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

Rogelio Siles; Yuko Kawasaki; Patrick Ross; Ernesto Freire

doi:10.1016/j.bmcl.2011.07.023

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

Rogelio Siles, Yuko Kawasaki, Patrick Ross, Ernesto Freire

School of Arts and Sciences

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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 language	English (US)
Pages (from-to)	5305-5309
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2011.07.023
State	Published - 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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10.1016/j.bmcl.2011.07.023

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

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.",

keywords = "Isothermal titration calorimetry, Sulfonamide synthesis, Thrombosis or thrombin inhibition, Triazole and tetrazole scaffolds, Trypsin selectivity",

author = "Rogelio Siles and Yuko Kawasaki and Patrick Ross and Ernesto Freire",

note = "Funding Information: This work was supported by grants from the National Institutes of Health ( GM56550 and GM57144 ) and the National Science Foundation ( MCB0641252 ). ",

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AU - Siles, Rogelio

AU - Kawasaki, Yuko

AU - Ross, Patrick

AU - Freire, Ernesto

N1 - Funding Information: This work was supported by grants from the National Institutes of Health ( GM56550 and GM57144 ) and the National Science Foundation ( MCB0641252 ).

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AB - 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.

KW - Isothermal titration calorimetry

KW - Sulfonamide synthesis

KW - Thrombosis or thrombin inhibition

KW - Triazole and tetrazole scaffolds

KW - Trypsin selectivity

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

Abstract

Keywords

ASJC Scopus subject areas

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