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Rob Leurs - One of the best experts on this subject based on the ideXlab platform.
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homologs of histamine as histamine h3 receptor antagonists a new potent and selective h3 antagonist 4 5 5 aminopentyl 1h imidazole
Journal of Medicinal Chemistry, 1995Co-Authors: R C Vollinga, Wiro M.b.p. Menge, Rob LeursAbstract:The influence of alkyl chain length variation on the histamine H 3 receptor activity of histamine homologs 1 was investigated. A series of 4(5)-(ω-aminoalkyl)-1H-imidazoles 1 was prepared with an alkyl chain length varying from one methylene group to 10 methylene groups. Besides the Hg activity, the affinities of these compounds for the H 1 and H 2 receptors were determined. The ethylene chain of histamine is optimal for agonistic activity on all three histamine receptor subtypes. For the H 3 receptor, elongation of the alkyl chain from three methylene groups on leads to compounds with antagonistic properties. 4(5)-(5-Aminopentyl)-1H-imidazole (impentamine, 1e) is the most potent and selective H 3 antagonist from this series of 4(5)-(ω-aminoalkyl)-1H-imidazoles 1, with a pA 2 value of 8.4 (on guinea pig jejunum). A specific antagonistic binding site for this compound is proposed
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homologs of histamine as histamine h3 receptor antagonists a new potent and selective h3 antagonist 4 5 5 aminopentyl 1h imidazole
Journal of Medicinal Chemistry, 1995Co-Authors: R C Vollinga, Rob Leurs, Wiro M.b.p. Menge, Hendrik TimmermanAbstract:The influence of alkyl chain length variation on the histamine H3 receptor activity of histamine homologs 1 was investigated. A series of 4(5)-(omega-aminoalkyl)-1H-imidazoles 1 was prepared with an alkyl chain length varying from one methylene group to 10 methylene groups. Besides the H3 activity, the affinities of these compounds for the H1 and H2 receptors were determined. The ethylene chain of histamine is optimal for agonistic activity on all three histamine receptor subtypes. For the H3 receptor, elongation of the alkyl chain from three methylene groups on leads to compounds with antagonistic properties. 4(5)-(5-Aminopentyl)-1H-imidazole (impentamine, 1e) is the most potent and selective H3 antagonist from this series of 4(5)-(omega-aminoalkyl)-1H-imidazoles 1, with a pA2 value of 8.4 (on guinea pig jejunum). A specific antagonistic binding site for this compound is proposed.
R C Vollinga - One of the best experts on this subject based on the ideXlab platform.
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homologs of histamine as histamine h3 receptor antagonists a new potent and selective h3 antagonist 4 5 5 aminopentyl 1h imidazole
Journal of Medicinal Chemistry, 1995Co-Authors: R C Vollinga, Wiro M.b.p. Menge, Rob LeursAbstract:The influence of alkyl chain length variation on the histamine H 3 receptor activity of histamine homologs 1 was investigated. A series of 4(5)-(ω-aminoalkyl)-1H-imidazoles 1 was prepared with an alkyl chain length varying from one methylene group to 10 methylene groups. Besides the Hg activity, the affinities of these compounds for the H 1 and H 2 receptors were determined. The ethylene chain of histamine is optimal for agonistic activity on all three histamine receptor subtypes. For the H 3 receptor, elongation of the alkyl chain from three methylene groups on leads to compounds with antagonistic properties. 4(5)-(5-Aminopentyl)-1H-imidazole (impentamine, 1e) is the most potent and selective H 3 antagonist from this series of 4(5)-(ω-aminoalkyl)-1H-imidazoles 1, with a pA 2 value of 8.4 (on guinea pig jejunum). A specific antagonistic binding site for this compound is proposed
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homologs of histamine as histamine h3 receptor antagonists a new potent and selective h3 antagonist 4 5 5 aminopentyl 1h imidazole
Journal of Medicinal Chemistry, 1995Co-Authors: R C Vollinga, Rob Leurs, Wiro M.b.p. Menge, Hendrik TimmermanAbstract:The influence of alkyl chain length variation on the histamine H3 receptor activity of histamine homologs 1 was investigated. A series of 4(5)-(omega-aminoalkyl)-1H-imidazoles 1 was prepared with an alkyl chain length varying from one methylene group to 10 methylene groups. Besides the H3 activity, the affinities of these compounds for the H1 and H2 receptors were determined. The ethylene chain of histamine is optimal for agonistic activity on all three histamine receptor subtypes. For the H3 receptor, elongation of the alkyl chain from three methylene groups on leads to compounds with antagonistic properties. 4(5)-(5-Aminopentyl)-1H-imidazole (impentamine, 1e) is the most potent and selective H3 antagonist from this series of 4(5)-(omega-aminoalkyl)-1H-imidazoles 1, with a pA2 value of 8.4 (on guinea pig jejunum). A specific antagonistic binding site for this compound is proposed.
Walter A Szarek - One of the best experts on this subject based on the ideXlab platform.
