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J Med Chem DOI:10.1021/acs.jmedchem.7b01319

Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis.

Publication TypeJournal Article
Year of Publication2018
AuthorsZhang, W, Lun, S, Wang, S-H, Jiang, X-W, Yang, F, Tang, J, Manson, AL, Earl, AM, Gunosewoyo, H, Bishai, WR, Yu, L-F
JournalJ Med Chem
Date Published2018 02 08
KeywordsAnimals, Cercopithecus aethiops, Coumarins, Enzyme Inhibitors, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Polyketide Synthases, Structure-Activity Relationship, Vero Cells

Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure-activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form coumestans that are shown to be active in SIT. Whole genome deep sequencing of the coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of this target for the development of new antitubercular agents.


Alternate JournalJ. Med. Chem.
PubMed ID29328655