94-63-3Relevant articles and documents
Radiosynthesis, ex Vivo Biodistribution, and in Vivo Positron Emission Tomography Imaging Evaluations of [11C]2-Pyridinealdoxime Methiodide ([11C]2-PAM): A First-In-Class Antidote Tracer for Organophosphate Intoxication
Neumann, Kiel D.,Blecha, Joseph E.,Hayes, Thomas R.,Huynh, Tony,Chao, Chih-Kai,Guilloteau, Nicolas,Zinn, Kurt R.,Vanbrocklin, Henry F.,Thompson, Charles M.,Gerdes, John M.
, p. 3007 - 3014 (2018/09/06)
2-Pyridinealdoxime methiodide (2-PAM) is a widely used antidote for the treatment of organophosphorus (OP) exposure that reactivates the target protein acetylcholinesterase. Carbon-11 2-PAM was prepared to more fully understand the in vivo mode of action, distribution, and dynamic qualities of this important countermeasure. Alkylation of 2-pyridinealdoxime with [11C]CH3I provided the first-in-class [11C]2-PAM tracer in 3.5% decay corrected radiochemical yield from [11C]CH3I, >99% radiochemical purity, and 4831 Ci/mmol molar activity. [11C]2-PAM tracer distribution was evaluated by ex vivo biodistribution and in vivo dynamic positron emission tomography (PET) imaging in na?ve (OP exposure deficient) rats. Tracer alone and tracer coinjected with a body mass-scaled human therapeutic dose of 30 mg/kg nonradioactive 2-PAM demonstrated statistically similar tissue and blood distribution profiles with the greatest uptake in kidney and significantly lower levels in liver, heart, and lung with lesser amounts in blood and brain. The imaging and biodistribution data show that radioactivity uptake in brain and peripheral organs is rapid and characterized by differential tissue radioactivity washout profiles. Analysis of arterial blood samples taken 5 min after injection showed ～82% parent [11C]2-PAM tracer. The imaging and biodistribution data are now established, enabling future comparisons to outcomes acquired in OP intoxicated rodent models.
Microwave-assisted quaternization of various pyridine derivatives and their antibacterial activity
Bu?i?, Valentina,Pavlovi?, Hrvoje,Roca, Sun?ica,Viki?-Topi?, Dra?en,Ga?o-Soka?, Dajana
, p. 425 - 433 (2018/01/26)
In this study, reactions of quaternization under microwave heating of pyridine, α-picoline, pyridine-4-aldoxime, pyridine-2-aldoxime, nicotinamide, isonicotinamide and pyridoxal oxime with different electrophiles: 2-bromo-4'-nitroacetophenone, 2-amino-4-chloro-methylthiazole hydrochloride, methyl iodide, 1, 3-diiodopropane and 1, 3-dibromopropane are reported. The synthesis yield by microwave dielectric heating is improved and reaction time shortened compared to conventional heating. The structure of obtained molecules were analyzed and determined by 1D and 2D NMR spectroscopy methods, IR spectroscopy and mass spectrometry. The highest antibacterial activity against two Gram-positive and two Gram-negative bacteria strains has been found for 1-[2-(4-nitrophenyl)-2-oxoethyl]pyridinium bromide (2).
Design, synthesis, and evaluation of guanylhydrazones as potential inhibitors or reactivators of acetylcholinesterase
Petronilho, Elaine da Concei??o,Rennó, Magdalena do Nascimento,Castro, Newton Gon?alves,da Silva, Fernanda Motta R.,Pinto, Angelo da Cunha,Figueroa-Villar, José Daniel
, p. 1069 - 1078 (2016/10/09)
Analogs of pralidoxime, which is a commercial antidote for intoxication from neurotoxic organophosphorus compounds, were designed, synthesized, characterized, and tested as potential inhibitors or reactivators of acetylcholinesterase (AChE) using the Ellman’s test, nuclear magnetic resonance, and molecular modeling. These analogs include 1-methylpyridine-2-carboxaldehyde hydrazone, 1-methylpyridine-2-carboxaldehyde guanylhydrazone, and six other guanylhydrazones obtained from different benzaldehydes. The results indicate that all compounds are weak AChE reactivators but relatively good AChE inhibitors. The most effective AChE inhibitor discovered was the guanylhydrazone derived from 2,4-dinitrobenzaldehyde and was compared with tacrine, displaying similar activity to this reference material. These results indicate that guanylhydrazones as well as future similar derivatives may function as drugs for the treatment of Alzheimer's disease.
NMR determination of Electrophorus electricus acetylcholinesterase inhibition and reactivation by neutral oximes
Da Cunha Xavier Soares, Sibelle Feitosa,Vieira, Andréia Aguiar,Delfino, Reinaldo Teixeira,Figueroa-Villar, José Daniel
, p. 5923 - 5930 (2013/09/12)
Neurotoxic organophosphorus compounds (OPs), which are used as pesticides and chemical warfare agents lead to more than 700,000 intoxications worldwide every year. The main target of OPs is the inhibition of acetylcholinesterase (AChE), an enzyme necessary for the control of the neurotransmitter acetylcholine (ACh). The control of ACh function is performed by its hydrolysis with AChE, a process that can be completely interrupted by inhibition of the enzyme by phosphylation with OPs. Compounds used for reactivation of the phosphylated AChE are cationic oximes, which usually possess low membrane and hematoencephalic barrier permeation. Neutral oximes possess a better capacity for hematoencephalic barrier permeation. NMR spectroscopy is a very confident method for monitoring the inhibition and reactivation of enzymes, different from the Ellman test, which is the common method for evaluation of inhibition and reactivation of AChE. In this work 1H NMR was used to test the effect of neutral oximes on inhibition of AChE and reactivation of AChE inhibited with ethyl-paraoxon. The results confirmed that NMR is a very efficient method for monitoring the action of AChE, showing that neutral oximes, which display a significant AChE inhibition activity, are potential drugs for Alzheimer disease. The NMR method showed that a neutral oxime, previously indicated by the Ellman test as better in vitro reactivator of AChE inhibited with paraoxon than pralidoxime (2-PAM), was much less efficient than 2-PAM, confirming that NMR is a better method than the Ellman test.