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heme oxygenase inhibition by 2 oxy substituted 1 azolyl 4 phenylbutanes effect of variation of the azole moiety x ray crystal structure of human heme oxygenase 1 in complex with 4 phenyl 1 1h 1 2 4 triazol 1 yl 2 butanone
Chemical Biology & Drug Design, 2010Co-Authors: Gheorghe Roman, Mona N Rahman, Dragic Vukomanovic, Zongchao Jia, Kanji Nakatsu, Walter A SzarekAbstract:A series of 1-azolyl-4-phenyl-2-butanones was designed and synthesized for the inhibition of heme oxygenases (heme oxygenase-1 and heme oxygenase-2). The replacement of imidazole by other azoles led to the discovery of novel 1H-1,2,4-triazole- and 1H-tetrazole-based inhibitors equipotent to a lead imidazole-based inhibitor. The inhibitors featuring 2H-tetrazole or 1H-1,2,3-triazole as the pharmacophore were less potent. Monosubstitution at position 2 or 4(5), or identical disubstitution at positions 4 and 5 of imidazole by a variety of electron-withdrawing or electron-donating, small or bulky groups, as well as the replacement of the traditional imidazole pharmacophore by an array of 3- or 5-substituted triazoles, identically 3,5-disubstituted triazoles, 5-substituted-1H- and 5-substituted-2H-tetrazoles proved to be detrimental to the inhibition of HO, with a few exceptions. The azole-dioxolanes and the azole-alcohols derived from the active azole-ketones were synthesized also, but these inhibitors were less active than the corresponding imidazole-based analogs. The first reported X-ray crystal structure of human heme oxygenase-1 in complex with a 1,2,4-triazole-based inhibitor, namely 4-phenyl-1-(1H-1,2,4-triazol-1-yl)-2-butanone, was also determined. The inhibitor binds to the human heme oxygenase-1 distal pocket through the coordination of heme iron by the N 4 in the triazole moiety, whereas the phenyl group is stabilized by hydrophobic interactions from residues within the binding pocket.
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heme oxygenase inhibition by 2 oxy substituted 1 1h imidazol 1 yl 4 phenylbutanes effect of halogen substitution in the phenyl ring
Bioorganic & Medicinal Chemistry, 2007Co-Authors: Gheorghe Roman, Kanji Nakatsu, John G Riley, Jason Z Vlahakis, Robert T Kinobe, James F Brien, Walter A SzarekAbstract:Abstract A series of 2-oxy-substituted 1-(1H-imidazol-1-yl)-4-phenylbutanes comprising imidazole–ketones, imidazole–dioxolanes, and imidazole–alcohols substituted with halogens in the phenyl ring were synthesized and evaluated as novel inhibitors of heme oxygenase which are structurally distinct from metalloporphyrins. The entire library of compounds was found to be highly active, with the bromine- and iodine-substituted derivatives being the most potent. The imidazole–dioxolanes were all selective for the HO-1 isozyme (inducible) and exhibited substantially lower activity toward the HO-2 isozyme (constitutive). The corresponding imidazole–ketones and imidazole–alcohols showed selectivity toward HO-1 to a lesser degree than the similarly substituted imidazole–dioxolanes.
Panayiotis A. Koutentis - One of the best experts on this subject based on the ideXlab platform.
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Reactions of Tetracyanoethylene with N′‑Arylbenzamidines: A Route to 2‑Phenyl‑3H‑imidazo[4,5‑b]quinoline-9-carbonitriles
2016Co-Authors: Styliana I. Mirallai, Maria Manoli, Panayiotis A. KoutentisAbstract:Eight 2-phenyl-3H-imidazo[4,5-b]quinoline-9-carbonitriles 15 are prepared in four steps from N′-arylbenzamidines 11 and tetracyanoethylene (TCNE) in ∼70–90% yields. The transformation involves the initial formation of N-aryl-N′-(1,2,2-tricyanovinyl)benzamidines 12 in 87–99% yields, which in MeCN undergo a 5-exodig cyclization to give the 2-[1-aryl-5-imino-2-phenyl-1H-imidazol-4(5H)-ylidene]malononitriles 13 in 84–92% yields, while in MeOH the (Z)-2-[2-phenyl-4-(arylimino)-1H-imidazol-5(4H)-ylidene]malononitriles 14 are formed in 85–94% yields. The imidazoles 14 can also be prepared directly from imidazoles 13 via a Dimroth rearrangement in either neat MeOH or in DCM with DBU. Subsequent thermolysis of imidazoles 14 in diphenyl ether affords 2-phenyl-3H-imidazo[4,5-b]quinoline-9-carbonitriles 15 in near quantitative yields. Mechanistic rationale is provided for all transformations
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reactions of tetracyanoethylene with n arylbenzamidines a route to 2 phenyl 3h imidazo 4 5 b quinoline 9 carbonitriles
Journal of Organic Chemistry, 2013Co-Authors: Styliana I. Mirallai, Maria Manoli, Panayiotis A. KoutentisAbstract:Eight 2-phenyl-3H-imidazo[4,5-b]quinoline-9-carbonitriles 15 are prepared in four steps from N′-arylbenzamidines 11 and tetracyanoethylene (TCNE) in ∼70–90% yields. The transformation involves the initial formation of N-aryl-N′-(1,2,2-tricyanovinyl)benzamidines 12 in 87–99% yields, which in MeCN undergo a 5-exodig cyclization to give the 2-[1-aryl-5-imino-2-phenyl-1H-imidazol-4(5H)-ylidene]malononitriles 13 in 84–92% yields, while in MeOH the (Z)-2-[2-phenyl-4-(arylimino)-1H-imidazol-5(4H)-ylidene]malononitriles 14 are formed in 85–94% yields. The imidazoles 14 can also be prepared directly from imidazoles 13 via a Dimroth rearrangement in either neat MeOH or in DCM with DBU. Subsequent thermolysis of imidazoles 14 in diphenyl ether affords 2-phenyl-3H-imidazo[4,5-b]quinoline-9-carbonitriles 15 in near quantitative yields. Mechanistic rationale is provided for all transformations.
