Identification of novel potent hydroxamic acid inhibitors of peptidyl deformylase and the importance of the hydroxamic acid functionality on inhibition

Peptidyl deformylase (PDF) is a metallo protease that catalyzes the removal of a formyl group from the N-termini of prokaryotic prepared polypeptides, an essential step in bacterial protein synthesis. Screening of our compoun d collection using Staphylococcus aureus PDF afforded a very potent inhibit or with an IC50 in the low nanomolar range. Unfortunately, the compound tha t contains a hydroxamic acid did not exhibit antibacterial activity (MIC). In order to address the lack of activity in the MIC assay and to determine what portion of the molecule was responsible for binding to PDF, we prepare d several analogues. This paper describes our findings that the hydroxamic acid functionality found in 1 is mainly responsible for the high affinity t o PDF. In addition, we identified an alternative class of PDF inhibitors, t he N-hydroxy urea 18, which has both PDF and antibacterial activity. (C) 20 01 Elsevier Science Ltd. All rights reserved.