Molecular structure and QSAR study on antispasmodic activity of some xanthoxyline derivatives

Semi-empirical molecular orbital calculations at AM1 level were done with the aim to investigate the structure-activity relationships of antispasmodic activities of ten 2-(X-benzyloxy)-4,6-dimethoxyacetophenones with X = H, 4'-F, 4'-NO2, 4'-CH3, 4'-Cl, 3',4'-(CH3)2, 4'-OCH3, 4'-Br, 4'-OCH2C6H5, and 4'-C(CH3)3, against acetylcholine-induced contraction of the guinea pig ileum. The most significant quantum chemical descriptors for this series of compounds were the net atomic charges, nucleophilic and electrophilic frontier electron density, HOMO and LUMO orbitals, and reactivity indices. While no significant correlations were found employing molecular parameters such as heat of formation, dipole moment, molecular polarizability, and so on, good correlations were obtained using the reactivity indices of HOMO and LUMO orbitals at specific atoms of the molecules. These results indicate that the spatial distribution of HOMO and LUMO orbitals over these specific atoms play an important role for an increase of biological activity.