Diarylquinolines, synthesis pathways and quantitative structure-activity relationship studies leading to the discovery of TMC207

Janssen-Cilag France, Campus de Maigremont, BP615, 27106, Val de Reuil Cedex, France.
Future medicinal chemistry (Impact Factor: 3.74). 09/2011; 3(11):1345-60. DOI: 10.4155/fmc.11.79
Source: PubMed


The emergence of multidrug-resistant strains of Mycobacterium tuberculosis and resistance to current anti-TB drugs call for the discovery and development of new effective anti-TB drugs. TMC207 is the lead candidate of a novel class of antimycobacterial agents, the diarylquinolines, which specifically inhibit mycobacterial ATP synthase and displays high activity against both drug-susceptible and multidrug-resistant strains of Mycobacterium tuberculosis. This article covers both synthesis pathways as well as qualitative and quantitative analyses of the structure-activity relationships of the diarylquinoline series on Mycobacterium smegmatis activity.

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    • "During the development of bedaquiline, the structure-activity relationship (SAR) has always been the focus of scientists' attention. Originally, the group led by Koen Andries at Janssen Pharmaceutica selected bedaquiline from more than 200 analogues[11]and, later, from over 500 compounds with a modulation on the aliphatic side chain; a total of 200 compounds with increased flexibility around the two stereogenic centers were synthesized and tested against Gram-positive bacteria to expand the diarylquinoline's (DARQ's) antibacterial spectrum[12]. Another group also greatly contributed to probing the SAR of bedaquiline by dividing bedaquiline into four quarters and modifying every quarter to evaluate the biologically active motifs1314151617. "

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    ABSTRACT: Mycobacterium tuberculosis is a difficult pathogen to combat and the first-line drugs currently in use are 40-60 years old. The need for new TB drugs is urgent, but the time to identify, develop and ultimately advance new drug regimens onto the market has been excruciatingly slow. On the other hand, the drugs currently in clinical development, and the recent gains in knowledge of the pathogen and the disease itself give us hope for finding new drug targets and new drug leads. In this article we highlight the unique biology of the pathogen and several possible ways to identify new TB chemical leads. The Global Alliance for TB Drug Development (TB Alliance) is a not-for-profit organization whose mission is to accelerate the discovery and development of new TB drugs. The organization carries out research and development in collaboration with many academic laboratories and pharmaceutical companies around the world. In this perspective we will focus on the early discovery phases of drug development and try to provide snapshots of both the current status and future prospects.
    Full-text · Article · Sep 2011 · Future medicinal chemistry
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