Masaryk University, Kotlarska 2, 61137 Brno, Czech Republic; Central European Institute of Technology (CEITEC), Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic.
  • 4 Department of Chemistry, Faculty of Science, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic; National Centre for Biomolecular Research (NCBR), Faculty of Science, Masaryk University, Kotlarska 2, 61137 Brno, Czech Republic; Central European Institute of Technology (CEITEC), Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. Electronic address: jozef.hritz@ceitec.muni.cz.
  • 5 Department of Chemical Drugs, Faculty of Pharmacy, Masaryk University of Brno, Palackeho trida 1946/1, 612 00 Brno, Czech Republic. Electronic address: havrankovae@pharm.muni.cz.
PMID: 41592468 DOI: 10.1016/j.bioorg.2026.109524
Abstract

This study presents the design, synthesis, and biological evaluation of a new series of 1,3,5-triazinyl benzenesulfonamide derivatives incorporating substituted piperazines, aminobenzenes, or adamantane moieties. The compounds were tested for inhibitory activity against human Carbonic Anhydrase isoenzymes II and IX, aiming for selectivity towards the latter, Cancer associated isoenzyme IX, on the basis of an initial molecular docking screening. Several compounds showed inhibitory activity and selectivity exceeding that of the clinical benchmark acetazolamide. Among the most effective compounds were derivatives 9 (KI = 7.4 nM, selectivity ratio = 3.4) and 38 (KI = 9.4 nM, selectivity ratio = 3.9). This activity trend was related to structural rigidity and hydrophobicity based on structure-activity analysis and molecular docking. The compound's inhibition constants were determined using stopped-flow spectrophotometry in an updated approach, which enables accurate KI determination with higher throughput. The methodology framework is described in detail to facilitate reproducibility in the field.

Keywords

1,3,5-Triazine; Aromatic substitution; Benzenesulfonamide; Carbonic anhydrase; Enzyme inhibition; Isozyme selectivity; Stopped-flow spectrophotometry.

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