- Methyl Scanning and Revised Binding Mode of 2-Pralidoxime, an Antidote for Nerve Agent Poisoning
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Organophosphorus nerve agents (OPNAs) inhibit acetylcholinesterase (AChE) and, despite the Chemical Weapons Convention arms control treaty, continue to represent a threat to both military personnel and civilians. 2-Pralidoxime (2-PAM) is currently the only therapeutic countermeasure approved by the United States Food and Drug Administration for treating OPNA poisoning. However, 2-PAM is not centrally active due to its hydrophilicity and resulting poor blood-brain barrier permeability; hence, these deficiencies warrant the development of more hydrophobic analogs. Specifically, gaps exist in previously published structure activity relationship (SAR) studies for 2-PAM, thereby making it difficult to rationally design novel analogs that are concomitantly more permeable and more efficacious. In this study, we methodically performed a methyl scan on the core pyridinium of 2-PAM to identify ring positions that could tolerate both additional steric bulk and hydrophobicity. Subsequently, SAR-guided molecular docking was used to rationalize hydropathically feasible binding modes for 2-PAM and the reported derivatives. Overall, the data presented herein provide new insights that may facilitate the rational design of more efficacious 2-PAM analogs.
- Gambino, Adriana,Burnett, James C.,Koide, Kazunori
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supporting information
p. 1893 - 1898
(2020/02/06)
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- ANALOGS OF 2-PRALIDOXIME AS ANTIDOTES AGAINST ORGANOPHOSPHORUS NERVE AGENTS
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Provided herein are compounds useful in treating exposure to an organophosphorus compound, such as a nerve agent, pesticide, or, generally, an acetylcholinesterase inhibitor, such as sarin. Compositions, e.g. pharmaceutical compositions or dosage forms, comprising the compounds also are provided herein. Methods of treating a patient exposed to a nerve agent, pesticide, or, generally, an acetylcholinesterase inhibitor, e.g., an organophosphorus compound, such as sarin, also are provided.
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Paragraph 00115
(2020/02/23)
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- Cobalt(II)-based Metalloradical Activation of 2-(Diazomethyl)pyridines for Radical Transannulation and Cyclopropanation
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A new catalytic method for the denitrogenative transannulation/cyclopropanation of in-situ-generated 2-(diazomethyl)pyridines is described using a cobalt-catalyzed radical-activation mechanism. The method takes advantage of the inherent properties of a CoIII-carbene radical intermediate and is the first report of denitrogenative transannulation/cyclopropanation by a radical-activation mechanism, which is supported by various control experiments. The synthetic benefits of the metalloradical approach are showcased with a short total synthesis of (±)-monomorine.
- Roy, Satyajit,Das, Sandip Kumar,Chattopadhyay, Buddhadeb
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supporting information
p. 2238 - 2243
(2018/02/19)
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- Tuning of the properties of transition-metal bispidine complexes by variation of the basicity of the aromatic donor groups
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Bispidines (3,7-diazabicyclo[3.3.1]nonanes) as very rigid and highly preorganized ligands find broad application in the field of coordination chemistry, and the redox potentials of their transition-metal complexes are of importance in oxidation reactions by high-valent iron complexes, aziridination catalyzed by copper complexes, and imaging by 64Cu positron emission tomography tracers. Here, we show that the redox potentials and stability constants of the copper(II) complexes of 15 tetradentate bispidines can be varied by substitution of the pyridine rings (variation of the redox potential over ca. 450 mV and of the complex stability over approximately 10 log units). It is also shown that these variations are predictable by the pKa values of the pyridine groups as well as by the Hammett parameters of the substituents, and the density functional theory based energy decomposition analysis also allows one to accurately predict the redox potentials and concomitant complex stability. It is shown that the main contribution emerges from the electrostatic interaction energy, and the partial charges of the pyridine donor groups therefore also correlate with the redox potentials.
