Janet C. Lynn

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 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.

Corrigendum to “Identification of novel potent hydroxamic acid inhibitors of peptidyl deformylase and the importance of the hydroxamic acid functionality on inhibition” [Bioorg. Med. Chem. Lett. 11 (2001) 1355]†

Medicinal Chemistry 7254-209-615, Pharmacia, Kalamazoo, MI 49001-0199, USA Protein Science, Pharmacia, Kalamazoo, MI 49001-0199, USA Computer Aided Drug Discovery Research, Pharmacia, Kalamazoo, MI 49001-0199, USA Discovery Technologies, Pharmacia, Kalamazoo, MI 49001-0199, USA Biology I, Pharmacia, Kalamazoo, MI 49001-0199, USA Structural, Analytical & Medicinal Chemistry Research, Pharmacia, Kalamazoo, MI 49001-0199, USA

Synthesis and pharmacological evaluation of sulfone substituted HIV protease inhibitors

Abstract The sulfonamide substituted pyranones ( 1 ) have recently been shown to be potent HIV protease inhibitors. We prepared a series of sulfone substituted analogs and compared their biological activities to those of the corresponding sulfonamide analogs. It was determined that although these compounds maintained activity as enzyme inhibitors, they showed somewhat diminished antiviral activity even though they may possess increased membrane permeability.