Nitrofurans as novel anti-tuberculosis agents: identification, development and evaluation.

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 anti-tuberculosis 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.