期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 23, 页码 10586-10604出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b01203
关键词
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资金
- EPSRC
- National Institutes of Health-Oxford-Cambridge Scholars Program
- Washington University in St. Louis Medical Scientist Training Program
- Intramural Research Program of NIH, NIAID [AI000693-25]
With the growing worldwide prevalence of antibiotic-resistant strains of tuberculosis (TB), new targets are urgently required for the development of treatments with novel modes of action. Fumarate hydratase (fumarase), a vulnerable component of the citric acid cycle in Mycobacterium tuberculosis (Mtb), is a metabolic target that could satisfy this unmet demand. A key challenge in the targeting of Mtb fumarase is its similarity to the human homolog, which shares an identical active site. A potential solution to this selectivity problem was previously found in a high-throughput screening hit that binds in a nonconserved allosteric site. In this work, a structure-activity relationship study was carried out with the determination of further structural biology on the lead series, affording derivatives with sub-micromolar inhibition. Further, the screening of this series against Mtb in vitro identified compounds with potent minimum inhibitory concentrations.
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