Synthesis and biochemical evaluation of triazole/tetrazole-containing sulfonamides against thrombin and related serine proteases

Rogelio Siles, Yuko Kawasaki, Patrick Ross, Ernesto Freire

Research output: Contribution to journalArticlepeer-review

Abstract

A small library of 25 triazole/tetrazole-based sulfonamides have been synthesized and further evaluated for their inhibitory activity against thrombin, trypsin, tryptase and chymase. In general, the triazole-based sulfonamides inhibited thrombin more efficiently than the tetrazole counterparts. Particularly, compound 26 showed strong thrombin inhibition (K i = 880 nM) and significant selectivity against other human related serine proteases like trypsin (K i = 729 μM). Thrombin binding affinity of the same compound was determined by ITC and demonstrated that the binding of this new triazole-based scaffold is enthalpically driven, making it a good candidate for further development.

Original languageEnglish (US)
Pages (from-to)5305-5309
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number18
DOIs
StatePublished - Sep 15 2011

Keywords

  • Isothermal titration calorimetry
  • Sulfonamide synthesis
  • Thrombosis or thrombin inhibition
  • Triazole and tetrazole scaffolds
  • Trypsin selectivity

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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