Abstract
During a search for new anti-tuberculosis agents, a screen of a commercially available library provided a hit nitrofuranyl amide. This hit was selected for further development due to its potential as an anti-tuberculosis agent with a novel mechanism of action, and its potential for activity against both actively growing and latent bacteria. This review covers the optimization of this lead and the strategies applied for developing this series into anti-tuberculosis agents. To optimize the hit, a series of libraries were synthesized, producing several compounds that showed increased antituberculosis activity along with a strong structure activity relationship. The most active compounds from the first optimization series showed good in vitro anti-tuberculosis activity and limited in vivo efficacy, but their application was restricted due to solubility problems. Therefore, a second generation optimization library was designed and synthesized in order to increase bioavailability and solubility while maintaining good anti-tuberculosis activity. Hydrophilic cyclic secondary amines were substituted to the core scaffold and a benzyl piperazine substitution was found to be most effective in achieving improved solubility and potent anti-tuberculosis activity. However, bioactivity studies of these 2nd generation leads showed that the in vivo anti-tuberculosis activity of these compounds was limited due to rapid metabolism. Consequently, a 3rd generation of compounds was designed and synthesized in which potential sites of metabolism were blocked.
Keywords: Anti-tuberculosis agents, antibacterial, nitrofurans, nitrofuranylamides
Current Topics in Medicinal Chemistry
Title: Nitrofurans as Novel Anti-tuberculosis Agents: Identification, Development and Evaluation
Volume: 7 Issue: 5
Author(s): Rajendra P. Tangallapally, Raghunandan Yendapally, AnTawan J. Daniels, Robin E.B. Lee and Richard E. Lee
Affiliation:
Keywords: Anti-tuberculosis agents, antibacterial, nitrofurans, nitrofuranylamides
Abstract: During a search for new anti-tuberculosis agents, a screen of a commercially available library provided a hit nitrofuranyl amide. This hit was selected for further development due to its potential as an anti-tuberculosis agent with a novel mechanism of action, and its potential for activity against both actively growing and latent bacteria. This review covers the optimization of this lead and the strategies applied for developing this series into anti-tuberculosis agents. To optimize the hit, a series of libraries were synthesized, producing several compounds that showed increased antituberculosis activity along with a strong structure activity relationship. The most active compounds from the first optimization series showed good in vitro anti-tuberculosis activity and limited in vivo efficacy, but their application was restricted due to solubility problems. Therefore, a second generation optimization library was designed and synthesized in order to increase bioavailability and solubility while maintaining good anti-tuberculosis activity. Hydrophilic cyclic secondary amines were substituted to the core scaffold and a benzyl piperazine substitution was found to be most effective in achieving improved solubility and potent anti-tuberculosis activity. However, bioactivity studies of these 2nd generation leads showed that the in vivo anti-tuberculosis activity of these compounds was limited due to rapid metabolism. Consequently, a 3rd generation of compounds was designed and synthesized in which potential sites of metabolism were blocked.
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Cite this article as:
Tangallapally P. Rajendra, Yendapally Raghunandan, Daniels J. AnTawan, Lee E.B. Robin and Lee E. Richard, Nitrofurans as Novel Anti-tuberculosis Agents: Identification, Development and Evaluation, Current Topics in Medicinal Chemistry 2007; 7 (5) . https://dx.doi.org/10.2174/156802607780059772
DOI https://dx.doi.org/10.2174/156802607780059772 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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