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

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 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.

Evaluation of antioxidant and cytotoxic properties of phenolic N -acylhydrazones: structure–activity relationship

“…For the SET-PT, ionization potential (IP) and proton dissociation enthalpy (PDE) values describe the preferability of this radical scavenging pathway. On the other hand, the SPLET pathway starts with the deprotonation of antioxidant, whereas in the second step an electron is moved to the radical from anion [ 67 ]. Therefore, proton affinity (PA) and electron transfer enthalpy (ETE) values designate the possibility of the SPLET route.…”

Pyrazolone-type compounds (part II): in vitro and in silico evaluation of antioxidant potential; structure–activity relationship

“…In the SPLET route, these two processes are observed oppositely, i.e., the reaction is initiated with the deprotonation of antioxidant, while in the second step the electrons are transferred. 69 Hence, the possibility of the SPLET pathway is affected by the values of PA and ETE. All these processes could be inuenced by the solvent's polarity; therefore, the calculations were performed in methanol, water, and benzene.…”

Free Radical Scavenging Activity of Five Benzoic Acid Derivatives: A Theoretical M06-2X Study

“…On this path, an ArO-H molecule consecutively withdraws one electron and a proton onto the free radical, leading to the same products as in the HAT route [38]. The ionization potential (IP) and proton dissociation enthalpy (PDE) of the antioxidant are the most used indicators of the antioxidant activity in this context, low IPs and PDEs being associated with great antioxidant properties [39].…”