title: Identification of novel potent hydroxamic acid inhibitors of peptidyl deformylase and the importance of the hydroxamic acid functionality on inhibition.
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.
authors.affiliation: Medicinal Chemistry 7254-209-615, Pharmacia, Kalamazoo, MI 49001-0199, USA. atli.thorarensen@am.pnu.com
authors.forename: A
authors.initials: A
authors.lastname: Thorarensen
authors.forename: M R
authors.initials: MR
authors.lastname: Deibel
authors.forename: D C
authors.initials: DC
authors.lastname: Rohrer
authors.forename: A F
authors.initials: AF
authors.lastname: Vosters
authors.forename: A W
authors.initials: AW
authors.lastname: Yem
authors.forename: V D
authors.initials: VD
authors.lastname: Marshall
authors.forename: J C
authors.initials: JC
authors.lastname: Lynn
authors.forename: M J
authors.initials: MJ
authors.lastname: Bohanon
authors.forename: P K
authors.initials: PK
authors.lastname: Tomich
authors.forename: G E
authors.initials: GE
authors.lastname: Zurenko
authors.forename: M T
authors.initials: MT
authors.lastname: Sweeney
authors.forename: R M
authors.initials: RM
authors.lastname: Jensen
authors.forename: J W
authors.initials: JW
authors.lastname: Nielsen
authors.forename: E P
authors.initials: EP
authors.lastname: Seest
authors.forename: L A
authors.initials: LA
authors.lastname: Dolak
mesh_terms: D000581:Amidohydrolases; D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011487:Protein Conformation; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D006877:Hydroxamic Acids; D000626:Aminopeptidases; D008666:Metalloendopeptidases; D000581:Amidohydrolases; C084507:peptide deformylase