Bioorg Med Chem Lett. 2001 Jun 4;11(11):1355-8.

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

Thorarensen A, Deibel MR Jr, Rohrer DC, Vosters AF, Yem AW, Marshall VD, Lynn JC, Bohanon MJ, Tomich PK, Zurenko GE, Sweeney MT, Jensen RM, Nielsen JW, Seest EP, Dolak LA.

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Medicinal Chemistry 7254-209-615, Pharmacia, Kalamazoo, MI 49001-0199, USA. atli.thorarensen@am.pnu.com

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Bioorg Med Chem Lett 2001 Aug 6;11(15):2053.

Abstract

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 compound collection using Staphylococcus aureus PDF afforded a very potent inhibitor with an IC(50) in the low nanomolar range. Unfortunately, the compound that 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 prepared several analogues. This paper describes our findings that the hydroxamic acid functionality found in 1 is mainly responsible for the high affinity to PDF. In addition, we identified an alternative class of PDF inhibitors, the N-hydroxy urea 18, which has both PDF and antibacterial activity.

PMID:: 11378353; [PubMed - indexed for MEDLINE]

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