Benzoylation of Gly-Leu and Ala-Val dipeptides in aqueous—organic solvents

Abstract

Rate constants of the reactions of Gly-l-Leu and d,l-Ala-d,l-Val with 2,4-dinitro- and 2,4,6-trinitrophenyl benzoates in a water—1,4-dioxane solvent under polythermal conditions were determined on the basis of the experimental study of the reaction kinetics. The rate constants vary in a range 0.5–28 L mol⁻¹ s⁻¹. The determined activation parameters of dipeptide benzoylation are comparable with the characteristics of the related reactions within the estimation error. A significant decrease in the rate constants of dipeptide benzoylation compared with the reactions of the corresponding α-amino acids was found, indicating a substantial influence of the basicity of the amino compounds on their reactivity. A conclusion about the bimolecular concerted nucleophilic substitution at the carbonyl center with the nucleophile attack angle changing during the reaction was drawn on the basis of the quantum chemical calculations of the potential energy surface of the model reaction of glycyl-α-leucine with phenyl acetate in the gas phase. According to the virtual screening of the dipeptide benzoylation products, their ability to inhibit a number of hydrolase enzymes decreases noticeably compared to the dipeptides themselves, and a probability of the appearance of toxic properties decreases by 1.5–2 times. Therefore, the benzoyl derivatives of glycylleucine and alanylvaline can be considered as promising drugs.