- Comba, Peter,Morgen, Michael,Wadepohl, Hubert
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p. 6481 - 6501
(2013/07/19)
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- Optimized strategies to synthesize β-cyclodextrin-oxime conjugates as a new generation of organophosphate scavengers
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A new generation of organophosphate (OP) scavengers was obtained by synthesis of β-cyclodextrin-oxime derivatives 8-12. Selective monosubstitution of β-cyclodextrin was the main difficulty in order to access these compounds, because reaction onto the olig
- Le Provost, Romain,Wille, Timo,Louise, Ludivine,Masurier, Nicolas,Mueller, Susanne,Reiter, Georg,Renard, Pierre-Yves,Lafont, Olivier,Worek, Franz,Estour, Franois
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supporting information; experimental part
p. 3026 - 3032
(2011/06/17)
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- AMINE COMPOUNDS AND USE THEREOF
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It is intended to provide novel amine compounds which are efficacious against diseases such as infection with HIV virus, rheumatism and cancer metastasis. Namely, amine compounds represented by the following general formula (1):In a typical case, A1 and A2 represent each an optionally substituted monocyclic or polycyclic aromatic heterocycle; W represents cyclic C3-10 alkylene, an optionally substituted monocyclic or polycyclic aromatic heterocycle, a monocyclic or polycyclic aromatic ring or a partly saturated polycyclic aromatic ring; X represents O, CH2, C(=O) or NR11; and D is a group represented by the following general formula (4) or (6).-Q-Y-BIn the formula (6), Q represents a single bond, S, O or NR12; and Y is a group represented by the following general formula (7). z represents an optionally substituted monocyclic or polycyclic aromatic ring. In the formula (6), B represents NR25R26. In the above formulae, R1 to R26 each represents hydrogen, alkyl, alkenyl or alkynyl.
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Page/Page column 76
(2010/02/12)
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- 1,3-BENZOTHIAZINONE DERIVATIVES AND USE THEREOF
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This invention provides a compound represented by the formula (I) :wherein R1 is a hydrogen atom, a halogen atom, hydroxy, nitro, optionally halogenated alkyl, alkoxy optionally having substituents, acyl or amino optionally having substituents;R2 is pyridyl, furyl, thienyl, pyrrolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, tetrahydroquinolyl or thiazolyl, each of which may have substituents;n is 1 or 2; or a salt. And this invention provides a safe pharmaceutical comprising the compound of the formula (I) , which has an excellent apoptosis inhibitory effect and MIF binding effect, for preventing and/or treating heart disease, nervous degenerative disease, cerebrovascular disease, central nervous infectious disease, traumatorathy, demyelinating disease, bone and articular disease, kidney disease, liver disease, osteomyelodysplasia, AIDS, cancer, and the like.
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- NEW COMPOUNDS
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The present invention relates to new compounds of formula I, wherein P Q X1 X2 X3 X4 X5 R R1 R2 R3 R4R5 G M1 M2 M3 m and n are defined as in formula I, a process for their preparation and new intermediates prepared therein, pharmaceutical formulations containing said compounds and to the use of said compounds in therapy.
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- NOVEL NITROGENOUS COMPOUND AND USE THEREOF
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A novel nitrogen-containing compound effective against diseases such as HIV viral infectious diseases, rheumatism, and cancerous metastasis. It is a nitrogen-containing compound represented by the following general formula (1). In the formula, A typically represents a group represented by the formula (2) (A1 is hydrogen or an optionally substituted, mono- or polycyclic, heteroaromatic or aromatic ring; G1 is a single bond or a hydrocarbon group represented by the following formula (3) wherein R1, R2, and R3 may be optionally substituted hydrocarbon groups); W is an optionally substituted hydrocarbon group or heterocyclic ring; x is -C(=O)NH-; y is -C(=O)-; and D1 is hydrogen atom, alkyl having a polycyclic aromatic ring, di (substituted alkyl)amine, or alicyclic amine.
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- Alpha-substituted pyrimidine-thioalkyl and alkylether compounds as inhibitors of viral reverse transcriptase
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The subject invention relates to pyrimidine-thioalkyl and alkylether compounds of Formula (I) and pyrimidine-thioalkyl and alkylethers of Formula (IA), namely the compounds of Formula (I) where R 4 is selected from the group consisitng of --H or --NR 15 R 16 where R 15 is --H and R 16 is --H, C 1 -C 6 alkyl, NH 2 or R 15 and R 16 taken together with the --N form 1-pyrrolidino, 1-morpholino or 1-piperidino; and R 6 is selected from the group consisting of --H, or halo (preferably --Cl); with the overall proviso that R 4 and R 6 are not both --H. The compounds of Formula (IA) are useful in the treatment of individuals who are HIV positive being inhibitors of viral reverse transcriptase. STR1
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- Substituted 6,11-ethano-6,11-dihydrobenzo[b] quinolizinium salts and compositions and methods of use thereof
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Substituted 6,11-ethano-6,11-dihydrobenzo[b]quinolizinium salts, pharmaceutical compositions containing them, and methods for the treatment of neurodegenerative disorders or neurotoxic injuries utilizing them, wherein the substituted 6,11-ethano-6,11-dihydrobenzo[b]quinolizinium salts have the formula: STR1 wherein: R1, R2, R3, R4, R5, R6, R7, X and p are as defined in the specification.
