Use of electron densities in comparative molecular field analysis (CoMFA): A quantitative structure activity relationship (QSAR) for electronic effects of groups.

The description of field-induction sigma (sigma(i)) parameters in Comparative Molecular Field Analysis has been previously attempted by incorporating electrostatic fields computed either from point charges or from electrostatic potentials. Also, sigma as well as sigma(i) have been correlated for a series of groups (-X) with the lowest electrostatic potential around the nitrogen in a series of singly substituted (NH2 - X) amines [6,7]. Here a correlation is established between both field-induction and resonance sigma (sigma(i) and sigma(r) respectively) parameters for a series of groups (-X) and electron densities of molecules (R-X) substituted with these groups, incorporated into a Comparative Molecular Field Analysis (CoMFA). The correlation has been established for a series of singly substituted amines (R=NH2-) as well as para substituted benzoic acids (R=HOOC(p)-C6H4-) with the correlation coefficients being explained quite well. The crossvalidated r(2) (q(2)) as well as the predicted r(2) for a different series of groups have provided valid stress tests for the correlations. The electron densities for the various substituted amines are calculated using the AMI Hamiltonian in MOPAC5 [19].