- Synthesis and anti-hiv activity of a novel series of isoquinoline-based cxcr4 antagonists
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An expansion of the structure–activity relationship study of CXCR4 antagonists led to the synthesis of a series of isoquinolines, bearing a tetrahydroquinoline or a 3-methylpyridinyl moiety as head group. All compounds were investigated for CXCR4 affinity and antagonism in competition binding and calcium mobilization assays, respectively. In addition, the anti-HIV activity of all analogues was determined. All compounds showed excellent activity, with compound 24c being the most promising one, since it displayed consistently low nanomolar activity in the various assays.
- Claes, Sandra,De Jonghe, Steven,Dehaen, Wim,Goffin, Eline,Schols, Dominique,Shad, Mastaneh Safarnejad,Van Loy, Tom
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- 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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- Effect of substituent in pyridine-2-carbaldehydes on their heterocyclization to 1,2,4-triazines and 1,2,4-triazine 4-oxides
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A series of substituted pyridine-2-carbaldehydes were brought into heterocyclization with isonitrosoacetophenone hydrazones, followed by aromatization by the action of oxidants or by dehydration in boiling acetic acid. As a result, substituted 3-(pyridin-2-yl)-1,2,4-triazines or 3-(pyridin-2-yl)-1,2,4-triazine 4-oxides were formed. 6-Formylpyridine-2-carbonitrile failed to undergo heterocyclization, 6-methylpyridine-2-carbaldehyde and methyl 6-formylpyridine-3-carboxylate can be converted to both 1,2,4-triazine and 1,2,4-triazine 4-oxide derivative, and only 1,2,4-triazine 4 oxides were obtained from 6-bromopyridine-2-carbaldehyde and 6-formyl-3-phenylpyridine-2-carbonitrile. Convenient procedures were proposed for the synthesis of some initial pyridinecarbaldehydes.
- Krinochkin,Kopchuk,Chepchugov,Kovalev,Zyryanov,Rusinov,Chupakhin
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p. 963 - 970
(2017/09/07)
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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 64
(2010/02/12)
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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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- Photochemical synthesis, conformational analysis, and transformation of [60]fullerene-o-quinodimethane adducts bearing a hydroxy group
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The photochemical reactions of [60]fullerene with various aromatic aldehydes or ketones 1a-n carrying an alkyl group at the ortho position were examined. Some of them afforded stable o-quinodimethane adducts 2 with a hydroxy group attached to the cyclohexene ring. The adducts 2 were found to adopt one or both of two conformers A and E, which possess pseudoaxial and pseudoequatorial hydroxy groups, respectively. The conformer ratios depended remarkably on the substituents attached to the aromatic nucleus and the cyclohexene ring. The dynamic behavior of 2 was also investigated by the VT-NMR technique.
- Nakamura, Yosuke,O-kawa, Kyoji,Minami, Satoshi,Ogawa, Toshio,Tobita, Seiji,Nishimura, Jun
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p. 1247 - 1252
(2007/10/03)
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- NITROGEN-CONTAINING HETEROCYCLIC COMPOUNDS AND BENAMIDE COMPOUNDS AND DRUGS CONTAINING THE SAME
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Disclosed are compounds represented by formula (I) which have triglyceride biosynthesis inhibitory activity in the liver and inhibitory activity against the secretion of apolipoprotein B-containing lipoprotein from the liver and particularly have excellent inhibitory activity against the secretion of apolipoprotein B-containing lipoprotein, are free from side effect of accumulation of lipids in the liver, and are useful for the treatment and prevention of hyperlipidemia and arteriosclerotic diseases. In formula (I), R1 and R2 represent alkyl, alkoxy, cycloalkyl, phenyl, alkenyl, alkynyl, or a five- or six-membered saturated or unsaturated heterocyclic ring, or R1 and R2, together with a nitrogen atom to which R1 and R2 are attached, may form a ring; R3 and R4 represent a hydrogen atom, alkyl, a halogen atom, hydroxyl, nitrile, alkoxycarbonyl, alkoxy, or carboxyl; or R2 and R3 may be attached to each other to form -(CH2)m-, -N=CH-, -CH=N-, or -(C1-6 alkyl)C=N-; A, D, E, and G each represent a carbon atom, or any one of A, D, E, and G represents a nitrogen atom with the other three each representing a carbon atom; Q represents a nitrogen atom or a carbon atom; Y represents a group represented by formula (II) wherein X represents a hydrogen atom, group -C(=O)N(R5)R6 or group -C(=O)OR7, R8 is absent or represents a bond, an oxygen atom, a sulfur atom, -SO2-, -SO-, -CH2-CH2-, or - CH=CH-, and R9 and R10 represent a hydrogen atom, alkyl, alkoxy, a halogen atom, or hydroxyl; and Z represents - (CH2)n-, -O-(CH2)i-, or -C(=O)NH-(CH2)i-.
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- Synthesis, rotamer orientation, and calcium channel modulation activities of alkyl and 2-phenethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates
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A group of racemic alkyl and 2-phenethyl 1,4-dihydro-2,6-dimethyl-3- nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates (13a-q) was prepared using a modified Hantzsch reaction that involved the condensation of a 3- or 6-substituted-2-pyridinecarboxaldehyde (7a-j) with an alkyl or 2- phenethyl 3-aminocrotonate (11a-d) and nitroacetone (12). Nuclear Overhauser (NOE) studies indicated there is a significant rotamer fraction in solution where the pyridyl nitrogen is oriented above the 1,4-dihydropyridine ring, irrespective of whether a substituent is located at the 3- or 6-position. A potential H-bonding interaction between the pyridyl nitrogen free electron pair and the suitably positioned 1,4-dihydropyridine NH moiety may stablize this rotamer orientation. In vitro calcium channel antagonist and agonist activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays, respectively. Compounds having an i-Pr ester substituent acted as dual cardioselective calcium channel agonists (GPLA)/smooth muscle-selective calcium channel antagonists (GPILSM), except for the C-4 3-nitro-2-pyridyl compound which exhibited an antagonist effect on both GPLA and GPILSM. In contrast, the compounds with a phenethyl ester group, which exhibited antagonist activity (IC50 = 10-5- 10-7 M range) on GPILSM, were devoid of cardiac agonist activity on GPLA. Structure-activity relationships showing the effect of a substituent (Me, CF3, C1, NO2, Ph) at the 3- or 6-position of a C-4 2-pyridyl moiety and a variety of ester substituents (Me, Et, i-Pr, PhCH2CH2-) upon calcium channel modulation are described. Compounds possessing a 3- or 6-substituted- 2-pyridyl moiety, in conjuction with an i-Pr ester substituent, are novel 1,4-dihydropyridine calcium channel modulators that offer a new drug design approach directed to the treatment of congestive heart failure and may also be useful as probes to study the structure-function relationships of calcium channels.
- Iqbal, Nadeem,Akula, Murthy R.,Vo, Dean,Matowe, Wandikayi C.,McEwen, Carol-Anne,Wolowyk, Michael W.,Knaus, Edward E.
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p. 1827 - 1837
(2007/10/03)
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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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