Diarylquinoline

Whole cell growth inhibition screens combined with subsequent target identification using molecular methods have proven viable approaches to the discovery of novel antibacterial inhibitors. Andries and colleagues (2005) at Johnson Johnson employed whole cell assays to discover a series of antimycobacterial diarylquinolines (DARQs). Chemical optimization of a lead compound led to DARQ derivatives exhibiting potent in vitro activities against several mycobacteria including Mycobacterium tuberculosis (Andries et al., 2005 Ji et al., 2006), with MICs below 0.5 pg/mL. Antimycobacterial efficacy in vivo was confirmed for three of the derivatives. 

Andries, K. et al. 2005. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. 

Bedaquiline (Situro) A Diarylquinoline that Blocks Tuberculosis ATP Synthase for the Treatment of Multi-Drug Resistant Tuberculosis... 

Mono and diarylquinolines are prepared via Diels-Alder reactions of iV-tosyl-l-azadienes and benzyne followed by aromatization via treatment of the 1,4-dihydroquinoline with NaOH in methanol (Scheme 58) (13SC2627). First, the azadienes were prepared via condensation of a,P-unsaturated aldehydes and ketones with p-TsNH2. The cycloaddition proceeded well when the azadiene aryl groups were p-substituted or mono o-substituted. 

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