Abstract
Antioxidants are an important component of our ability to combat free radicals, an excess of which leads to oxidative stress that is related to aging and numerous human diseases. Oxidative damage also shortens the shelf-life of foods and other commodities. Understanding the structure–activity relationship of antioxidants and their mechanisms of action is important for designing more potent antioxidants for potential use as therapeutic agents as well as preservatives. We report the first computational study on the electronic effects of ortho-substituents in dendritic tri-phenolic antioxidants, comprising a common phenol moiety and two other phenol units with electron-donating or electron-withdrawing substituents. Among the three proposed antioxidant mechanisms, sequential proton loss electron transfer (SPLET) was found to be the preferred mechanism in methanol for the dendritic antioxidants based on calculations using Gaussian 16. We then computed the total enthalpy values by cumulatively running SPLET for all three rings to estimate electronic effects of substituents on overall antioxidant activity of each dendritic antioxidant and establish their structure–activity relationships. Our results show that the electron-donating o-OCH3 group has a beneficial effect while the electron-withdrawing o-NO2 group has a negative effect on the antioxidant activity of the dendritic antioxidant. The o-Br and o-Cl groups did not show any appreciable effects. These results indicate that electron-donating groups such as o-methoxy are useful for designing potent dendritic antioxidants while the nitro and halogens do not add value to the radical scavenging antioxidant activity. We also found that the half-maximal inhibitory concentration (IC50) values of 2,2-diphenyl-1-picrylhydrazyl (DPPH) better correlate with the second step (electron transfer enthalpy, ETE) than the first step (proton affinity, PA) of the SPLET mechanism, implying that ETE is the better measure for estimating overall radical scavenging antioxidant activities.
Highlights
The use of antioxidants to combat oxidative damage caused by excess free radicals is important for food, medical, cosmetics and other industries
None of the steps showed a significant increase in the corresponding enthalpy values, suggesting that the multiple sequential proton loss electron transfer (SPLET) process can occur and all three PhOH rings in our dendritic significant increase the enthalpy values, suggesting that the multiple SPLET process antioxidants arein able to corresponding scavenge free radicals
Enthalpy values for model dendritic antioxidants with either an o-electron-donating groups (EDGs) or o-electron-withdrawing groups (EWGs) were determined for each step of the three proposed mechanisms (HAT, single electron transfer-proton transfer (SET-PT) and SPLET) in methanol using Density Functional Theory (DFT)
Summary
The use of antioxidants to combat oxidative damage caused by excess free radicals is important for food, medical, cosmetics and other industries. We reported a new class of phenolic antioxidants that we called dendritic antioxidants. Syringaldehyde and vanillin, very weak natural antioxidants, were used as building blocks to assemble potent phenolic antioxidant dendrimers with half-maximal inhibitory concentration (IC50) values significantly smaller than the building blocks. Dendrimers with 4, 6 and 8 syringol units had 27-, 100-, and 170-fold higher scavenging activities, respectively, than the syringaldehyde building block [1,2,3]. The dendritic architecture allowed metal chelation, thereby preventing potentially deleterious pro-oxidant effects of the antioxidants. Dendritic antioxidants offer several advantages similar to dendrimers. Their size, solubility, chelation ability, and antioxidant activity may be precisely manipulated by using appropriate cores and building blocks. Understanding the structure–activity relationship of dendritic antioxidants and their mechanism of action is paramount
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