Quantitative Structure – ActivityRelationship (QSAR) of N-Arylsubstituted Hydroxamic Acids as Inhibitors of Human Adenocarinoma Cells A431

Ram   Prakash   Rajwade; Rama      Pande; K.   P.   Mishra; Amit      Kumar; B.   N.   Pandey

doi:10.2174/157340608784325106

Abstract

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 adenocarcinama cell line by MTT assay. The IC50 values were found to be in the range from 12 to 152.8μM. The most potent product identified is N-p-chlorophenyl-4-nitrobenzohydroxamic acid with IC50 value 12μM. The RP-HPLC experiment of these molecules was performed with 50:50V/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 crossvalidated Q2cum values for two optimal PLS models of hydroxamic acids are above 0.690 (remarkably higher 0.500), indicating good predictive abilities for log1/IC50 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, ICl , are important determinants for the inhibitory potency against A431 cells.

Keywords: QSAR, PLS, hydroxamic acids, A431 cell

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