Nosocomial infections are still major threat to human beings and clinicians’ needs to have new class of antibacterial agents which show potent activity against multi-drug resistant bacteria are very high. We aimed to obtain new class of antibacterial agent which can cover both drug resistant Gram-positives (MRSA, VRE etc.) and Gram-negatives (resistant E. coli, K. pneumoniae, A. baumannii, P. aeruginosa, etc.), and could be used for empiric therapy. At first, we set the reported compound 1 as an initial lead. 1 showed very potent activity both against Gram-positives and Gram-negatives, but its hERG inhibition was found to be very potent, and it showed low plasma concentration/high volume of distribution. To overcome such issues of this class of compounds we next referred to mono-amine type compound 2, and focused on the design and the synthesis which can make the compounds less basic and/or less lipophilic. As the result we obtained a series of promising compounds with pyrrolidinone ring. Especially, DS10440313 showed very potent activity against drug-resistant Gram-positive and Gram-negative bacteria including clinical isolates, and also showed strong activity in in vivo models. DS10440313 indicated favorable physicochemical and PK profiles, and its QT risk was estimated to be lower than moxifloxacin by dog telemetry study.

Synthesis and biological evaluation of novel bacterial topoisomerase inhibitors with pyrrolidinone ring for nosocomial infections

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.