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Antimicrobial Agents and Chemotherapy, September 2002, p. 2752-2764, Vol. 46, No. 9
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.9.2752-2764.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

N-Alkyl Urea Hydroxamic Acids as a New Class of Peptide Deformylase Inhibitors with Antibacterial Activity

Corinne J. Hackbarth,1 Dawn Z. Chen,1 Jason G. Lewis,1 Kirk Clark,2 James B. Mangold,3 Jeffrey A. Cramer,3 Peter S. Margolis,1 Wen Wang,1 Jim Koehn,2 Charlotte Wu,1 S. Lopez,1 George Withers III,1 Helen Gu,3 Elina Dunn,3 R. Kulathila,2 Shi-Hao Pan,2 Wilma L. Porter,3 Jeff Jacobs,1 Joaquim Trias,1 Dinesh V. Patel,1 Beat Weidmann,2 Richard J. White,1 and Zhengyu Yuan1*

Versicor, Inc., Fremont, California 94555,1 Novartis Pharmaceuticals Corporation, Summit, New Jersey 07901,2 Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 079363

Received 17 December 2001/ Returned for modification 16 March 2002/ Accepted 5 June 2002

Peptide deformylase (PDF) is a prokaryotic metalloenzyme that is essential for bacterial growth and is a new target for the development of antibacterial agents. All previously reported PDF inhibitors with sufficient antibacterial activity share the structural feature of a 2-substituted alkanoyl at the P1' site. Using a combination of iterative parallel synthesis and traditional medicinal chemistry, we have identified a new class of PDF inhibitors with N-alkyl urea at the P1' site. Compounds with MICs of <=4 µg/ml against gram-positive and gram-negative pathogens, including Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae, have been identified. The concentrations needed to inhibit 50% of enzyme activity (IC50s) for Escherichia coli Ni-PDF were <=0.1 µM, demonstrating the specificity of the inhibitors. In addition, these compounds were very selective for PDF, with IC50s of consistently >200 µM for matrilysin and other mammalian metalloproteases. Structure-activity relationship analysis identified preferred substitutions resulting in improved potency and decreased cytotoxity. One of the compounds (VRC4307) was cocrystallized with PDF, and the enzyme-inhibitor structure was determined at a resolution of 1.7 Å. This structural information indicated that the urea compounds adopt a binding position similar to that previously determined for succinate hydroxamates. Two compounds, VRC4232 and VRC4307, displayed in vivo efficacy in a mouse protection assay, with 50% protective doses of 30.8 and 17.9 mg/kg of body weight, respectively. These N-alkyl urea hydroxamic acids provide a starting point for identifying new PDF inhibitors that can serve as antimicrobial agents.

* Corresponding author. Mailing address: Versicor, Inc., 34790 Ardentech Ct., Fremont, CA 94555. Phone: (510) 739-3026. Fax: (510) 739-3086. E-mail: zyuan{at}versicor.com.

Antimicrobial Agents and Chemotherapy, September 2002, p. 2752-2764, Vol. 46, No. 9
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.9.2752-2764.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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