|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Zhang, W, Lun, S, Wang, S-H, Jiang, X-W, Yang, F, Tang, J, Manson, AL, Earl, AM, Gunosewoyo, H, Bishai, WR, Yu, L-F|
|Journal||J Med Chem|
|Date Published||2018 02 08|
|Keywords||Animals, 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 Journal||J. Med. Chem.|