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- Substituted 2-acylpyridine-α-(N)-hetarlyhydrazones and medicaments containing the same
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Substituted 2-acylpyridine-α-(N)-hetarylhydrazones are described, which are suitable as active substances for the treatment of antimicrobial and in particular antimycobacterial diseases, as well as active substances for the treatment of malaria or malignant tumours. The compounds have a marked synergistic activity combined with inhibitors of folate synthase, dihydrofolic acid reductase, DNA-synthesis and RNA-synthesis.
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- Design, synthesis, and characterization of bis(μ-oxo)dimanganese(III,III) complexes. Steric and electronic control of redox potentials
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The syntheses of three bis(μ-oxo)dimanganese(III,III) complexes and one bis(μ-oxo)dimanganese(III,IV) complex are described. The Mn(III/III) complexes are all of the general formulation [(L)MnO]22+, where the ligands L are related to N,N′-bis(2-pyridylmethyl)-1,2-ethanediamine (bispicen, la) and tris(2-pyridylmethyl)amine (tmpa, 2a). The complex bis(μ-oxo)bis[N,N′-bis((6-methylpyrid-2-yl)methyl)ethane-1,2-diamine] dimanganese(III) perchlorate monohydrate, [(1b)MnO]2(ClO4)2·H2O, Mn2C32H46Cl2N8O 11 (4), crystallizes in the triclinic space group P1? with two binuclear complexes in a cell of dimensions a = 8.487 (3) A?, b = 10,868 (2) A?, c = 20.816 (5) A?, α = 77.34 (2)°, β= 88.28 (2)°, and γ = 84.02 (2)°. The structure has been refined to a value of the conventional R factor of 0.0759 based on 2787 independent observations. The complex bis(μ-oxo)bis[N,N-bis((6-methylpyrid-2-yl)methyl)-N-2-pyridylmethylamine] dimanganese(III) nitrate hexahydrate, [(2c)MnO]2(NO3)2·6H2O, Mn2C40H56N10O14 (5), crystallizes in the monoclinic space group C2/c with four binuclear complexes in a cell of dimensions a = 22.122 (7)A?, b = 16.419 (6) A?, c = 14.461 (4) A?, β = 117.15(2)°. The structure has been refined to an R factor of 0.0683 based on 1396 independent observations. The complex bis(μ-oxo)bis[N,N′-bis(2-methylpyrazyl)ethane-1,2-diamine] dimanganese(III) perchlorate heptahydrate, [(1d)MnO]2(ClO4)2·7H2O, Mn2C24H46Cl2N12O 17 (7), crystallizes in the monoclinic space group C2 with four binuclear complexes in a cell of dimensions a = 21.371 (5) A?, b = 9.301 (3) A?, c = 21.180 (7) A?, β= 108.54 (2)°. The structure has been refined to an R value of 0.0515 based on 3766 independent observations. The complexes are all found to contain the isomer in which the substituted pyridine (or the pyrazine) groups are trans axially disposed around the metal relative to the bridging oxo groups. Complexes 4 and 5 display very long axial Mn-N bonds which can be attributed to the presence of the 6-methyl groups on the pyridine rings, and this steric constraint has been demonstrated to be the cause of the stabilization of the Mn(III,III) form in these complexes. In complex 7, the stabilization of the III/III form is an electronic consequence of the change from pyridine (pKa = 5.20) to pyrazine (pKa = 0.65). Cyclic voltammograms of 4 and 5 show that the two redox waves are shifted by approximately 0.4 V in the positive direction in each case relative to the "parent" bispicen and tmpa complexes. The fully oxidized form of complex 5 has been shown to act as a two-electron electrocatalytic oxidant, selectively oxidizing benzyl alcohol to benzaldehyde.
- Goodson, Patricia A.,Oki, Aderemi R.,Glerup, J?rgen,Hodgson, Derek J.
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p. 6248 - 6254
(2007/10/02)
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- REACTIVITY OF METHYL DERIVATIVES OF NITROGENOUS HETEROCYCLES IN VAPOR-PHASE CATALYTIC OXIDATION
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A study has been made of the reactivity of methylpyridines, methylpyrazines, and methylquinolines in oxidation in the vapor phase in the presence of β-VO(PO3)2.Relationships have been found between the overall reaction rates of heterocyclic compounds and the charge on the ring nitrogen, and between the partial oxidation rate and the charge on the ring carbon atom adjacent to the methyl group.The partial oxidation rate of methylpyridines is given to a first approximation by the Hammett-type expression lnWa = -3.5 + 4.6 Σ?, with a correlation coefficient of 0.93.
- Leitis, L. Ya.,Skolmeistere, R. A.,Golender, L. O.,Yansone, D. P.,Meksh, P. A.,Shimanskaya, M. V.
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