The overall aim of this application is to characterize a new class of drugs to treat tuberculosis (TB) that are structurally unrelated to any existing anti-TB drugs. Three years ago, Sequella received a Challenge grant to synthesize and characterize combinatorial libraries of analogues to ethambutol, an existing front-line tuberculosis drug. While we did identify several promising ethambutol analogues that we are taking forward as a result of this work (our first lead compound is in preclinical toxicology studies in preparation for an IND-submission), we also identified a new class of compounds that are essentially structurally unrelated to ethambutol. This class of compounds has not previously been described, and several representatives of this class have excellent activity against M. tuberculosis in vitro. In this application, we propose to use an integrated approach to characterize these active compounds, then develop and refine them into lead molecules that have potential for therapeutic usage in TB. Briefly, we will use combinatorial chemistry to create a targeted library of analogues around to improve upon the desirable characteristics, building on our previous success with this approach. Chemical, biological, and pharmacological data will be used to develop desired profiles of the selected lead series; refinement of the series will result in candidates for further characterization and preclinical development. The process and the specific aims are highly iterative, and lessons learned from later aims will be cycled back to Specific Aim I to assist in the design of more active compounds.
| Bogatcheva, Elena; Hanrahan, Colleen; Nikonenko, Boris et al. (2011) Identification of SQ609 as a lead compound from a library of dipiperidines. Bioorg Med Chem Lett 21:5353-7 |
| Nikonenko, Boris V; Protopopova, Marina; Samala, Rowena et al. (2007) Drug therapy of experimental tuberculosis (TB): improved outcome by combining SQ109, a new diamine antibiotic, with existing TB drugs. Antimicrob Agents Chemother 51:1563-5 |
