2. Academic Validation
  3. 1,2,3-Triazole-based esters and carboxylic acids as nonclassical carbonic anhydrase inhibitors capable of cathepsin B inhibition

1,2,3-Triazole-based esters and carboxylic acids as nonclassical carbonic anhydrase inhibitors capable of cathepsin B inhibition

  • Arch Pharm (Weinheim). 2024 Mar;357(3):e2300372. doi: 10.1002/ardp.202300372.
Kiran Siwach 1,  Manishita Rani 1,  Lalit Vats 1 2,  Simone Giovannuzzi 3,  Avijit Kumar Paul 4,  Mettle Brahma 5,  Neetu Kumari 5,  Mulaka Maruthi 5,  Neera Raghav 1,  Claudiu T Supuran 3,  Pawan K Sharma 1 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Kurukshetra University, Kurukshetra, Haryana, India.
  • 2 Department of Chemistry, Government College Bherian, Pehowa, Kurukshetra, Haryana, India.
  • 3 Neurofarba Department, Pharmaceutical and Nutraceutical Section, University of Florence, Florence, Italy.
  • 4 Department of Chemistry, National Institute of Technology, Kurukshetra, Haryana, India.
  • 5 Department of Biochemistry, Central University of Haryana, Mahendergarh, India.
  • 6 Department of Chemistry, Central University of Haryana, Mahendergarh, India.
PMID: 38012535 DOI: 10.1002/ardp.202300372
Abstract

Herein, we report the design and synthesis of a library of 28 new 1,2,3-triazole derivatives bearing carboxylic acid and ester moieties as dual inhibitors of Carbonic Anhydrase (CA) and Cathepsin B enzymes. The synthesised compounds were assayed in vitro for their inhibition potential against four human CA (hCA) isoforms, I, II, IX and XII. The carboxylic acid derivatives displayed low micromolar inhibition against hCA II, IX and XII in contrast to the ester derivatives. Most of the target compounds showed poor inhibition against the hCA I isoform. 4-Fluorophenyl appended carboxylic acid derivative 6c was found to be the most potent inhibitor of hCA IX and hCA XII with a KI value of 0.7 μM for both the isoforms. The newly synthesised compounds showed dual inhibition towards CA as well as Cathepsin B. The ester derivatives exhibited higher % inhibition at 10-7 M concentration as compared with the corresponding carboxylic acid derivatives against Cathepsin B. The results from in silico studies of the target compounds with the active site of Cathepsin B were found in good correlation with the in vitro results. Moreover, two compounds, 5i and 6c, showed cytotoxic activity against A549 lung Cancer cells, with IC50 values lower than 100 μM.

Keywords

1,2,3-triazoles; cathepsin B inhibitors; nonclassical carbonic anhydrase inhibitors.

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