116035-71-3Relevant academic research and scientific papers
Fragment-Based Drug Discovery of Inhibitors of Phosphopantetheine Adenylyltransferase from Gram-Negative Bacteria
Moreau, Robert J.,Skepper, Colin K.,Appleton, Brent A.,Blechschmidt, Anke,Balibar, Carl J.,Benton, Bret M.,Drumm, Joseph E.,Feng, Brian Y.,Geng, Mei,Li, Cindy,Lindvall, Mika K.,Lingel, Andreas,Lu, Yipin,Mamo, Mulugeta,Mergo, Wosenu,Polyakov, Valery,Smith, Thomas M.,Takeoka, Kenneth,Uehara, Kyoko,Wang, Lisha,Wei, Jun-Rong,Weiss, Andrew H.,Xie, Lili,Xu, Wenjian,Zhang, Qiong,De Vicente, Javier
supporting information, p. 3309 - 3324 (2018/05/01)
The discovery and development of new antibiotics capable of curing infections due to multidrug-resistant and pandrug-resistant Gram-negative bacteria are a major challenge with fundamental importance to our global healthcare system. Part of our broad program at Novartis to address this urgent, unmet need includes the search for new agents that inhibit novel bacterial targets. Here we report the discovery and hit-to-lead optimization of new inhibitors of phosphopantetheine adenylyltransferase (PPAT) from Gram-negative bacteria. Utilizing a fragment-based screening approach, we discovered a number of unique scaffolds capable of interacting with the pantetheine site of E. coli PPAT and inhibiting enzymatic activity, including triazolopyrimidinone 6. Structure-based optimization resulted in the identification of two lead compounds as selective, small molecule inhibitors of bacterial PPAT: triazolopyrimidinone 53 and azabenzimidazole 54 efficiently inhibited E. coli and P. aeruginosa PPAT and displayed modest cellular potency against the efflux-deficient E. coli ΔtolC mutant strain.
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
, 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.
