Last week we posted information about two special issues of Future Medicinal Chemistry focused on neglected diseases. Future Medicinal Chemistry (September 2011, Volume 3, Number 11) have a few articles on tuberculosis drug development:
Diarylquinolines, synthesis pathways and quantitative structure–activity relationship studies leading to the discovery of TMC207. Jerome Guillemont, Christophe Meyer, Alain Poncelet, Xavier Bourdrez, Koen Andries. Future Medicinal Chemistry, September 2011, Vol. 3, No. 11, Pages 1345-1360.
Abstract: 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.
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.
Abstract: Tuberculosis remains a leading cause of death resulting from an infectious agent, and the spread of multi- and extensively drug-resistant strains of Mycobacterium tuberculosis poses a threat to management of global health. New drugs that effectively shorten the duration of treatment and are active against drug-resistant strains of this pathogen are urgently required to develop effective chemotherapies to combat this disease. Two nitroimidazoles, PA-824 and OPC-67683, are currently in Phase II clinical trials for the treatment of TB and the outcome of these may determine the future directions of drug development for anti-tubercular nitroimidazoles. In this review we summarize the development of these nitroimidazoles and alternative analogs in these series that may offer attractive alternatives to PA-824 and OPC-67683 for further development in the drug-discovery pipeline. Lastly, the potential pitfalls in the development of nitroimidazoles as drugs for TB are discussed.
Additional TB R&D News: