The functional groups of cage dimeric N-alkyl substituted 3,5-bis(hydroxymethyl)-4-(4-methoxyphenyl)-1,4-dihydropyridines are similar to those of cyclic and azacyclic ureas that are potent inhibitors of HIV-1 protease of the dihydroxyethylene- and hydroxyethylene type, respectively. In the following study the conformity of common functional groups is investigated concerning their orientation in space as well as in the enzyme HIV-1 protease. Starting from X-ray crystal data of the centrosymmetric cage dimeric N-benzyl derivative with ester groups, the derivative with hydroxymethylene groups was built and a systematic conformational search was performed for the conformationally important torsion angles considering electrostatic and van der Waals interactions. From the huge number of conformations those comprising centrosymmetrical and C2-symmetrical energy minima were selected and minimized. The three remaining conformers were fitted to the azacyclic urea A-98881 selected from the HIV-1 protease enzyme-inhibitor complex using the centroids of the corresponding aromatic residues and additionally by the field fit option of the Advanced CoMFA module of SYBYL. Interestingly, the energetically most favourable one, which, additionally, possesses C2-symmetry like the active site cavity of HIV-1 protease, showed the best fit. Comparing the electrostatic potential (EP) of the latter with the EP of A-98881 the aromatic residues show excellent accordance. Slight differences in the extent of the EP were found in the areas of the hydroxymethylene groups of the cage dimer and the single hydroxy group as well as the urea carbonyl group of A-98881, respectively. In order to compare the binding possibilities to the enzyme HIV-1 protease for the cage dimer and A-98881, their interaction fields with certain probes (CH3 for alkyl, NHamide, and carbonyl, O- of COO-), representing the decisive functional groups of the active site, have been calculated using GRID and projected into the enzyme placing the structures according to the position of A-98881 in the enzyme-inhibitor complex. The strongest calculated fields of the O- probe were found near Asp 25 for both structures. Another respective conformity consists in the overlap of the fields for the NHamide probe near Ile 50 and 50' for the investigated cage dimer and A-98881.

An extended set of multidrug-resistance modulators of the propafenone type were investigated using CoMFA and CoMSIA. A number of 3D-QSAR models were derived from steric, electrostatic, and hydrophobic fields and their combinations. The hydrophobic fields alone and in combination with the steric and both (steric and electrostatic) fields yielded the models with the highest cross-validated predictivity, in agreement with a previous analysis of a smaller data set of propafenone-type multidrug-resistance (MDR) modulators. Inclusion of lipophilicity did not lead to an improvement of the models. The results point to the importance of hydrophobicity as a space-directed molecular property for MDR-modulating activity. The influence of variable selection applying the GOLPE procedure was investigated with an external test set. Variable-selection procedure was repetitively applied, keeping at each stage variables with uncertain contribution to the models. For the CoMFA-based 3D-QSAR models, an increase in external prediction quality was found. In contrast, the CoMSIA-based 3D-QSAR models were not improved by the GOLPE variable-selection procedure.

An evaluation of quantitative structure-activity relationships (QSAR) for 28 N 1 -phenyl-2-phenylhydrazonoacetamides, that are inhibitors of soybean 15-lipoxygenase was carried out with different statistical methods. Initially the variation of structure was characterized by the Free-Wilson method and analyzed by multiple linear regression (MLR) and partial least squares analysis (PLS). Both methods revealed an increase in activity, if the N 1 -phenyl substituent of the parent molecule is meta-substituted with groups, that show a positive resonance effect at the annular structure. To include physicochemical aspects a combined Free-Wilson-Hansch approach was used. Because of high intercorrelations among some physicochemical parameters a principal component-analysis (PCA) was performed to extract information from those intercorrelated variables in a few principal components (PC's). The resulting equations indicate that besides an electron donating group at the central amidrazone moiety electronic effects at the arylhydrazone substituent play an important role for the biological activity. * To receive all correspondence

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