- Fragment-Based Drug Discovery of Inhibitors of Phosphopantetheine Adenylyltransferase from Gram-Negative Bacteria
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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.
- 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
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supporting information
p. 3309 - 3324
(2018/05/01)
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- Theoretical and experimental NMR data of 3,5-dinitro-2-(2-phenylhydrazinyl) pyridine and of its 4- and 6-methyl derivatives
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3,5-Dinitro-2-(2-phenylhydrazinyl)pyridine and its methyl derivatives: 4-methyl-3,5-dinitro-2-(2-phenylhydrazinyl)pyridine and 6-methyl-3,5-dinitro-2- (2-phenylhydrazinyl)pyridine were synthesized and characterized by 1H NMR and 13C NMR. Calculations were also performed where the above molecules were optimized using the methods of density functional theory (DFT) with 6-31G(d,p) and 6-311G(d,p) basis sets. For all molecules studied, the lowest energy was obtained using the 6-311G(d,p) basis set. The GIAO/DFT (Gauge Invariant Atomic Orbitals/Density Functional Theory) calculations on the 6-311G and 6-311++G and 6-311G* basis sets were carried out to determine proton and carbon chemical shifts and to find they were close to the experimental values. It has been also found that intramolecular hydrogen bonding exists between hydrogen atom (in 2-NH group) and oxygen atom (pyridine-3-NO2). Moreover, resonances between pyridine ring and electron withdrawing 3-nitro group as well between that ring and the lone electron pair of NH group favor a co-planarity of the structure; this means a chelate ring created by above-mentioned intramolecular hydrogen bond is almost co-planar with pyridine ring.
- Wandas,Talik
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- Synthesis of some fluorine-containing pyridinealdoximes of potential use for the treatment of organophosphorus nerve-agent poisoning
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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
- Timperley, Christopher M.,Banks, R. Eric,Young, Ian M.,Haszeldine, Robert N.
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scheme or table
p. 541 - 547
(2011/09/15)
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- THE NITROPYRIDINYL ETHYLENEIMINE COMPOUND, THE PHARMACEUTICAL COMPOSITION CONTAINING IT, THE PREPARATION METHOD AND USE THEREOF
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The present invention discloses a nitropyridinyl ethyleneimine compound as shown in the formula I and a preparation method of the same, as well as use of the compound in manufacture of a prodrug and in manufacture of a drug for treating a tumor.
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Page/Page column 11
(2011/10/10)
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- Discovery of heterobicyclic templates for novel metabotropic glutamate receptor subtype 5 antagonists
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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.
- Kulkarni, Santosh S.,Newman, Amy Hauck
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p. 2987 - 2991
(2008/02/07)
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- IMIDAZO(1,2-a)PYRIDINE DERIVATIVE
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A compound reprsented by the following formula (I), its salts or nsolvates thereof capable of specifically or selectively expressig an antifungal activity in a broad spectrum based on the novel mechanism thereof of 1,6-β-glucan synthesis inhibition, and an antifungal agent containing any of them.
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- Method for stimulating bone formation
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A method for stimulating bone formation by administering integrin binding compounds which cause the release of osteocalcin from osteoblasts is disclosed.
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- Benzimidazoles/Imidazoles Linked to a Fibrinogen Receptor Antagonist Template Having Vitronectin Receptor Antagonist Activity
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Vitronectin receptor antagonists having the formula: STR1 which are useful for the treatment of inflammation, cancer and cardiovascular disorders, such as atherosclerosis and restenosis, and diseases wherein bone resorption is a factor, such as osteoporsis.
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- Discovery of an imidazopyridine-containing 1,4-benzodiazepine nonpeptide vitronectin receptor (αvβ3) antagonist with efficacy in a restenosis model
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In the 3-oxo-1,4-benzodiazepine-2-acetic acid series of vitronectin receptor (αvβ3) antagonists, a compound containing an imidazopyridine arginine mimetic was discovered which had sufficient potency and iv pharmacokinetics for demonstration of efficacy in a rat restenosis model.
- Keenan, Richard M.,Lago, M. Amparo,Miller, William H.,Ali, Fadia E.,Cousins, Russell D.,Hall, Leon B.,Hwang, Shing-Mei,Jakas, Dalia R.,Kwon, Chet,Louden, Calvert,Nguyen, Thomas T.,Ohlstein, Eliot H.,Rieman, David J.,Ross, Steven T.,Samanen, James M.,Smith, Brian R.,Stadel, Jeffrey,Takata, Dennis T.,Vickery, Lynne,Yuan, Catherine C. K.,Yue, Tian-Li
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p. 3171 - 3176
(2007/10/03)
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- Versatile synthesis of 6-substituted 8-deazapteridine-2,4-diamines. Formal total synthesis of 8,10-dideazaminopterin
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A new synthesis of 4-amino-4-deoxy-8,10-dideazapteroic acid (11d) and 6-substituted and 5,6-anellated 8-deazapteridine-2,4-diamines, 10a, 10d, 25, is described. Starting from keteneaminals 1 or 12 and enaminones 4 or β-aminoketone 17 the title compounds can be prepared via functional group transformation of 2-amino-3-nitropyridines 5 or nicotinate 13a yielding 3-amino-α-picolinonitriles 9 which are cyclocondensed with guanidine.
