Synthesis and SAR of 5-Amino- and 5-(Aminomethyl)benzofuran Histamine H<sub>3</sub> Receptor Antagonists with Improved Potency

Sun, Minghua; Zhao, Chen; Gfesser, Gregory A.; Thiffault, Christine; Miller, Thomas R.; Marsh, Kennan C.; Wetter, J.; Curtis, Michael; Faghih, Ramin; Esbenshade, Timothy A.; Hancock, and Arthur A.; Cowart, Marlon

doi:10.1021/jm0504398

Cited by 62 publications

(36 citation statements)

References 41 publications

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“…[183] Subsequent deprotection allowed a more efficient access to the aniline 71 than a alternative route which involved reduction of an aromatic nitro group.…”

Section: Applications In Pharmaceutical Synthesismentioning

confidence: 99%

Biaryl Phosphane Ligands in Palladium‐Catalyzed Amination

2008

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Palladium-catalyzed amination of aryl halides has undergone rapid development in the last 12 years. This has been largely driven by implementation of new classes of ligands. Biaryl phosphines have proven to provide especially active catalysts in this context. This review discusses the applications that these catalysts have found in C-N cross-coupling in heterocycle synthesis, pharmaceuticals, materials science and natural product synthesis.

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“…[183] Subsequent deprotection allowed a more efficient access to the aniline 71 than a alternative route which involved reduction of an aromatic nitro group.…”

Section: Applications In Pharmaceutical Synthesismentioning

confidence: 99%

Biaryl Phosphane Ligands in Palladium‐Catalyzed Amination

2008

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“…8) They are also potent and selective oxytocin antagonists, 9) PDE5 inhibitor for treatment of erectile dysfunction, 10) and H 3 receptor antagonists. 11) In order to synthesise new quinone derivatives we studied the electrochemical oxidation of benzenediols in the presence of a variety of nucleophiles. 12,13) Also, in order to synthesise benzofuran derivatives we investigated the electrochemical oxidation of catechols in the presence of b-diketones such as acetylacetone, 14) dimedone, 15) and dibenzoylmethane.…”

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confidence: 99%

Mechanistic Study of Electrochemical Oxidation of 2,5-Dihydroxybenzoic Acid and 3,4-Dihydroxybenzaldehyde in the Presence of 3-Hydroxy-1H-phenalene-1-one

Nematollahi

Amani

2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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Quinones are of considerable interest because many drugs such as doxorubicin, daunurobicin and mitomycin C in cancer chemotherapy contain quinones, 1) whereas various other quinones have found use in industry.2) Some of them also exhibit antitumor and antimalarial activities 3) and many of them are also involved in enzyme inhibition and DNA cross-linking.4) On the other hand, in recent years, medicinal properties of benzofuran derivatives have been investigated widely and were shown to be effective as antitumor, 5) anti-depressant, 6) antifungal, 7) anti-hypertensive, and cytotoxic. 8) They are also potent and selective oxytocin antagonists, 9) PDE5 inhibitor for treatment of erectile dysfunction, 10) and H 3 receptor antagonists.11) In order to synthesise new quinone derivatives we studied the electrochemical oxidation of benzenediols in the presence of a variety of nucleophiles.12,13) Also, in order to synthesise benzofuran derivatives we investigated the electrochemical oxidation of catechols in the presence of b-diketones such as acetylacetone, 14) dimedone, 15) and dibenzoylmethane. 16) In this connection, the electrochemical oxidation of hydroquinones and catechols in the presence of 3-hydroxy-1H-phenalene-1-one (3) as a nucleophile has been recently reported by us (Chart 1). 17)In the present paper, we describe the preparation of the new polycyclic quinone derivative 6a and the new polycyclic benzofuran derivative 8b using electrooxidation of 2,5-dihydroxybenzoic acid (1a) and 3,4-dihydroxybenzaldehyde (1b) in the presence of 3-hydroxy-1H-phenalene-1-one (3) as a nucleophile via ECE and ECEC electrochemical mechanisms respectively. Results and DiscussionElectrochemical Study of 2,5 Dihydroxybenzoic Acid Cyclic voltammogram of a 0.5 mM of 2,5-dihydroxybenzoic acid (1a) in water/acetonitrile (80/20) solution containing 0.1 M acetate buffer (pHϭ5.5) is shown in Fig. 1 curve a. As can be seen, one anodic (A 1 ) and its corresponding cathodic peak (C 1 ) was obtained, which correspond to the transformation of 2,5-dihydroxybenzoic acid (1a) to the related p-benzoquinone 2a and vice versa within a quasi-reversible twoelectron process. A peak current ratio (I pA1 /I pC1 ) of nearly unity in the cyclic voltammogram can be considered as a criterion for a stable benzoquinone produced at the surface of electrode under the experimental conditions. In other words, any side reactions such as hydroxylation and/or dimerization reactions are too slow to be observed at the time scale of cyclic voltammetry.17) The oxidation of 2,5-dihydroxybenzoic acid (1a) in the presence of 3 as a nucleophile was studied in some detail. Figure 1 (curve b) shows the cyclic voltammogram obtained for a 0.5 mM solution of 1a in the presence of 0.5 mM 3. The voltammogram exhibits one anodic peak A 1 and two cathodic peaks (C 1 and C 0 ). The second cycle in the cyclic voltammogram (Fig. 1, curve c) shows that, parallel to the decrease in current of A 1 and the shift of its potential in a positive direction, a new anodic peak The mechanism of th...

