Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 23, Pages 9371-9381Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01542
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Funding
- Novartis Research Foundation
- Bill & Melinda Gates Foundation
- Strategic Health Innovation Partnership (SHIP) unit of the South African Medical Research Council (SAMRC)
- University of Cape Town
- SAMRC
- South African Research Chairs Initiative of the Department of Science and Technology
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High-throughput screening of a library of small polar molecules against Mycobacterium tuberculosis led to the identification of a phthalimide-containing ester hit compound (1), which was optimized for metabolic stability by replacing the ester moiety with a methyl oxadiazole bioisostere. A route utilizing polymer-supported reagents was designed and executed to explore structure activity relationships with respect to the N-benzyl substituent, leading to compounds with nanomolar activity. The frontrunner compound (5h) from these studies was well tolerated in mice. A M. tuberculosis cytochrome bd oxidase deletion mutant (Delta cydKO) was hypersusceptible to compounds from this series, and a strain carrying a single point mutation in qcrB, the gene encoding a subunit of the menaquinol cytochrome c oxidoreductase, was resistant to compounds in this series. In combination, these observations indicate that this novel class of antimycobacterial compounds inhibits the cyto chrome bc1 complex, a validated drug target in M. tuberculosis.
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