QSAR by LFER model of cytotoxicity data of anti-HIV 5-phenyl-1-phenylamino-1 H-imidazole derivatives using principal component factor analysis and genetic function approximation

Abstract

Cytotoxicity data of anti-HIV 5-phenyl-1-phenylamino-1 H-imidazole derivatives were subjected to quantitative structure–activity relationship (QSAR) study using linear free energy related (LFER) model of Hansch using electronic (Hammett σ), hydrophobicity ( π) and steric (molar refractivity and STERIMOL L, B1, B2, B3 and B4) parameters of phenyl ring substituents of the compounds, along with appropriate indicator variables. Principal component factor analysis (FA) was used as the data-preprocessing step to identify the important predictor variables contributing to the response variable and to avoid collinearities among them. The generated multiple linear regression (MLR) equations were statistically validated using leave-one-out technique. Genetic function approximation (GFA) was also used on the same data set to develop QSAR equations, which produced the same best equation as obtained with FA-MLR. The final equation is of acceptable statistical quality (explained variance 80.2%) and predictive potential (leave-one-out predicted variance 74%). The analysis explores the structural and physicochemical contributions of the compounds for cytotoxicity. A thiol substituent at 2 position of the imidazole nucleus decreases cytotoxicity when compared to the corresponding unsubstituted congener. Presence of hydrogen bond donor group at meta position of the phenyl ring present at 5 position of the imidazole nucleus also reduces cytotoxicity. Additionally, absence of any substituent at 2 and 3 positions of the phenyl ring of 1-phenylamino fragment reduces the cytotoxicity. The negative coefficient of σ p indicates that presence of electron-withdrawing substituents at the para position of the phenyl ring of the 1-phenylamino fragment is not favourable for the cytotoxicity. Again, lipophilicity of meta substituents of the 5-phenyl ring increases cytotoxicity. The coefficients of molar refractivity (MR m ) and STERIMOL parameters for meta substituents ( L m , B1 m and B4 m ) of the phenyl ring of 1-phenylamino fragment indicate that the length, width and overall size of meta substituents are conducive factors for the cytotoxicity.