Protease inhibitors: synthesis of a series of bacterial collagenase inhibitors of the sulfonyl amino acyl hydroxamate type.
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.
Clare
B W
BW
Department of Chemistry, The University of Western Australia, 35 Stirling Highway, Crawley, W.A. 6009 Australia. bwc@crystal.uwa.edu.au
Scozzafava
A
A
Supuran
C T
CT
D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D003012:Microbial Collagenase / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013055:Spectrophotometry, Infrared; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology*
D006877:Hydroxamic Acids; D007202:Indicators and Reagents; D011480:Protease Inhibitors; D013450:Sulfones; D003012:Microbial Collagenase