Synthesis of 2-phenylisothiazol-3(2H)-one 1,1-dioxides: Inhibitors of human leukocyte elastase

A series of 2-phenylisothiazol-3(2H)-one 1,1-dioxides 14a-q were synthesized by oxidation of isothiazolium perchlorates 12. The inhibition of the serine proteases cathepsin G, chymotrypsin and human leukocyte elastase (HLE) by 14 was investigated. Some 4,5-diphenyl substituted derivatives (14i-k) were found to inhibit HLE in a time-dependent manner and exhibited kobs/[I] values > 500 M-1s-1. 14k (kobs/[I] = 2400 M-1s-1), was the most potent HLE inhibitor of this series. Kinetic investigations led to the conclusion that 2-phenylisothiazol-3(2H)-one 1,1-dioxides interact with HLE at the active site as well as at another binding site, resulting in a complex type of inhibition.