QSAR of antilipid peroxidative activity of substituted benzodioxoles using chemometric tools

Search and development of new effective antioxidant molecules with improved activity is of both biological and commercial importance. In this background, we have modeled antioxidant activities of a series of benzodioxoles for their ability to inhibit lipid peroxidation (pC) using quantitative structure activity relationship (QSAR) technique. The QSAR models were developed using different chemometric tools such as GFA and G/PLS techniques. Two different sets of descriptors were used for developing these QSAR models. Molecular shape analysis (MSA) and spatial (charged partial surface area and shadow) descriptors were included in the one set, whereas quantum chemical (Mulliken charges on common atoms of the molecules calculated at the AM1 level) and physicochemical (hydrophobic parameter and molar refractivity) descriptors were included in the other set. All the models developed were validated internally by leave‐one‐out cross‐validation and randomization techniques. The model predictivity was judged by their cross‐validated squared correlation coefficient ( Q 2 ) and the modified r 2 ( r   m(LOO) 2 ) values, whereas the robustness of the models was judged from the value of R   p 2(Roy and Paul, QSAR Comb Sci DOI:10.1002/qsar.200810130). The developed models suggest that the antilipid peroxidative activity of the molecules largely depends on the charges of the carbon atoms connected to the oxygen atoms of the dioxole ring. Besides this, the activity also depends on the charged surface area of the molecules and the dipole moment of the molecules. Presence of the methoxy substituents ( ortho or meta ) on the phenyl ring at the R 1 position of the benzodioxoles significantly lowers the antioxidant activity of these molecules. © 2009 Wiley Periodicals, Inc. J Comput Chem 2009