2区 · 医学
Article
作者: Hackbarth, Corinne J. ; Chen, Dawn Z. ; Lewis, Jason G. ; Clark, Kirk ; Mangold, James B. ; Cramer, Jeffrey A. ; Margolis, Peter S. ; Wang, Wen ; Koehn, Jim ; Wu, Charlotte ; Lopez, S. ; Withers, George III ; Gu, Helen ; Dunn, Elina ; Kulathila, R. ; Pan, Shi-Hao ; Porter, Wilma L. ; Jacobs, Jeff ; Trias, Joaquim ; Patel, Dinesh V. ; Weidmann, Beat ; White, Richard J. ; Yuan, Zhengyu
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 P(1)' 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 P(1)' site. Compounds with MICs of 200 micro M 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 A. 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.