Strategies for finding novel structures of therapeutic interest are discussed. The rationale for the selection of the two scaffolds N-4-(m-aminophenyl)-piperazine-2-carboxylic acid (I) and N-4-(o-aminophenyl)-piperazine-2-carboxylic (II) is described. The synthesis of the appropriate precursors to scaffold I and II and their use in solid-phase chem. are described. A 160-member library was produced combining these novel piperazine scaffolds with eight

MTD-PLS, the Partial Least Squares (PLS) variant of the Min. Topol. Difference (MTD) method is described. In MTD-PLS, mols. are characterized not only by the occupancy or nonoccupancy of the hypermol. vertices (as in classical MTD), but also by addnl. descriptors for each vertex: fragmental van der Waals vols., fragmental hydrophobicities, partial at. charges, etc. This method was applied to a series of 73 polyhalogenated derivs. of dibenzo-p-dioxine,

Novel NPH (Nonpolar, Polar, H) descriptors for rapid estn. of hydrophobicity, amenable for filtering extremely large virtual combinatorial libraries (VCL) are proposed, based on atom counts; Pat, the sum of polar atoms (sum of O, N, P and S); NPat, the sum of nonpolar atoms (the sum of carbons and halogens minus Pat); SHDA (the sum of H bond donors and acceptors). In combination with mol. wt., the following related parameters are defined; MWPat (the

Linear regressions of exptl. electron affinities, EA, and their values calcd. by semiempirical MO methods (CNDO, INDO, ZINDO/1, MNDO, AM1, PM3) were obtained for three classes of arom. derivs., ring-substituted nitrobenzenes, substituted 1,4-benzo-, naphtho- and anthraquinones and polycondensed arom. hydrocarbons. The most closed values to the exptl. EAs are obtained by the AM1 method which gives also a good correlation coeff. r = 0.97 and std. error