Hydroxamic Acids Analogous Against Breast Cancer Cells: 2D‐QSAR and 3D‐QSAR Studies

Abstract

AbstractThe cytotoxicity of 19 N‐aryl‐substituted hydroxamic acids has been tested in vitro towards human breast cancer MCF–7 cell lines by MTT assay. The IC50 values were found to be in the range from 61.94 to 337.54 μM. A total of 18 out of 19 molecules had higher inhibitory activities than hydroxyurea against MCF–7 cell. Five compounds with IC50 values in micromolar range were 3‐ to 5‐folds more potent than hydroxyurea (IC50=307.15 μM). By partial least squares (PLS) regression, 2D‐QSAR model reported herein provide interesting insight in understanding hydrophobic, electronic, and structural requirements of antitumor activity among these set of the compounds. The cross‐validated Q2cum values for optimal PLS model of hydroxamic acids is above 0.638 (remarkably higher 0.50), indicating good predictive abilities for log 1/IC50 values of hydroxamic acids (HAs). The k‐nearest neighbor molecular field analysis (kNN‐MFA) approach was used to generate three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) models for these sets of molecules. Statistically stepwise variable selection k‐nearest neighbor molecular field analysis (SW‐kNN‐MFA) model is comparatively better as compared to the other two (i.e. simulated annealing k‐nearest neighbor molecular field analysis, SA‐kNN‐MFA, and genetic algorithm k‐nearest neighbor molecular field analysis, GA‐kNN‐MFA) with respect to both the internal (q2=0.7461) as well as external (pred_r2=0.6107) model validation and correctly predicts activity of ca. 74.61% and ca. 61.07% for the training and test set, respectively. It uses one steric and one electrostatic fields along with its 3k nearest neighbor (k=3) to evaluate the activity of new molecules. The developed SW‐kNN‐MFA model field plot indicated that the positive steric and electric potential are favorable for the increase in the activity and hence more bulky substituent at 5‐position of phenyl ring connected at amide group and less electronegative substituent at 3‐position of phenyl ring connected to carboxyl group are favourable for the increase in the potency of the molecules.