Benzimidazole Derivatives. 2. Synthesis and Structure−Activity Relationships of New Azabicyclic Benzimidazole-4-carboxylic Acid Derivatives with Affinity for Serotoninergic 5-HT<sub>3</sub> Receptors

Ml, López-Rodríguez; Benhamú, Bellinda; Mj, Morcillo; Id, Tejada; Orensanz, Luis M.; Mj, Alfaro; Mi, Martín

doi:10.1021/jm991076c

Cited by 43 publications

(16 citation statements)

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“…Benzimidazole derivatives have a myriad of pharmacological uses, including as inhibitors of serotonin-activated neurotransmission (Ló pez-Rodríguez et al, 1999) and as antiviral agents (Varala et al, 2007). They are also used in antiarrhythmic, antihistamine, antiulcer, anticancer, fungicidal, and anthelmintical drugs (Horton et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Structure determination of three furan-substituted benzimidazoles and calculation of π–π and C—H...π interaction energies

Geiger

Deck

2014

Acta Crystallogr C

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The synthesis and structural characterization of 2-(furan-2-yl)-1-(furan-2-ylmethyl)-1H-benzimidazole [C16H12N2O2, (I)], 2-(furan-2-yl)-1-(furan-2-ylmethyl)-1H-benzimidazol-3-ium chloride monohydrate [C16H13N2O2(+)·Cl(-)·H2O, (II)] and the hydrobromide salt 5,6-dimethyl-2-(furan-2-yl)-1-(furan-2-ylmethyl)-1H-benzimidazol-3-ium bromide [C18H17N2O2(+)·Br(-), (III)] are described. Benzimidazole (I) displays two sets of aromatic interactions, each of which involves pairs of molecules in a head-to-tail arrangement. The first, denoted set (Ia), exhibits both intermolecular C-H···π interactions between the 2-(furan-2-yl) (abbreviated as Fn) and 1-(furan-2-ylmethyl) (abbreviated as MeFn) substituents, and π-π interactions involving the Fn substituents between inversion-center-related molecules. The second, denoted set (Ib), involves π-π interactions involving both the benzene ring (Bz) and the imidazole ring (Im) of benzimidazole. Hydrated salt (II) exhibits N-H···OH2···Cl hydrogen bonding that results in chains of molecules parallel to the a axis. There is also a head-to-head aromatic stacking of the protonated benzimidazole cations in which the Bz and Im rings of one molecule interact with the Im and Fn rings of adjacent molecules in the chain. Salt (III) displays N-H···Br hydrogen bonding and π-π interactions involving inversion-center-related benzimidazole rings in a head-to-tail arrangement. In all of the π-π interactions observed, the interacting moieties are shifted with respect to each other along the major molecular axis. Basis set superposition energy-corrected (counterpoise method) interaction energies were calculated for each interaction [DFT, M06-2X/6-31+G(d)] employing atomic coordinates obtained in the crystallographic analyses for heavy atoms and optimized H-atom coordinates. The calculated interaction energies are -43.0, -39.8, -48.5, and -55.0 kJ mol(-1) for (Ia), (Ib), (II), and (III), respectively. For (Ia), the analysis was used to partition the interaction energies into the C-H···π and π-π components, which are 9.4 and 24.1 kJ mol(-1), respectively. Energy-minimized structures were used to determine the optimal interplanar spacing, the slip distance along the major molecular axis, and the slip distance along the minor molecular axis for 2-(furan-2-yl)-1H-benzimidazole.

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Section: Introductionmentioning

confidence: 99%

Structure determination of three furan-substituted benzimidazoles and calculation of π–π and C—H...π interaction energies

Geiger

Deck

2014

Acta Crystallogr C

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“…Reich et al (2004) Table 1 Hydrogen-bond geometry (Å , ). -Rodríguez et al, 1999) and antiarrhythmic, antihistamine, antiulcer, anticancer, fungicidal, and anthelmintical drugs (Horton et al, 2003). The title compound was prepared as part of our efforts to characterize benzimidazole analogues with thiophene substitutents (Geiger & Nellist, 2013a;Geiger & Nellist, 2013b;Geiger & Destefano, 2012;.…”

Section: Related Literaturementioning

confidence: 99%

5,6-Dimethyl-2-(5-methylthiophen-2-yl)-1-[(5-methylthiophen-2-yl)methyl]-1H-benzimidazole