- Troschutz,Karger
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p. 1815 - 1821
(2007/10/03)
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- Novel α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonists: Synthesis and structure-activity relationships of 6-(1H- imidazol-1-yl)-7-nitro-2,3(1H,4H)-pyrido[2,3-b]pyrazinedione and related compounds
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We have synthesized and evaluated azaquinoxalinediones 3a-c for their activity in inhibiting [3H]AMPA binding from rat whole brain. It was found that the azaquinoxalinedione nucleus functions as a bioisostere for quinoxalinedione in AMPA receptor binding. The detailed structure-activity relationships of 6- and/or 7-substituted 2,3(1H,4H)-pyrido[2,3- b]pyrazinedione derivatives 4, 7-10, 13, 15, and 16 showed some differences in comparison with those of the corresponding substituted quinoxalinediones, including 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione (1) (YM90K). The X-ray study exhibited that conformation of the 7-nitro group of 1 · HCl was nearly coplanar with the quinoxaline ring, whereas the 6- imidazol1-yl group was rotated with respect to the aromatic ring. From the glycine site on NMDA receptor binding study, it is indicated that bulkiness of 6-substituents on pyridopyrazinediones may be responsible for the selectivity against the glycine site. Among the series of azaquinoxalinediones, 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-pyrido[2,3- b]pyrazinedione (8c) exhibited a combination of the best affinity to the AMPA receptors with a K(i) value of 0.14 μM and selectivity against the glycine site (no affinity at 10 μM). In vivo, 8c also protected against sound- induced seizure in DBA/2 mice (minimum effective dose, 10 mg/kg ip).
- Ohmori,Kubota,Shimizu-Sasamata,Okada,Sakamoto
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p. 1331 - 1338
(2007/10/03)
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- Pyrido[3,2-e][1,4]diazepines - Synthesis and anti-HIV-1-activity tests
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Starting from the commercially available 6-methyl-2-pyridylamine (1) the pyrido[3,2-e][1,4]diazepine 14a was synthesized in 12 steps with 7% total yield. 14a, the N-methyl derivative 14b, the thiolactam 15a, the amidine 16, and the 1,2,4-triazole 17 were tested for anti-HIV-1-activity. None of the compounds tested possesses antiviral activity comparable to that of zidovudine (3'-azido-3'-desoxythymidine = AZT).
- Gorlitzer,Wilpert,Rubsamen-Waigmann,Suhartono,Wang,Immelmann
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p. 247 - 255
(2007/10/02)
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- Synthesis of 2-Amino-3-nitropyridines and -1,4-dihydropyridines
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The title compounds 4 and 5 can be synthesized from the primary nitroketene aminal 2 and 1,3-biselectrophiles like β-aminoketones (ketonic Mannich bases) or enaminoketones.
- Mertens, Hubert,Troschuetz, Reinhard,Roth, Hermann J.
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p. 380 - 383
(2007/10/02)
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- SYNTHESES WITH AROMATIC NITRAMINES, VI SUBSTITUENT EFFECT IN THE PHOTOLYTIC REARRANGEMENT OF NITRAMINOPYRIDINES
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All isomeric ring-substituted methyl-2-nitraminopyridines, both 3-nitro- and 5-nitro-2-nitraminopyridines, 5-chloro- and 3-carboxy-2-nitraminopyridines, as well as 3,5-dibromo-2-nitraminopyridine were photolyzed in methanol by irradiation with a low-pressure mercury lamp (253.7 nm).Preference was generally noted for the migration of the side-chain nitro group to the vicinal β-position. 3,5-Dibromo-2-nitraminopyridine gave both 2-amino-3,5-dibromopyridine and 3,5-dibromopyridine-2-one.The ratio of the preparative and quantum yields of the two products were 2.5 and 3.0, respectively.
- Sepiol, Jadwiga,Tomasik, Piotr
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p. 333 - 338
(2007/10/02)
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- Chemotherapeutically effective nitro compounds. III. Nitropyridines, nitroimidazopyridines and related compounds
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New 2 nitropyridines and 3 nitropyridines, and 3 nitroimidazo [1,2 a] pyridines and related compounds (together 106) were synthesized and tested for their chemotherapeutic efficacy against trichomonads, amoebas and other organisms, such as Eimeria tenella, bacteria, fungi and helminths. Several 2 nitropyridines revealed a detectable systemic effect against Entamoeba histolytica (extraintestinal amoebiasis of the golden hamster) and also a weak activity against Trichomonas fetus in the NMRI mouse. Only a few 3 nitropyridines showed a marked systemic effect against trichomonads. Of the 3 nitroimidazo [1,2 a] pyridines, only the electroneutral carboxylic acid amide group exhibited a pronounced activity, exclusively against trichomonads; however, the activity was nullified by electronegative, electropositive and other electroneutral substituents. As they were not superior in chemotherapeutic respect compared to the known standard preparations (metronidazole), no further tests were carried out with the most effective compounds.
- Winkelmann,Raether,Hartung,Wagner
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