Molecular design of curcumin analogues with potent antioxidant properties and thermodynamic evaluation of their mechanism of free radical scavenge

Abstract

Abstract 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 CH 3 OO·) 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 CH 3 OO· 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 CH 3 OO· 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 ∆ r G BDE gas = − 58.18, $$ {\Delta _r{G}_{BDE}}_{H_2O}=-73.77 $$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msub><mml:mrow><mml:msub><mml:mi>∆</mml:mi><mml:mi>r</mml:mi></mml:msub><mml:msub><mml:mi>G</mml:mi><mml:mi>BDE</mml:mi></mml:msub></mml:mrow><mml:mrow><mml:msub><mml:mi>H</mml:mi><mml:mn>2</mml:mn></mml:msub><mml:mi>O</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mo>−</mml:mo><mml:mn>73.77</mml:mn></mml:math> , ∆ r G AIP gas = 611.48, $$ {\Delta _r{G}_{AIP}}_{H_2O}=-74305.49 $$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msub><mml:mrow><mml:msub><mml:mi>∆</mml:mi><mml:mi>r</mml:mi></mml:msub><mml:msub><mml:mi>G</mml:mi><mml:mi>AIP</mml:mi></mml:msub></mml:mrow><mml:mrow><mml:msub><mml:mi>H</mml:mi><mml:mn>2</mml:mn></mml:msub><mml:mi>O</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mo>−</mml:mo><mml:mn>74305.49</mml:mn></mml:math> , ∆ r G PDE gas = − 669.66, $$ {\Delta _r{G}_{PDE}}_{H_2O}=74231.72 $$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msub><mml:mrow><mml:msub><mml:mi>∆</mml:mi><mml:mi>r</mml:mi></mml:msub><mml:msub><mml:mi>G</mml:mi><mml:mi>PDE</mml:mi></mml:msub></mml:mrow><mml:mrow><mml:msub><mml:mi>H</mml:mi><mml:mn>2</mml:mn></mml:msub><mml:mi>O</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mn>74231.72</mml:mn></mml:math> , ∆ r G PA gas = − 271.40, $$ {\Delta _r{G}_{PA}}_{H_2O}=-73.09 $$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msub><mml:mrow><mml:msub><mml:mi>∆</mml:mi><mml:mi>r</mml:mi></mml:msub><mml:msub><mml:mi>G</mml:mi><mml:mi>PA</mml:mi></mml:msub></mml:mrow><mml:mrow><mml:msub><mml:mi>H</mml:mi><mml:mn>2</mml:mn></mml:msub><mml:mi>O</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mo>−</mml:mo><mml:mn>73.09</mml:mn></mml:math> , ∆ r G ETE gas = 213.22, and $$ {\Delta _r{G}_{ETE}}_{H_2O}=-0.69 $$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msub><mml:mrow><mml:msub><mml:mi>∆</mml:mi><mml:mi>r</mml:mi></mml:msub><mml:msub><mml:mi>G</mml:mi><mml:mi>ETE</mml:mi></mml:msub></mml:mrow><mml:mrow><mml:msub><mml:mi>H</mml:mi><mml:mn>2</mml:mn></mml:msub><mml:mi>O</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mo>−</mml:mo><mml:mn>0.69</mml:mn></mml:math> . 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.