Structural and Computational Studies of Anticonvulsants: A Search for Correlation Between Molecular Systematics and Activity

Codding, Penelope W.; Duke, N. E.; Aha, L. J.; Palmér, Lars; McClurg, Doreen; Szkaradzinska, M. B.

doi:10.1007/978-1-4612-3374-9_10

Cited by 2 publications

(12 citation statements)

References 12 publications

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“…It may be tempting to compare the structures of the aminopyrroles and other molecules with anticonvulsant activity to find out the structural elements essential for action. In the past, several attempts were made to postulate a general pharmacophore for the different anticonvulsant classes, e.g., benzodiazepines, barbiturates, triazolines, and enaminones, respectively, − and also for structurally different compounds with similar anticonvulsant profiles. − The various postulated pharmacophore models show no uniform picture. Nevertheless, the presence of at least one aryl unit, one or two electron donor atoms, and/or an NH group in a special spatial arrangement seems to be recommended. − On the basis of some ideas of Camerman and Camerman 30 and Wong et al, respectively, Jones and Woodbury 32,33 defined a model with two electron donors in some proximity to a bulky hydrophobic moiety.…”

Section: Structure−activity Relationshipsmentioning

confidence: 99%

“…In the past, several attempts were made to postulate a general pharmacophore for the different anticonvulsant classes, e.g., benzodiazepines, barbiturates, triazolines, and enaminones, respectively, − and also for structurally different compounds with similar anticonvulsant profiles. − The various postulated pharmacophore models show no uniform picture. Nevertheless, the presence of at least one aryl unit, one or two electron donor atoms, and/or an NH group in a special spatial arrangement seems to be recommended. − On the basis of some ideas of Camerman and Camerman 30 and Wong et al, respectively, Jones and Woodbury 32,33 defined a model with two electron donors in some proximity to a bulky hydrophobic moiety. Selecting other compounds as those of Jones and Woodbury, Codding et al postulated a pharmacophore consisting of a linear arrangement of a rotated phenyl ring, an electron donor atom, and a hydrogen donor site, which partially agrees with the model of Jones and Woodbury.…”

Section: Structure−activity Relationshipsmentioning

confidence: 99%

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Synthesis, Anticonvulsant Activity, and Structure−Activity Relationships of Sodium Channel Blocking 3-Aminopyrroles

Unverferth¹,

Engel²,

Höfgen³

et al. 1998

J. Med. Chem.

158

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Starting from the corresponding acetophenone and glycine derivatives, a series of new 3-aminopyrroles was synthesized in few steps. Using this procedure with hydrazine and hydroxylamine instead of the glycinates provides access to 3-aminopyrazoles and 5-amino 1,2-oxazoles. The various derivatives were tested for anticonvulsant activity in a variety of test models. Several compounds exhibit considerable activity with a remarkable lack of neurotoxicity. 4-(4-Bromophenyl)-3-morpholinopyrrole-2-carboxylic acid methyl ester, 3, proved to be the most active compound. It was protective in the maximal electroshock seizure (MES) test in rats with an oral ED50 of 2.5 mg/kg with no neurotoxicity noted at doses up to 500 mg/kg. Compound 3 blocks sodium channels in a frequency-dependent manner. The essential structural features which could be responsible for an interaction with an active site of the voltage-dependent sodium channel are established within a suggested pharmacophore model.

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Section: Structure−activity Relationshipsmentioning

confidence: 99%

Section: Structure−activity Relationshipsmentioning

confidence: 99%

Synthesis, Anticonvulsant Activity, and Structure−Activity Relationships of Sodium Channel Blocking 3-Aminopyrroles

Unverferth¹,

Engel²,

Höfgen³

et al. 1998

J. Med. Chem.

158

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“…The crystallographic studies of the anticonvulsant drugs enable identification of structural requirements for the biological activity and provide an insight into the probable molecular environment at their binding sites. , In the case of hydantoin derivatives, the crystallographic data have been applied in proposing the mechanism of action because structural elements of their binding sites are present within the molecules themselves. This comprises a combination of both hydrogen bond acceptors and donors to bind the hydantoin moiety and lipophilic groups to bind the alkyl and aryl substituents in position C5 of the hydantoin ring.…”

Section: Introductionmentioning

confidence: 99%

“…This comprises a combination of both hydrogen bond acceptors and donors to bind the hydantoin moiety and lipophilic groups to bind the alkyl and aryl substituents in position C5 of the hydantoin ring. Regarding the steric mode of behavior for hydantoin derivatives, it has been indicated that the spatial properties of these substituents relative to the rest of the molecule is an important factor in mediating the biological activity. − In this context, Camerman and Camerman have suggested that the conformational rather than chemical similarities to the conventional anticonvulsant drugs should be a criterion for the selection of novel drug candidates …”

Section: Introductionmentioning

confidence: 99%

“…Regarding the steric mode of behavior for hydantoin derivatives, it has been indicated that the spatial properties of these substituents relative to the rest of the molecule is an important factor in mediating the biological activity. [7][8][9][10] In this context, Camerman and Camerman have suggested that the conformational rather than chemical similarities to the conventional anticonvulsant drugs should be a criterion for the selection of novel drug candidates. 9 Regarding mechanism of their action, hydantoin derivatives reduce the electrical conductance among neurons through stabilization of voltage-gated sodium channels (VGSCs) in the inactive state.…”

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confidence: 99%

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Substituent Effects on the Patterns of Intermolecular Interactions of 3-Alkyl and 3-Cycloalkyl Derivatives of Phenytoin: A Crystallographic and Quantum-Chemical Study

Trišović

Radovanović

Janjić

et al. 2019

Crystal Growth & Design

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A series of five derivatives of the anticonvulsant drug phenytoin was synthesized and their crystal structures were determined. The relationship between the molecular and crystal structure of the investigated compounds was rationalized in context of contribution of intermolecular interactions and supramolecular structural motifs. The conformational preferences were analyzed by comparing the rotational freedom of the phenyl groups in the investigated compounds with 5,5-diphenylhydantoins from the Cambridge Structural Database. With exception of compound 3 bearing the cyclopropyl group, the crystal packing of the investigated compounds contains centrosymmetric dimers linked by paired N-H•••O hydrogen bonds which further selforganize through pairs of C-H•••O interactions and a parallel interaction of two phenyl rings at a large offset into chains running along the c-axis. The principal feature of the crystal structure of compound 3 is formation of the chains by N-H•••O hydrogen bonds, C-H•••O and C-H•••π interactions. The coordination of phenytoin enables more rotational freedom for the phenyl groups. An emphasis was placed on docking of the investigated compounds into the voltage-gated ion channel in the open and closed state. The obtained results indicate that hydrogen bonding and hydrophobic interactions are dominant in stabilizing energetically-favored orientations of the investigated compounds bound to the protein.

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Structural and Computational Studies of Anticonvulsants: A Search for Correlation Between Molecular Systematics and Activity

Cited by 2 publications

References 12 publications

Synthesis, Anticonvulsant Activity, and Structure−Activity Relationships of Sodium Channel Blocking 3-Aminopyrroles

Synthesis, Anticonvulsant Activity, and Structure−Activity Relationships of Sodium Channel Blocking 3-Aminopyrroles

Substituent Effects on the Patterns of Intermolecular Interactions of 3-Alkyl and 3-Cycloalkyl Derivatives of Phenytoin: A Crystallographic and Quantum-Chemical Study

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