Improved quantitative structure–activity relationship models to predict antioxidant activity of flavonoids in chemical, enzymatic, and cellular systems

Abstract

Quantitative structure-activity relationship (QSAR) models are useful in understanding how chemical structure relates to the biological activity of natural and synthetic chemicals and for design of newer and better therapeutics. In the present study, 46 flavonoids and related polyphenols were evaluated for direct/indirect antioxidant activity in three different assay systems of increasing complexity (chemical, enzymatic, and intact phagocytes). Based on these data, two different QSAR models were developed using i) physicochemical and structural (PC&S) descriptors to generate multiparameter partial least squares (PLS) regression equations derived from optimized molecular structures of the tested compounds and ii) a partial 3D comparison of the 46 compounds with local fingerprints obtained from fragments of the molecules by the frontal polygon (FP) method. We obtained much higher QSAR correlation coefficients (r) for flavonoid end-point antioxidant activity in all 3 assay systems using the FP method (0.966, 0.948, and 0.965 for datasets in evaluated in the biochemical, enzymatic, and whole cells assay systems, respectively). Furthermore, high leave-oneout cross-validation coefficients (q 2 ) of 0.907, 0.821, and 0.897 for these datasets, respectively, indicated enhanced predictive ability and robustness of the model. Using the FP method, structural fragments (submolecules) responsible for the end-point antioxidant activity in the three assay systems were also identified. To our knowledge, this is the first QSAR model derived for description of flavonoid direct/indirect antioxidant effects in a cellular system, and this model could form the basis for further drug development of flavonoid-like antioxidant compounds with therapeutic potential.

In vitro antioxidant capacity of tea of Echinodorus grandiforus, “leather hat,” in Wistar rat liver

“…As we know, antioxidants can neutralize oxidative stress in different ways, such as inhibiting free radical formation (preventive antioxidants), interrupting autoxidation chain reactions (chain breaking antioxidants), up-regulating and protecting cellular antioxidant defense mechanisms (indirect antioxidants), neutralizing the action of metal prooxidant ions (metal chelators), inhibiting the action of prooxidative enzymes (enzyme inhibitors) and increasing the activities of other antioxidants (Khlebnikov et al 2007, Carocho and Ferreira 2013, Georgiev et al 2014. As also mentioned, polyphenols are involved in the defense against oxidative damage, which could explain why these food components contributed to preventing oxidative damage and lipid peroxidation by E. grandiflorus tea as well.…”

Neuroprotective Effects of Quercetin and Rutin on Spatial Memory Impairment in an 8-Arm Radial Maze Task and Neuronal Death Induced by Repeated Cerebral Ischemia in Rats

“…The 2,3-double bond and 4-oxo group in flavonols are thought to relate to the differences between flavonols and flavanols in the repeated cerebral ischemia model. Many papers have reported an antioxidant action of flavonoids and their structure-activity relationships in vitro (22). Flavonoids have more complex mechanisms of action in vivo.…”

Proliferation of human adipose tissue-derived stem cells stimulated by oil rich in thymol of Lippia origanoides

“…These phenomena limit in vitro cell expansion and might hinder their therapeutic applications 8 . Antioxidants are compounds that directly or indirectly inhibit production of reactive oxygen species 9 (ROS). In recent years, there is an increasing interest in finding antioxidant phytochemicals, because they can inhibit the propagation of free radical reactions 10 .…”