59649-56-8Relevant 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.
Exploration of SAR for novel 2-benzylbenzimidazole analogs as inhibitor of transcription factor NF-κB
Boggu, Pulla Reddy,Venkateswararao, Eeda,Manickam, Manoj,Kim, Youngsoo,Jung, Sang-Hun
, p. 469 - 479 (2017/04/13)
A novel series of 2-benzylbenzimidazole analogs was designed, synthesized and investigated for their in vitro activities against LPS induced NF-κB inhibition in RAW 264.7 cells using the SEAP assay. Among them, 4-((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)phenol (6e, >100% inhibition at 30?μM, IC50?=?3.0?μM), 4-((5-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)phenol (6j, 96% inhibition at 30?μM, IC50?=?4.0?μM) and 2-((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)phenol (6k, 95% inhibition at 30?μM, IC50?=?5.0?μM) showed strong inhibitory activity. The structure activity relationship confirmed that the substitution on benzimidazole ring A with hydrophobic cyclohexylmethoxy group at position 4 or 5 markedly enhances the activity. In addition, the hydrophilic hydrogen bonding donor group (OH) at position 2 or 4 on phenyl ring B connected with one methylene spacer to the benzimidazole ring is favorable for the inhibitory activity. However, hydrophobic (–OCH3 and –Cl) groups on phenyl ring B decrease the activity.
NOVEL FLUORINE-CONTAINING DICARBOXYLIC ACIDS AND THEIR NOVEL POLYMER COMPOUNDS
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, (2009/02/11)
Disclosed is a fluorine-containing dicarboxylic acid represented by formula (1), wherein n represents an integer of 1-4, and the two carboxylic groups are not adjacent to each other on the aromatic ring. It is possible to obtain a linear polymer compound by reacting the fluorine-containing dicarboxylic acid with a comonomer (e.g., diaminodiol). By thermal cyclization, this linear polymer compound can be converted into another polymer compound having superior characteristics.
