Computer-aided design of caffeic acid derivatives: free radical scavenging activity and reaction force

Antioxidants are known to play a beneficial role in human health. Caffeic acid has been previously recognized as efficient in this context. However, such a capability can be enhanced through structural modification. Thus, 3829 caffeic acid derivatives were computational designed to that purpose by adding functional groups (-OH, -SH, -OCH₃, -COOCH₃, -F, -CF₃, and -N(CH₃)(C₂H₅)) to its framework. Promising candidates were chosen considering drug-like behavior, toxicity, and synthetic accessibility. The best candidates, dCAF-2, dCAF-16, and dCAF-82, were identified by comparison with reference antioxidants. The thermochemistry and kinetics of their reaction with ^•OOH are provided. The global rate coefficients were estimated to be 1.76 × 10⁹ M^-1 s^-1, 3.19 × 10⁹ M^-1 s^-1, and 1.79 × 10⁹ M^-1 s^-1 in aqueous solution for dCAF-2, dCAF-16, and dCAF-82, respectively. In lipid medium, their total rate coefficients were estimated to be 3.65 × 10³ M^-1 s^-1, 3.73 × 10³ M^-1 s^-1, and 8.63 × 10⁴ M^-1 s^-1 for dCAF-2, dCAF-16, and dCAF-82, respectively. These values allow predicting the designed caffeic acid derivatives as excellent antioxidants in both environments. The reaction forces for the main reaction path of the dCAF-2, dCAF-16, and dCAF-82 reactions with ^•OOH were explored.

Three protocols were used: (i) CADMA-Chem (computer-assisted design of multifunctional antioxidants, based on chemical properties) to quantify ADME (absorption, distribution, metabolism, and excretion) properties, toxicity and synthetic accessibility; (ii) eH-DAMA (electron and hydrogen donating ability map) tool, to identify the derivatives expected to behave as the best antioxidants; (iii) QM-ORSA (quantum mechanics-based test for overall free radical scavenging activity), to calculate the rate constants. Electronic structure calculations were performed with Gaussian 09, at the M05-2X/6-311 + g(d,p) level of theory. Both aqueous and lipid environments were considered using the SMD continuous solvation model. Intrinsic reaction coordinate (IRC) calculations, as implemented in Gaussian 09, were used to obtain the reaction force.