Hydrolysis of carboxylate and phosphate esters using monopyridinium oximes in cationic micellar media
Singh, Namrata,Ghosh, Kallol K.,Marek, Jan,Kuca, Kamil
experimental part, p. 569 - 578 (2012/01/14)
The reactions of p-nitrophenyl acetate (PNPA) with a series of monopyridinium oximes, viz. 2-PAM (2-hydroxyiminomethyl-1-methylpyridinium iodide), 3-PAM (3-hydroxyiminomethyl-1-methylpyridinium iodide), and 4-PAM (4-hydroxyiminomethyl-1-methylpyridinium iodide) have been studied in the presence of cationic surfactants of same hydrophobic chain length (C 16) within the concentration range of 0.5-6.0 mM at pH 8.0 under the pseudo-first-order condition. The observed rate constant (kobs) increases with increasing surfactant concentration culminating into a maximum, and this has been analyzed in detail following the concepts of micellar catalysis. The structure-activity relationship of the investigated oximes has been discussed, and 2-PAM was found to be the most reactive among all the three investigated oximes for the cleavage of PNPA. Esterolytic decomposition of p-nitrophenyldiphenyl phosphate with oximate ions (-CH=NO-) was followed in cetyltrimethylammonium bromide micelles at pH 9.0, and 4-PAM was the most reactive oxime for the micellar hydrolysis of phosphate ester. The apparent acid dissociation constants (pKa) of the investigated oximes have been determined spectrophotometrically.
Monoquaternary pyridinium salts with modified side chain-synthesis and evaluation on model of tabun- and paraoxon-inhibited acetylcholinesterase
Musilek, Kamil,Kucera, Jiri,Jun, Daniel,Dohnal, Vlastimil,Opletalova, Veronika,Kuca, Kamil
scheme or table, p. 8218 - 8223 (2009/04/11)
Acetylcholinesterase reactivators are crucial antidotes for the treatment of organophosphate intoxication. Eighteen monoquaternary reactivators of acetylcholinesterase with modified side chain were developed in an effort to extend the properties of pralidoxime. The known reactivators (pralidoxime, HI-6, obidoxime, trimedoxime, methoxime) and the prepared compounds were tested in vitro on a model of tabun- and paraoxon-inhibited AChE. Monoquaternary reactivators were not able to exceed the best known compounds for tabun poisoning, but some of them did show reactivation better or comparable with pralidoxime for paraoxon poisoning. However, extensive differences were found by a SAR study for various side chains on the non-oxime part of the reactivator molecule.
QUATERNARY HETEROARENIUM ALDOXIMES AS CATALYSTS FOR CLEAVAGE OF PHOSPHATE ESTERS
Hampl, Frantisek,Mazac, Jiri,Liska, Frantisek,Spogl, Jiri,Kabrt, Lubomir,Suchanek, Miloslav
, p. 883 - 893 (2007/10/02)
!-Methyl- (Ia - Id) and 1-dodecyl-2-, 3- and 4-hydroxyiminomethylpyridinium salts (Ie - Ih), as well as 1-methyl- (IIa) and 1-dodecyl-3-hydroxyiminomethylpyridazinium salts (IIb, IIc), were synthesized as catalysts for hydrolytic cleavage of organophosphates.The activities of the prepared catalysts were evaluated by measuring rate constants of hydrolysis of 4-nitrophenyl diphenyl phosphate (PNPDPP) under conditions of a pseudo-first-order reaction.The observed reactivity of pyridinium aldoximes Ia - Ih towards PNPDPP in neutral or slightly basic aqueous solutions (pH 7.2 and 7.8) depends on the acidity of the hydroxyimino group.The cleavage of PNPDPP is strongly accelerated in solutions of 1-dodecylhydroxyiminomethylpyridinium salts Ie - Ih above their critical micellar concentration (CMC).Considerable effect on the velocity of PNPDPP cleavage was observed when quaternary pyridinium aldoximes Ie - Ih were comicellized with inert cationic tenside hexadecyltrimethylammonium bromide (CTAB). 1-Dodecyl-3-hydroxyiminomethylpyridazinium salts IIb and IIc were unstabel in aqueous solutions under the above-mentioned conditions.
Carbon-13 NMR Characterization of the Bispyridinium Oximes, Toxogonin, HS-3, HS-6 and HI-6
Waysbort, D.,Balderman, D.,Amitai, G.
, p. 7 - 10 (2007/10/02)
The structure of the bispyridinium oximes, toxogonin, HS-3, HS-6 and HI-6, used as antidotes in organophosphorus poisoning, is confirmed by 13C NMR spectroscopy.The 13C NMR spectra of the corresponding monopyridinium precursors substantiate the signal assignment in the bispyridinium oxime spectra.In all oximes studied the hydroxyiminomethyl group (-CH=N-OH) exists in the syn configuration.The 13C signal differences also readily allow analysis of binary mixtures of the oximes and provide an easy method for monitoring their stability.
