Combinatorial lead discovery and optimization of antimicrobial oxazolidinones

Oxazolidinones are a new class of synthetic protein synthesis inhibitors with a novel mode of action, which are active against multidrug-resistant pathogens. The recent approval of the first drug of this class linezolid (Zyvox, Pharmacia) has sparked further interest in the development of novel antibiotics of this structural type. Combinatorial chemistry is an important tool capable of facilitating the discovery and optimization of the next generation leads with enhanced potency and improved activity spectrum. Combichem integration into a medicinal chemistry project is a multifactorial task that is reviewed herein in a context of efforts targeting novel oxazolidinone antimicrobials. Key strategic considerations that govern projects of this type are analyzed, and a survey of combichem methodologies and oxazolidinone libraries is presented with attention to biological evaluation results.