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.
authors.affiliation: Department of Biology, The Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Rogelio
authors.initials: R
authors.lastname: Siles
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kawasaki
authors.forename: Patrick
authors.initials: P
authors.lastname: Ross
authors.forename: Ernesto
authors.initials: E
authors.lastname: Freire
mesh_terms: D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D015394:Molecular Structure; D057057:Serine Proteases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013777:Tetrazoles / Q000737:chemistry*; D013816:Thermodynamics; D014230:Triazoles / Q000737:chemistry*
chemical_list: D015842:Serine Proteinase Inhibitors; D054852:Small Molecule Libraries; D013449:Sulfonamides; D013777:Tetrazoles; D014230:Triazoles; D057057:Serine Proteases