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The thermodynamics of free radical scavenge of 1,3,4-oxadiazole derivatives towards oxygen-centred free radicals were investigated by the density functional theory (DFT) method in the gas phase and aqueous solution. Three mechanisms of free radical scavenge namely, hydrogen atom transfer (HAT), single electron transfer followed by proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET) were considered. The antioxidant descriptors that characterize these mechanisms such as, bond dissociation enthalpy (BDE), adiabatic ionization potential (AIP), proton dissociation enthalpy (PDE), proton affinity (PA) and electron transfer enthalpy (ETE) were evaluated. The sequence of electron donation as predicted by the HOMO results were in good agreement with the sequence of ETE for the considered molecules at their favoured sites of free radical scavenge. The reaction Gibbs free energy for inactivation of the selected peroxyl radicals, show that 1,3,4-oxadiazole antioxidants are more efficient radical scavengers by HAT and SPLET mechanisms than SET-PT mechanism in vacuum. In aqueous solution, the SET-PT mechanism was observed to be the dominant reaction pathway.

Background: Antioxidants are very crucial in maintaining the normal function of body cells, as they scavenge excess free radical in the body. A set of hydrazone antioxidants was designed by in silico screening. The density functional theory (DFT) method was employed to explore the reaction energetics of their free radicalscavenging mechanism. With the aid of the developed quantitative structure-activity relationship (QSAR) model for hydrazone antioxidants, the structure and antioxidant activity of these compounds were predicted. Three potential reaction mechanisms were investigated, namely, hydrogen atom transfer (HAT), single-electron transfer followed by proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET). Bond dissociation enthalpy (BDE), adiabatic ionization potential (AIP), proton dissociation enthalpy (PDE), proton affinity (PA), electron transfer enthalpy (ETE) and Gibbs free energy that characterize the various steps in these mechanisms were calculated in the gas phase. Results: A total of 25 hydrazone antioxidants were designed, in which the molecule MHD 017 gave the best antioxidant activity. Among the tested molecules, MHD 017 at the 10-OH site gave the best results for the various thermodynamic parameters calculated. The reaction Gibbs free energy results also indicate that this is the most favoured site for free radical scavenge. Conclusion: The obtained results show that HAT and SPLET mechanisms are the thermodynamically plausible reaction pathways of free radical scavenge by hydrazone antioxidants. The reactivity of these compounds towards the hydroperoxyl radical (HOO•) was greater than that towards the methyl peroxyl radical (CH 3 OO•) based on the exergonicity of the calculated reaction Gibbs free energy.

