Journal of Medicinal Chemistry p. 2253 - 2258 (2001)
Update date:2022-08-03
Topics: Characterization Hydroxamates Sulfonyl Purification Protection of Functional Groups Scale-up and optimization Structure-Activity Relationship (SAR) Studies Bioassays De-Protection
Clare
Scozzafava
Supuran
A series of sulfonyl amino acyl hydroxamates incorporating alkyl/arylsulfonyl-N-2-nitrobenzylL-alanine was prepared. Related compounds were obtained by reaction of N-2-nitrobenzyl-LAla 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 P1 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 P2 anchoring moiety for obtaining potent bacterial collagenase inhibitors.
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