Skepper, Colin K.; Moreau, Robert J.; Appleton, Brent A.; Benton, Bret M.; Drumm, Joseph E.; Feng, Brian Y.; Geng, Mei; Hu, Cheng; Li, Cindy; Lingel, Andreas; Lu, Yipin; Mamo, Mulugeta; Mergo, Wosenu; Mostafavi, Mina; Rath, Christopher M.; Steffek, Micah; Takeoka, Kenneth T.; Uehara, Kyoko; Wang, Lisha; Wei, Jun-Rong; Xie, Lili; Xu, Wenjian; Zhang, Qiong; de Vicente, Javier published the artcile< Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity>, Category: pyridine-derivatives, the main research area is triazolopyrimidinone azabenzimidazole preparation phosphopantetheine adenylyltransferase inhibitor antibacteria Escherichia.
In the preceding manuscript the authors described a successful fragment-based lead discovery (FBLD) strategy for discovery of bacterial phosphopantetheine adenylyltransferase inhibitors (PPAT, CoaD). Following several rounds of optimization two promising lead compounds were identified: triazolopyrimidinone (I) and 4-azabenzimidazole (II). Here the authors disclose the efforts to further optimize these two leads for on-target potency and Gram-neg. cellular activity. Enabled by a robust x-ray crystallog. system, the authors’ structure-based inhibitor design approach delivered compounds with biochem. potencies 4-5 orders of magnitude greater than their resp. fragment starting points. Addnl. optimization was guided by observations on bacterial permeability and physicochem. properties, which ultimately led to the identification of PPAT inhibitors with cellular activity against wild-type E. coli.
Journal of Medicinal Chemistry published new progress about Antibacterial agents. 21901-29-1 belongs to class pyridine-derivatives, and the molecular formula is C6H7N3O2, Category: pyridine-derivatives.