Background Free radical attack of cellular structures in the human system is the major cause of various forms of degenerative diseases. Consequently, recent research has been focused on the development of new antioxidants with more efficient free radical scavenging potentials. Ligand-based virtual screening was employed in the rational design of potent antioxidant derivatives of curcumin by the density functional theory method. Various antioxidant descriptors that characterize the three major mechanisms of free radical scavenge, namely, hydrogen atom transfer (HAT), single electron transfer followed by proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET), were calculated. Also, the spin density distribution on the generated radicals and the frontier orbital distribution and energy of the studied compounds were evaluated in order to gain further insight on the reaction mechanism. The reaction Gibbs free energy for scavenging the two important peroxyl radicals (HOO· and CH3OO·) was calculated in order to evaluate the preferred mechanism of free radical scavenge by these compounds. Results The investigated compounds were able to scavenge HOO· and CH3OO· radicals by HAT and SPLET mechanisms in the gas phase and aqueous solution, based on the computed results of reaction enthalpies and Gibbs free energy. The SET-PT mechanism for these compounds was observed to be thermodynamically unfeasible in the gas phase. However, the thermodynamic feasibility of free radical scavenge by SET-PT mechanism was observed in aqueous solution. Among the investigated compounds, MCC 009 (1E,4E)-1-(3-(aminomethyl)-4-hydroxyphenyl)-5-(4-hydroxy-3-((hydroxy (methyl)amino)methyl)phenyl)penta-1,4-dien-3-one at the 19-OH position possessed the highest capacity to scavenge both HOO· and CH3OO· radicals by HAT, SET-PT, and SPLET mechanisms. The reaction Gibbs free energy of scavenging HOO· radical by this molecule in the gas phase and aqueous solution is ∆rGBDEgas =  − 58.18, $$ {\Delta _r{G}_{BDE}}_{H_2O}=-73.77 $$ ∆ r G BDE H 2 O = − 73.77 , ∆rGAIPgas = 611.48, $$ {\Delta _r{G}_{AIP}}_{H_2O}=-74305.49 $$ ∆ r G AIP H 2 O = − 74305.49 , ∆rGPDEgas =  − 669.66, $$ {\Delta _r{G}_{PDE}}_{H_2O}=74231.72 $$ ∆ r G PDE H 2 O = 74231.72 , ∆rGPAgas =  − 271.40, $$ {\Delta _r{G}_{PA}}_{H_2O}=-73.09 $$ ∆ r G PA H 2 O = − 73.09 ,∆rGETEgas = 213.22, and $$ {\Delta _r{G}_{ETE}}_{H_2O}=-0.69 $$ ∆ r G ETE H 2 O = − 0.69 . Conclusion New set of curcumin derivatives with potent free radical scavenging properties was successfully designed, and their mechanism of free radical scavenging evaluated by thermodynamic studies. This research is a gateway to the exploitation of the considered curcumin derivatives in food chemistry and pharmacy.

The 2, 2-diphenyl-1-picrylhydrazyl (<strong>DPPH</strong>) free radical scavenging properties of selected hydrazone antioxidants was investigated by the application of Quantitative Structure Activity Relationship (<strong>QSAR</strong>). Density functional theory (<strong>DFT</strong>) was employed in the optimization of the molecular structures. Internal and external validation as well as y-randomization tests were conducted in order to confirm the statistical reliability and acceptability of the developed models. The leverage approach was employed in the assessment of the applicability domain of the developed model. While the relative contribution and strength of each descriptor in the model was obtained by estimating the variation inflation factor, mean effect, and degree of contribution of each descriptor in the developed model. Model 3 which gave the best validation results was chosen as the best of the five models. This model dictates that the most important descriptors that influence the free radical scavenging activities of  the hydrazone antioxidants are the Broto-Moreau autocorrelation - lag 2 / weighted by polarizabilities; Count of atom-type H E-State: H on C  bonded to saturated C; Number of hydrogen bond donors (using CDK H Bond Donor Count Descriptor algorithm); Structural information content index (neighborhood symmetry of 1-order) and the 3D topological distance based autocorrelation - lag 7 / weighted by I-state descriptors. The Structural information content index descriptor was observed to be the most influential of all the descriptors

The free radical scavenging properties of 1,3,4-oxadiazoles have been explored by the application of quantitative structure activity relationship (QSAR) studies. The entire data set of the oxadiazole derivatives were minimized and subsequently optimized at the density functional theory (DFT) level in combination with the Becke's three-parameter Lee-Yang-Parr (B3LYP) hybrid functional and 6-311G* basis set. Kennard Stone algorithm was employed in data division into training and test sets. The training set was employed in QSAR model development by genetic function algorithm (GFA), while the test set was used to validate the developed models. The applicability domain of the developed model was accessed by the leverage approach. The variation inflation factor, degree of contribution and mean effect of each descriptor were calculated. Quantum chemical and molecular descriptors were generated for each molecule in the data set. Five predictive models that met all the requirements for acceptability with good validation results were developed. The best of the five models gave the following validation results: = 0.944, 2 = 0.891, 2 (2) = 0.831, 2 = 0.858 and c 2 = 0.810 = 0.114, rmsep = 0.121. The QSAR analysis revealed that the sum of estate descriptors of strength for potential hydrogen bonds of path length 9 (SHBint9) and topological radius (topoRadius) are the most crucial descriptors that influence the free radical scavenging activities of 1,3,4-oxadiazole derivatives.

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