Quantitative structure-activity relationship (QSAR) of N-arylsubstituted hydroxamic acids as inhibitors of human adenocarcinoma cells A431.

Hydroxamic acids the multifunctional molecules with general formula R'-C(=O)NROH have interesting medicinal and biological potentiality. The antiproliferative activity of 12 hydroxamic acids has been tested in vitro towards human adenocarcinoma cell line by MTT assay. The IC(50) values were found to be in the range from 12 to 152.8 microM. The most potent product identified is N-p-chlorophenyl-4-nitrobenzohydroxamic acid with IC(50) value 12 microM. The RP-HPLC experiment of these molecules was performed with 50:50(V)/(V) % methanol - water mixture as mobile phase. A QSAR is developed for the human adenocarcinoma cells inhibitory activity of a series of hydroxamic acids (n=1-12) that are structurally related to hydroxyurea. Multivariate analytical tool, projection to latent structures was used to develop a suitably predictive model for the purpose of optimizing and identifying members with more potent inhibitory activity. The cross- validated Q(2)cum values for two optimal PLS models of hydroxamic acids are above 0.690 (remarkably higher 0.500), indicating good predictive abilities for log1/IC(50) values of HAs. By partial least squares regression, two QSAR models revealed that, besides the essential pharmacophore - NOH.C=O, retention capacity factor, logk', polar surface area, PSA, Dipole moment, Dm, total no. of hydrogen bond donor and acceptor atoms, H, and chlorine atoms attached in upper or/and lower phenyl rings, I(Cl) , are important determinants for the inhibitory potency against A431 cells.

Evaluation of lipophilicity of N-arylhydroxamic acids by reversed phase-high performance liquid chromatographic method and self-organizing molecular field analysis.

The RP-HPLC experiment of 19 N-arylsubstituted hydroxamic acids was carried out using a C18 (Hypersil Gold) column as a stationary phase and methanol-water mixture as mobile phase. The retention parameter, log k(w), was obtained by linear extrapolation of the logk' retention to pure water as the mobile phase. Self-organizing molecular field analysis (SOMFA), is used to generate three-dimensional quantitative structure-property relationship (3D-QSPR) models for log k(w) values of these set of molecules. The statistical results, cross-validation q(2) (0.859) and noncross-validation r(2) (0.878), show a satisfied predictive ability.