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“…The molecules were from diverse classes: 5-arylaminobenzofuran [19], aliphatic ether [20], cinnamic amides [21], urea analogs of cinnamic amides [22], 4-(aminoalkoxy)benzylamines [8], imidazopyridines [23], 4-phenoxypiperidine [24], indazoline [25], omega-piperidinoalkalamine [26], d-amino acid homopiperazineamides [27], azepine [28], quinoline [29], and benzimidazolones [30].…”

Section: Biological Datamentioning

confidence: 99%

Pharmacophore Refinement and 3D‐QSAR Studies of Histamine H₃ Antagonists

Narkhede

Degani

2007

QSAR Comb. Sci.

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Molecular modeling studies were performed to develop a predictive Common Pharmacophore Hypothesis (CPH) and use it for alignment in 3D-QSAR studies using CoMFA and CoMSIA, with a diverse set of 106 histamine H 3 antagonists. A five point CPH with three hydrophobic features, a basic or positive ionizable feature and an acceptor, for pharmacophore-based alignment of molecules, was derived using PHASE. This hypothesis was selected from a pool, by correlating the observed and estimated activity for the training set and test set of molecules using partial least square analysis. It was found to be comparable to the previously reported hypothesis. The validated pharmacophore hypothesis was used for alignment of molecules in CoMFA and CoMSIA model development. The models so generated showed a good "predictive" r 2 value of 0.763 and 0.820 for CoMFA and CoMSIA, respectively. The contour maps of the models were analyzed to give structural insight for activity improvement of future novel histamine H 3 antagonists. The CPH can also provide a powerful template for virtual screening and design of new histamine H 3 antagonists.

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Synthesis and SAR of 5-Amino- and 5-(Aminomethyl)benzofuran Histamine H₃ Receptor Antagonists with Improved Potency

Cited by 62 publications

References 41 publications

Biaryl Phosphane Ligands in Palladium‐Catalyzed Amination

Biaryl Phosphane Ligands in Palladium‐Catalyzed Amination

Mechanistic Study of Electrochemical Oxidation of 2,5-Dihydroxybenzoic Acid and 3,4-Dihydroxybenzaldehyde in the Presence of 3-Hydroxy-1H-phenalene-1-one

Pharmacophore Refinement and 3D‐QSAR Studies of Histamine H₃ Antagonists

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Synthesis and SAR of 5-Amino- and 5-(Aminomethyl)benzofuran Histamine H3 Receptor Antagonists with Improved Potency

Cited by 62 publications

References 41 publications

Biaryl Phosphane Ligands in Palladium‐Catalyzed Amination

Biaryl Phosphane Ligands in Palladium‐Catalyzed Amination

Mechanistic Study of Electrochemical Oxidation of 2,5-Dihydroxybenzoic Acid and 3,4-Dihydroxybenzaldehyde in the Presence of 3-Hydroxy-1H-phenalene-1-one

Pharmacophore Refinement and 3D‐QSAR Studies of Histamine H3 Antagonists

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Synthesis and SAR of 5-Amino- and 5-(Aminomethyl)benzofuran Histamine H₃ Receptor Antagonists with Improved Potency

Pharmacophore Refinement and 3D‐QSAR Studies of Histamine H₃ Antagonists