Synthesis of 2-Phenylisothiazol-3(2H)-One 1,1-Dioxides: Inhibitors of Human Leukocyte Elastase

Abstract

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.

Reaction kinetic monitoring by high performance liquid chromatography coupled to mass spectrometry: Oxidation processes of selected isothiazoles

“…Furthermore several compounds possess an antidepressive as well as anxiolytic effect [6] or could inhibit the human leukocyte elastase (HLE) [7 10]. Against this background, a series of new isothiazol-3(2H)-one 1,1-dioxides were synthesized by Schulze et al and investigated due to their inhibition effects [11 ].…”

Aniline Exchange of 2-Aryl-4,5-diphenyl-substituted Isothiazolium Salts

“…Therefore, the acceptor-substituted salts 4a [14], b [15] and 4d [16] (R 1 ) were reacted with donorsubstituted anilines 2f, g, i in alcohol (Table 1). Not surprisingly, the salts 4a, b, c (R 1 ) were converted by exchange of aniline to isothiazolium salts 4f, g and 4i [17] (R 2 ) in good yields (55 -73 %).…”

“…Further, we studied the reaction of acceptorsubstituted salts 4a [14], b [15], c, d [16], e with the unsubstituted aniline 2h (R 2 = H). The results are presented in Table 2.…”

“…Compounds 4a [14], 4b [15], 4d [16], 4h [17] and 4i [17] have been described elsewhere. CCDC 678529 contains the supplementary crystallographic data for this paper.…”

Sultam and Sultim Structures, Part 5 [1]. Weak Hydrogen Bonds in Molecular Networks of 2-Hetaryl-3-oxosultams in Comparison with 2-Aryl-3-oxosultams

“…Monocyclic 2,4,5-triarylsubstituted isothiazol-3-(2H)-one 1,1-dioxides, which are synthesized by oxidation of the corresponding isothiazolium salts [6], cause inhibition of the human leukocyte elastase (HLE) [7,8]. Recently we reported the crystal structures of 3-hydroxy-, 3-hydroperoxyand 3-oxo-sultims and -sultams [9,10].…”