Protease inhibitors: Synthesis of a series of bacterial collagenase inhibitors of the sulfonyl amino acyl hydroxamate type

被引:32
作者
Clare, BW
Scozzafava, A
Supuran, CT
机构
[1] Univ Western Australia, Dept Chem, Crawley, WA 6009, Australia
[2] Univ Florence, Lab Chim Inorgan & Bioinorgan, I-50121 Florence, Italy
关键词
D O I
10.1021/jm010087e
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of sulfonyl amino acyl hydroxamates incorporating alkyl/arylsulfonyl-N-2-nitrobenzyl-L-alanine was prepared. Related compounds were obtained by reaction of N-2-nitrobenzyl-L-Ala with aryl isocyanates, arylsulfonyl isocyanates, or benzoyl isothiocyanate, followed by the conversion of the COOH into the CONHOH moiety. The new compounds were assayed as inhibitors of the Clostridium histolyticum collagenase (ChC), a bacterial protease involved in the degradation of extracellular matrix. Many of the obtained hydroxamates proved to be effective bacterial collagenase inhibitors, the main contributor to activity being the substitution pattern at the sulfonamido moiety. The best ChC inhibitors were those containing pentafluorophenylsulfonyl and 3- and 4-protected-aminophenylsulfonyl P-1 groups among others, with affinities in the low nanomolar range. This study also proves that the 2-nitrobenzyl- moiety, similarly to the 4-nitrobenyl one previously investigated (Scozzafava, A.; Supuran, C. T. J. Med. Chem. 2000, 43, 1858-1865) is an efficient P-2 anchoring moiety for obtaining potent bacterial collagenase inhibitors.
引用
收藏
页码:2253 / 2258
页数:6
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