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

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

Access to Document

10.1016/j.bmcl.2011.07.023

Fingerprint Dive into the research topics of 'Synthesis and biochemical evaluation of triazole/tetrazole-containing sulfonamides against thrombin and related serine proteases'. Together they form a unique fingerprint.

Cite this

@article{c136b2ec58854daeb75c3da7fd68f4f5,

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",

year = "2011",

month = sep,

day = "15",

doi = "10.1016/j.bmcl.2011.07.023",

language = "English (US)",

volume = "21",

pages = "5305--5309",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Limited",

number = "18",

}

TY - JOUR

T1 - Synthesis and biochemical evaluation of triazole/tetrazole-containing sulfonamides against thrombin and related serine proteases

AU - Siles, Rogelio

AU - Kawasaki, Yuko

AU - Ross, Patrick

AU - Freire, Ernesto

PY - 2011/9/15

Y1 - 2011/9/15

N2 - 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.

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

UR - http://www.scopus.com/inward/record.url?scp=80051918474&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80051918474&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2011.07.023

DO - 10.1016/j.bmcl.2011.07.023

M3 - Article

C2 - 21807511

AN - SCOPUS:80051918474

VL - 21

SP - 5305

EP - 5309

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 18

ER -