From sensors to silencers: quinoline- and benzimidazole-sulfonamides as inhibitors for zinc proteases.
Derived from the extensive work in the area of small molecule zinc(II) ion sensors, chelating fragment libraries of quinoline- and benzimidazole-sulfonamides have been prepared and screened against several different zinc(II)-dependent matrix metalloproteinases (MMPs). The fragments show impressive inhibition of these metalloenzymes and preferences for different MMPs based on the nature of the chelating group. The findings show that focused chelator libraries are a powerful strategy for the discovery of lead fragments for metalloprotein inhibition.
Rouffet
Matthieu
M
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA.
de Oliveira
César Augusto F
CA
Udi
Yael
Y
Agrawal
Arpita
A
Sagi
Irit
I
McCammon
J Andrew
JA
Cohen
Seth M
SM
D001562:Benzimidazoles / Q000737:chemistry*; D055808:Drug Discovery; D020128:Inhibitory Concentration 50; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*; D015032:Zinc / Q000378:metabolism
D001562:Benzimidazoles; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011804:Quinolines; D013449:Sulfonamides; C031000:benzimidazole; C037219:quinoline; D020782:Matrix Metalloproteinases; D015032:Zinc