Optimization of a novel potent and selective bacterial DNA helicase inhibitor scaffold from a high throughput screening hit

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:23

Article

Li, Bing¹  Pai, Ramdas¹  Aiello, Daniel¹  Di, Ming¹  Barnes, Marjorie H.¹  Peet, Norton P.¹  Bowlin, Terry L.¹  Moir, Donald T.¹ 

[1] Microbiotix Inc, Worcester, MA 01605 USA

关键词: Optimization;    DNA helicase;    DNA replication;    Inhibitor;   

DOI  :  10.1016/j.bmcl.2013.04.055

来源: Elsevier

【 摘 要 】

Benzobisthiazole derivatives were identified as novel helicase inhibitors through high throughput screening against purified Staphylococcus aureus (Sa) and Bacillus anthracis (Ba) replicative helicases. Chemical optimization has produced compound 59 with nanomolar potency against the DNA duplex strand unwinding activities of both B. anthracis and S. aureus helicases. Selectivity index (SI = CC50/IC50) values for 59 were greater than 500. Kinetic studies demonstrated that the benzobisthiazole-based bacterial helicase inhibitors act competitively with the DNA substrate. Therefore, benzobisthiazole helicase inhibitors represent a promising new scaffold for evaluation as antibacterial agents. (C) 2013 Elsevier Ltd. All rights reserved.

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