Protease inhibitors - Part 5. Alkyl/arylsulfonyl- and arylsulfonylureido-/arylureido- glycine hydroxamate inhibitors of Clostridium histolyticum collagenase

Reaction of alkyl/arylsulfonyl halides with glycine afforded a series of de rivatives which were first N-benzylated by treatment with benzyl chloride, and then converted to the corresponding hydroxamic acids with hydroxylamine in the presence of carbodiimide derivatives. Other derivatives were obtain ed by reaction of N-benzyl-glycine with aryl isocyanates, arylsulfonyl isoc yanates or benzoyl isothiocyanate, followed by conversion of their COOH gro up into the CONHOH moiety, as mentioned above. The 90 new compounds reporte d here were assayed as inhibitors of the Clostridium histolyticum collagena se (EC 3.4.24.3), a zinc enzyme which degrades triple helical regions of na tive collagen. The prepared hydroxamate derivatives were generally 100-500 times more active than the corresponding carboxylates. In the series of syn thesized hydroxamates, substitution patterns leading to the best inhibitors were those involving perfluoroalkylsulfonyl- and substituted-arylsulfonyl moieties, such as pentafluorophenylsulfonyl, 3- and 4-carboxyphenylsulfonyl -, 3-trifluoromethyl-phenylsulfonyl or 1- and 2-naphthyl among others. Thus , it seems that similarly to the matrix metalloproteinase (MMP) hydroxamate inhibitors, Clostridium histolyticum collagenase inhibitors should incorpo rate hydrophobic moieties at the P-1- and P-2- sites, whereas the alpha-car bon substituent may be a small and compact moiety (such as H, for the Gly d erivatives reported here). Such compounds might lead to the design of colla genase inhibitor-based drugs useful as anti-cancer, anti-arthritis or anti- bacterial agents for the treatment of corneal keratitis. (C) 2000 Editions scientifiques et medicales Elsevier SAS.