Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity

• Published in: Journal of medicinal chemistry Vol. 61; no. 8; pp. 3325 - 3349
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 26-04-2018
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - metabolism; Benzimidazoles - pharmacology; Binding Sites; Drug Discovery; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Escherichia coli - drug effects; Escherichia coli - enzymology; Escherichia coli Proteins - antagonists & inhibitors; Escherichia coli Proteins - chemistry; Escherichia coli Proteins - genetics; Escherichia coli Proteins - metabolism; Heterocyclic Compounds, 2-Ring - chemical synthesis; Heterocyclic Compounds, 2-Ring - chemistry; Heterocyclic Compounds, 2-Ring - metabolism; Heterocyclic Compounds, 2-Ring - pharmacology; Microbial Sensitivity Tests; Molecular Structure; Mutation; Nucleotidyltransferases - antagonists & inhibitors; Nucleotidyltransferases - chemistry; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; Protein Binding; Pyrimidinones - chemical synthesis; Pyrimidinones - chemistry; Pyrimidinones - metabolism; Pyrimidinones - pharmacology; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - metabolism; Triazoles - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b01861

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.