Journal of Medicinal Chemistry p. 791 - 803 (2018)
Update date:2022-08-05
Topics:
Zhang, Wei
Lun, Shichun
Wang, Shu-Huan
Jiang, Xing-Wu
Yang, Fan
Tang, Jie
Manson, Abigail L.
Earl, Ashlee M.
Gunosewoyo, Hendra
Bishai, William R.
Yu, Li-Fang
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.
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