A quantum chemical study on a set of non-imidazole H(3) antihistamine molecules

Molecular orbital calculations were carried out on a set of 28 non-imidazole H(3) antihistamine compounds using the Hartree-Fock method in order to investigate the possible relationships between electronic structural properties and binding affinity for H3 receptors (pK(i)). It was observed that the frontier effective-for-reaction molecular orbital (FERMO) energies were better correlated with pK(i) values than highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy values. Exploratory data analysis through hierarchical cluster (HCA) and principal component analysis (PCA) showed a separation of the compounds in two sets, one grouping the molecules with high pK(i) values, the other gathering low pK(i) value compounds. This separation was obtained with the use of the following descriptors: FERMO energies (epsilon(FERMO)), charges derived from the electrostatic potential on the nitrogen atom (N(1)), electronic density indexes for FERMO on the N(1) atom (Sigma((FERMO))c(i)(2)). and electrophilicity (omega`). These electronic descriptors were used to construct a quantitative structure-activity relationship (QSAR) model through the partial least-squares (PLS) method with three principal components. This model generated Q(2) = 0.88 and R(2) = 0.927 values obtained from a training set and external validation of 23 and 5 molecules, respectively. After the analysis of the PLS regression equation and the values for the selected electronic descriptors, it is suggested that high values of FERMO energies and of Sigma((FERMO))c(i)(2), together with low values of electrophilicity and pronounced negative charges on N(1) appear as desirable properties for the conception of new molecules which might have high binding affinity. 2010 Elsevier Inc. All rights reserved.

Solvent assisted decomposition of the tetrahedral intermediate of the transesterification reaction to biodiesel production. A density functional study

B3LYP/6-31 + G(d) calculations were employed to investigate the mechanism of the transesterification reaction between a model monoglyceride and the methoxide and ethoxide anions. The gas-phase results reveal that both reactions have essentially the same activation energy (5.9 kcal mol(-1)) for decomposition of the key tetrahedral intermediate. Solvent effects were included by means of both microsolvation and the polarizable continuum solvation model CPCM. Both solvent approaches reduce the activation energy, however, only the microsolvation model is able to introduce some differentiation between methanol and ethanol, yielding a lower activation energy for decomposition of the tetrahedral intermediate in the reaction with methanol (1.1 kcal mol(-1)) than for the corresponding reaction with ethanol (2.8 kcal mol(-1)), in line with experimental evidences. Analysis of the individual energy components within the CPCM approach reveals that electrostatic interactions are the main contribution to stabilization of the transition state. (C) 2009 Elsevier Ltd. All rights reserved.