Effect of branching in 4-alkylpyrazoles on liver alcohol dehydrogenase inhibition: A shape analysis study

doi:10.1016/0263-7855(94)80103-7

Journal of Molecular Graphics

Volume 12, Issue 4, December 1994, Pages 267-274

Journal of Molecular...

https://doi.org/10.1016/0263-7855(94)80103-7 Get rights and content

Abstract

Shape analysis methodology is applied to the study of 4-alkylpyrazoles which are known inhibitors of liver alcohol dehydrogenase. Elongation of the alkyl chain increases the inhibitory power, whereas branching of the chain diminishes the activity. These two counterpoised effects are studied simultaneously in a selected set of 4-alkylpyrazoles. A systematic conformational analysis followed by topological characterization of the van der Waals surfaces of all the local minima restricts the conformational space to potential bioactive structures. The analysis of the interrelation between the molecular electrostatic potential and van der Waals surfaces provides certain shape codes characteristic of each 4-alkylpyrazole. In both topological analyses van der Waals surfaces and molecular electrostatic potential van der Waals surface interrelations) graphical representations and analytical methods were used. A good correlation between the shape codes and the inhibitory activity is found for the linear derivatives. For branched pyrazoles, a tendency in their inhibitory power is predicted. Isopentylpyrazole is suggested to have the same inhibitory profile as 4-butylpyrazole, the linear derivative with one less carbon atom.

References (27)

M. Martín
(1993)
I. Rozas et al.
On the inhibition of alcohol dehydrogenase: shape group analysis of molecular electrostatic potential on van der Waals surfaces for some pyrazole deriv
Int. J. Quantum Chem.: QBS.
(1991)
I. Rozas et al.
Modeling the effect of Zn(II) on the hydrogen transfer inhibition processes
Can. J. Chem.
(1992)
Rozas I. and Arteca G.A. unpublished...
T.-K. Li
Enzymology of human alcohol metabolism
Adv. Enzymol. Rel. Areas Mol.
(1977)
H. Theorell et al.
On the effects of some heterocyclic compounds on the enzymatic activity of liver alcohol dehydrogenase
Acta Chem. Scand.
(1969)
R.W. Fries et al.
3-Substituted pyrazole derivatives as inhibitors and inactivators of liver alcohol dehyrogenase
J. Med. Chem.
(1979)
M.S. Tute
Principle and practice of Hansch analysis: A Guide to structure-activity correlation for the medicinal chemist
Adv. Drug Res.
(1971)
B.-R. Tolf et al.
Synthetic inhibitors of Alcohol Dehydrogenase. 4-Substituted alkyl and cyclo-alkylpyrazoles
Acta Chem. Scand.
(1979)

P.G. Mezey

Group theory of electrostatic potentials: a tool for quantum chemical drug design

Int. J. Quantum Chem.: QBS.

(1986)

P.G. Mezey

Group theory of shapes of asymmetric biomolecules

(1987)

P.G. Mezey

The shape of molecular charge distributions: group theory without symmetry

J. Comput. Chem.

(1987)

CHEMX, developed and distributed by Chemical Design Ltd., Oxford (G.B.). Implemented in a VAX 9300 with a Macintosh...

G.A. Arteca et al.

A method for the characterization of molecular conformations

Int. J. Quantum Chem.: QBS.

(1987)

Cited by (6)

Similarity studies on guanidinium, imidazolinium, and imidazolium cations: Toward new bradykinin antagonists
1998, Journal of Molecular Graphics and Modelling
Bradykinin (BK) is a potent nociceptive agent and its antagonists show analgesic activity. In the search for new antagonists of BK, the design of nonpeptidic derivatives with different terminal cations has been considered. Among these new antagonists, the guanidinium cations, which appear not only in the terminal arginine residues of BK but also in several nonpeptidic antagonists, will be substituted by groups with characteristics similar in terms of electrostatic potential, electron density, shape, etc. Several similarity indexes have been calculated for guanidinium, 2-aminoimidazolinium, and 2-aminoimidazolium cations and their corresponding neutral species to design new nonpeptidic BK antagonists. The geometric and electronic characteristics of the molecules were compared by means of: (1) the Carbo index, (2) the Hodgkin index, and (3) a shape similarity index based on the volume of each molecule as defined by a certain electron density. Molecular geometries and energies were optimized by ab initio calculations at the B3LYP/6-311++G∗∗ level. The molecular electrostatic potential (MEP) and the electron density (ρ) were then computed in a cubic grid of points around each molecule. These molecular properties were used to calculate similarity indexes with the guanidinium cation or guanidine as the reference molecule in each family. In addition, three-dimensional similarity maps were generated to localize those molecular areas more alike in each of the sets.
Pyrazoles
1996, Comprehensive Heterocyclic Chemistry II: A Review of the Literature 1982-1995
Some aryl semicarbazones possessing anticonvulsant activitie
1995, European Journal of Medicinal Chemistry
A number of aryl semicarbazones displayed anticonvulsant activity in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens when administered intraperitoneally to mice. When given by the oral route to rats, protection was afforded in the MES but not scPTZ tests. Correlations were noted between the σ and σ^* values of the aryl substituents, the interplanar angles made by the aryl rings with the adjacent carbimino groups and the shapes of certain semicarbazones determined by X-ray crystallography, and the activities in the rat oral MES screen. Molecular modeling studies revealed a number of statistically significant descriptors which contributed to anticonvulsant activity.
A theoretical study of the structure of 6,6-dimethyl-7-nitroso-4,5,6, 7-tetrahydro-1H-pyrazolo[3,4-b]pyridine
2016, Afinidad
Heuristic molecular lipophilicity potential (HMLP): A 2D-QSAR study to LADH of molecular family pyrazole and derivatives
2005, Journal of Computational Chemistry
Molecular lipophilic potential on van der Waals surfaces as a tool in the study of 4-alkylpyrazoles
1996, Journal of Chemical Information and Computer Sciences

View full text

PapersEffect of branching in 4-alkylpyrazoles on liver alcohol dehydrogenase inhibition: A shape analysis study

Abstract

On the inhibition of alcohol dehydrogenase: shape group analysis of molecular electrostatic potential on van der Waals surfaces for some pyrazole deriv

Int. J. Quantum Chem.: QBS.

Modeling the effect of Zn(II) on the hydrogen transfer inhibition processes

Can. J. Chem.

Enzymology of human alcohol metabolism

Adv. Enzymol. Rel. Areas Mol.

On the effects of some heterocyclic compounds on the enzymatic activity of liver alcohol dehydrogenase

Acta Chem. Scand.

3-Substituted pyrazole derivatives as inhibitors and inactivators of liver alcohol dehyrogenase

J. Med. Chem.

Principle and practice of Hansch analysis: A Guide to structure-activity correlation for the medicinal chemist

Adv. Drug Res.

Synthetic inhibitors of Alcohol Dehydrogenase. 4-Substituted alkyl and cyclo-alkylpyrazoles

Acta Chem. Scand.

Group theory of electrostatic potentials: a tool for quantum chemical drug design

Int. J. Quantum Chem.: QBS.

Group theory of shapes of asymmetric biomolecules

The shape of molecular charge distributions: group theory without symmetry

J. Comput. Chem.

A method for the characterization of molecular conformations

Int. J. Quantum Chem.: QBS.

Papers
Effect of branching in 4-alkylpyrazoles on liver alcohol dehydrogenase inhibition: A shape analysis study