Gheorghe Roman - One of the best experts on this subject based on the ideXlab platform.
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A novel antifungal agent with broad spectrum: 1-(4-biphenylyl)-3-(1H-imidazol-1-yl)-1-propanone.
Archiv der Pharmazie, 2012Co-Authors: Gheorghe Roman, Mihai Mares, Valentin NastasaAbstract:A series of (1-substituted aryl)-3-(1H-imidazol-1-yl)-1-propanones was synthesized through the N-alkylation of imidazole with 3-dimethylamino-1-(substituted aryl)-1-propanone hydrochlorides (ketonic Mannich bases). A second series of N(1) -substituted imidazoles was obtained by the reduction of the carbonyl function of the imidazole-ketones in the previous series by means of NaBH(4) . All of the compounds were evaluated for antifungal activity against 16 strains of Candida, and 3-(1H-imidazol-1-yl)-1-(4-biphenylyl)-1-propanone emerged as a broad-spectrum antifungal agent. Several 3-(1H-imidazol-1-yl)-1-(2'-(substituted benzyl)oxyphenyl)-1-propanones were also active towards Candida kefyr.
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heme oxygenase inhibition by 2 oxy substituted 1 azolyl 4 phenylbutanes effect of variation of the azole moiety x ray crystal structure of human heme oxygenase 1 in complex with 4 phenyl 1 1h 1 2 4 triazol 1 yl 2 butanone
Chemical Biology & Drug Design, 2010Co-Authors: Gheorghe Roman, Mona N Rahman, Dragic Vukomanovic, Zongchao Jia, Kanji Nakatsu, Walter A SzarekAbstract:A series of 1-azolyl-4-phenyl-2-butanones was designed and synthesized for the inhibition of heme oxygenases (heme oxygenase-1 and heme oxygenase-2). The replacement of imidazole by other azoles led to the discovery of novel 1H-1,2,4-triazole- and 1H-tetrazole-based inhibitors equipotent to a lead imidazole-based inhibitor. The inhibitors featuring 2H-tetrazole or 1H-1,2,3-triazole as the pharmacophore were less potent. Monosubstitution at position 2 or 4(5), or identical disubstitution at positions 4 and 5 of imidazole by a variety of electron-withdrawing or electron-donating, small or bulky groups, as well as the replacement of the traditional imidazole pharmacophore by an array of 3- or 5-substituted triazoles, identically 3,5-disubstituted triazoles, 5-substituted-1H- and 5-substituted-2H-tetrazoles proved to be detrimental to the inhibition of HO, with a few exceptions. The azole-dioxolanes and the azole-alcohols derived from the active azole-ketones were synthesized also, but these inhibitors were less active than the corresponding imidazole-based analogs. The first reported X-ray crystal structure of human heme oxygenase-1 in complex with a 1,2,4-triazole-based inhibitor, namely 4-phenyl-1-(1H-1,2,4-triazol-1-yl)-2-butanone, was also determined. The inhibitor binds to the human heme oxygenase-1 distal pocket through the coordination of heme iron by the N 4 in the triazole moiety, whereas the phenyl group is stabilized by hydrophobic interactions from residues within the binding pocket.
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heme oxygenase inhibition by 2 oxy substituted 1 1h imidazol 1 yl 4 phenylbutanes effect of halogen substitution in the phenyl ring
Bioorganic & Medicinal Chemistry, 2007Co-Authors: Gheorghe Roman, Kanji Nakatsu, John G Riley, Jason Z Vlahakis, Robert T Kinobe, James F Brien, Walter A SzarekAbstract:Abstract A series of 2-oxy-substituted 1-(1H-imidazol-1-yl)-4-phenylbutanes comprising imidazole–ketones, imidazole–dioxolanes, and imidazole–alcohols substituted with halogens in the phenyl ring were synthesized and evaluated as novel inhibitors of heme oxygenase which are structurally distinct from metalloporphyrins. The entire library of compounds was found to be highly active, with the bromine- and iodine-substituted derivatives being the most potent. The imidazole–dioxolanes were all selective for the HO-1 isozyme (inducible) and exhibited substantially lower activity toward the HO-2 isozyme (constitutive). The corresponding imidazole–ketones and imidazole–alcohols showed selectivity toward HO-1 to a lesser degree than the similarly substituted imidazole–dioxolanes.
