290374-51-5Relevant articles and documents
Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity
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
supporting information, p. 3325 - 3349 (2018/05/01)
In the preceding manuscript [Moreau et al. 2018, 10.1021/acs.jmedchem.7b01691] we 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 3 and 4-azabenzimidazole 4. Here we disclose our efforts to further optimize these two leads for on-target potency and Gram-negative cellular activity. Enabled by a robust X-ray crystallography system, our structure-based inhibitor design approach delivered compounds with biochemical potencies 4-5 orders of magnitude greater than their respective fragment starting points. Additional optimization was guided by observations on bacterial permeability and physicochemical properties, which ultimately led to the identification of PPAT inhibitors with cellular activity against wild-type E. coli.
GENERATION OF AN ACTIVE ACYL SPECIES FROM STABLE 1-METHYL-2-ACYL-1H-IMIDAZOLES
Ohta, Shunsaku,Hayakawa, Satoshi,Okamoto, Masao
, p. 5681 - 5684 (2007/10/02)
1-Methyl-2-(1'-cyano-1'-trimethylsilyloxy)alkyl-1H-imidazoles (2) were easily prepared from the corresponding stable carbonyl compounds, 1-methyl-2-acyl-1H-imidazoles (1).When the quarternary salts of 2 were treated with various nucleophiles, reactive acyl species, which was presumed to be acylcyanide (12), was generated in situ under C-C bond fission to result in producing the corresponding acylated compounds (5-10) in good yields.
