Novel water-soluble nocathiacin analogs as potent antibacterial agents

MEDI 279

Libo Xu, libo_xu@merck.com1, Kun Liu, kun_liu@merck.com2, Amy Farthing2, Sheryl Debenham2, Fengqi Zhang2, Guo Q. Shi, guoqiang_shi@merck.com2, James F. Dropinski, james_dropinski@merck.com2, Peter T. Meinke2, Christrine McCallum3, and Emily Hickey3. (1) Department of Medicinal Chemisty, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, (2) Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, (3) Infectious Diseases, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065
Nocathiacin I is a new member of the thiazolyl peptide antibiotics family and displays potent antibacterial activity against a variety of Gram-positive and drug resistant bacteria. Nocathiacin I disrupts bacterial protein biosynthesis by interacting directly with the ribosomal site. Poor water solubility is the key limitation to the development of this compound as an IV drug. Several approaches trying to obtain analogs of nocathiacins with increased water solubility have been reported in the literature. In this presentation, we will describe novel synthetic strategies to instill water-solubilizing groups onto nocathiacins. We discovered a mild and selective method to transform nocathiacin I to the highly desirable carboxylic acid intermediate which allowed for easy access to a variety of novel amides. The in vitro and in vivo antibacterial activities of nocathiacin analogs will be presented.

 

Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007