Journal
JOURNAL OF FLUORINE CHEMISTRY
Volume 196, Issue -, Pages 44-56Publisher
ELSEVIER SCIENCE SA
DOI: 10.1016/j.jfluchem.2016.07.020
Keywords
Mycobacterium tuberculosis; Antibacterial; Fluorine-containing benzimidazoles; FtsZ; Structure-activity relationship; Metabolic and plasma stability; Docking; Molecular modeling
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Funding
- National Institutes of Health [AI078251, U01 A1082164]
- New York State Office of Science, Technology and Academic Research (NYSTAR)
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This article presents an account of our research on the discovery and development of new-generation fluorine-containing antibacterial agents against drug-resistant tuberculosis, targeting FtsZ. FtsZ is an essential protein for bacterial cell division and a highly promising therapeutic target for antibacterial drug discovery. Through design, synthesis and semi-HTP screening of libraries of novel benzimidazoles, followed by SAR studies, we identified highly potent lead compounds. However, these lead compounds were found to lack sufficient metabolic and plasma stabilities. Accordingly, we have performed extensive study on the strategic incorporation of fluorine into lead compounds to improve pharmacological properties. This study has led to the development of highly efficacious fluorine-containing benzimidazoles as potential drug candidates. We have also performed computational docking analysis of these novel FtsZ inhibitors to identify their putative binding site. Based on the structural data and docking analysis, a plausible mode-of-action for this novel class of FtsZ inhibitors is proposed. (C) 2016 Elsevier B.V. All rights reserved.
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