Geiger¹,

Isaac²

2014

Acta Cryst E

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The title molecule, C20H20N2S2, is T-shaped and consists of a nearly flat 5,6-dimethyl-2-(5-methylthiophen-2-yl)benzimidazole system approximately perpendicular to the 5-methylthiophen-2-ylmethyl substituent. The 5,6-dimethyl-2-(5-methylthiophen-2-yl)benzimidazole system is rotationally disordered about the two imidazole N atoms as approximated by a twofold rotation axis with a refined major/minor occupancy ratio of 0.884 (2):0.116 (2). The benzimidazole ring system is essentially planar, the largest deviations being 0.026 (2) and 0.044 (18) Å in the major and minor components, respectively. The interplanar angles between the benzimidazole unit and the 5-methylthiophen-2-yl substituent are 10.8 (3) and 8(3)° in the major and minor components, respectively, and the corresponding angles with the 5-methylthiophen-2-ylmethyl substituent are 88.12 (8) and 89.5 (4)°. In the crystal, molecules are oriented with their 2-(5-methylthiophen-2-yl)benzimidazole mean planes approximately parallel to (11) and appear to be held together by π–π [2-thiophene⋯imidazole centroid–centroid distance = 4.1383 (7) Å] and C—H⋯π contacts. A weak C—H⋯N hydrogen bond generates infinite chains parallel to [100].

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“…Regions of steric tolerance and intolerance, based on the van der Waals surfaces of active and inactive 5-HT 3 and 5-HT 4 ligands for both receptors have been proposed [82], and these models have received some support from the design and synthesis [82,[86][87][88] of two active and selective antagonist ligands (Figure 2): UCM-30593 [K i (5-HT 3 ) = 3.7 nM; K i (5-HT 4 ) > 1000 nM] and UCM-21195 [K i (5- The major difference between the 5-HT 3 and 5-HT 4 R cavities is in the region occupied by the substituent of the HT 4 ) = 13.7 nM; K i (5-HT 3 ) > 10000 nM]. The novel ligand UCM-21195 was used as a lead compound for the design of a new series of benzimidazole-4-carboxylic acid derivatives 1 (Figure 2), in order to analyze the influence of some structural variations of the different pharmacophore elements on the affinity for the 5-HT 4 R, and to develop a novel class of potent and selective 5-HT 4 R antagonists [86,88,89].…”

Section: -Ht 4 Antagonist Pharmacophorementioning

confidence: 99%

5-HT4 Receptor Antagonists: Structure-Affinity Relationships and Ligand- Receptor Interactions

López-Rodrı́guez¹,

Benhamú²,

Morcillo³

et al. 2002

CTMC

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Among serotonin receptors (5-HTRs), the 5-HT(4) subtype is of considerable interest because it is involved in (patho)physiological processes both in peripheral and central nervous systems. In addition to the clinical use of 5-HT(4R) agonists in the treatment of gastrointestinal motility disorders, the potential use of antagonists in the treatment of irritable bowel syndrome, arrhythmias and micturition disturbances are currently under investigation. This article will review the development of the most important classes of 5-HT(4R) antagonists with an emphasis on benzimidazole derivatives, their structure-affinity relationships, ligand-receptor interactions and pharmacological applications.

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Benzimidazole Derivatives. 2. Synthesis and Structure−Activity Relationships of New Azabicyclic Benzimidazole-4-carboxylic Acid Derivatives with Affinity for Serotoninergic 5-HT₃ Receptors

Cited by 43 publications

References 46 publications

Structure determination of three furan-substituted benzimidazoles and calculation of π–π and C—H...π interaction energies

Structure determination of three furan-substituted benzimidazoles and calculation of π–π and C—H...π interaction energies

5,6-Dimethyl-2-(5-methylthiophen-2-yl)-1-[(5-methylthiophen-2-yl)methyl]-1H-benzimidazole

5-HT4 Receptor Antagonists: Structure-Affinity Relationships and Ligand- Receptor Interactions

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Benzimidazole Derivatives. 2. Synthesis and Structure−Activity Relationships of New Azabicyclic Benzimidazole-4-carboxylic Acid Derivatives with Affinity for Serotoninergic 5-HT3 Receptors

Cited by 43 publications

References 46 publications

Structure determination of three furan-substituted benzimidazoles and calculation of π–π and C—H...π interaction energies

Structure determination of three furan-substituted benzimidazoles and calculation of π–π and C—H...π interaction energies

5,6-Dimethyl-2-(5-methylthiophen-2-yl)-1-[(5-methylthiophen-2-yl)methyl]-1H-benzimidazole

5-HT4 Receptor Antagonists: Structure-Affinity Relationships and Ligand- Receptor Interactions

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Benzimidazole Derivatives. 2. Synthesis and Structure−Activity Relationships of New Azabicyclic Benzimidazole-4-carboxylic Acid Derivatives with Affinity for Serotoninergic 5-HT₃ Receptors