21901-29-1Relevant articles and documents
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.
Synthesis of some fluorine-containing pyridinealdoximes of potential use for the treatment of organophosphorus nerve-agent poisoning
Timperley, Christopher M.,Banks, R. Eric,Young, Ian M.,Haszeldine, Robert N.
scheme or table, p. 541 - 547 (2011/09/15)
Fluoroheterocyclic aldoximes were screened as therapeutic agents for the treatment of anticholinesterase poisoning. 2-Fluoropyridine-3- and -6-aldoxime, and 3-fluoropyridine-2- and -4-aldoxime, were synthesised. Attempts to obtain 3,5,6-trifluoropyridine-2,4-bis(aldoxime) and -2-aldoxime, however, proved unsuccessful. Pentafluorobenzaldoxime was prepared by oximation of pentafluorobenzaldehyde. Acid dissociation constants (pKa) and second-order rate constants (kox-) of the fluorinated pyridinealdoximes towards sarin were measured. 2,3,5,6-Tetrafluoropyridine-4- aldoxime had the best profile: its kox- approached that of the therapeutic oxime P2S (310 vs. 120 l mol-1 min-1), but its higher pKa (9.1 vs. 7.8) fell short of the target figure of 8 required for reactivation of inhibited acetylcholinesterase in vivo. N-alkylation of the fluorinated pyridine-aldoximes may reduce their pK a nearer to 8 and enhance their therapeutic potential. Crown Copyright
Discovery of heterobicyclic templates for novel metabotropic glutamate receptor subtype 5 antagonists
Kulkarni, Santosh S.,Newman, Amy Hauck
, p. 2987 - 2991 (2008/02/07)
Investigation of a series of heterobicyclic compounds with essential pharmacophoric features of the metabotropic glutamate receptor 5 (mGluR5) antagonists MPEP and MTEP provided novel structural templates with sub-micromolar affinities at the mGluR5.
