Late-Stage Functionalization of Platensimycin Leading to Multiple Analogues with Improved Antibacterial Activity in Vitro and in Vivo

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2019 Jul 3

PMID 31265289

Citations 8

Authors

Youchao Deng

Xiang Weng

Yuling Li

Meng Su

Zhongqing Wen

Xinxin Ji

Nan Ren

Ben Shen

Yanwen Duan

Yong Huang

Affiliations

Soon will be listed here.

Abstract

Bacterial fatty acid synthases are promising antibacterial targets against multidrug-resistant pathogens. Platensimycin (PTM) is a potent FabB/FabF inhibitor, while its poor pharmacokinetics hampers the clinical development. In this study, a focused library of PTM derivatives was prepared through thiolysis of PTM oxirane (), followed by various C-C cross-coupling reactions in high yields. Antibacterial screening of these compounds in vitro yielded multiple hits with improved anti- activities over PTM. Among them, compounds , , , and exhibited improved antibacterial activities over PTM against methicillin-resistant (MRSA) in a mouse peritonitis model. Compound was further shown to be effective against MRSA infection in a mouse wound model, in comparison to mupirocin. Therefore, the facile preparation and screening of these PTM derivatives, together with their potent antibacterial activities in vivo, suggest a promising strategy to improve the antibacterial activity and pharmacokinetic properties of PTM.

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