Structural requirements for nucleophilicity and antioxidant capacity on quinoline derivatives: a theoretical study

Abstract

Abstract Context Quinoline derivatives play a crucial role in antimalarial therapy, and their biological properties are highly dependent on the basicity, particularly on the amine groups. The Amine moieties significantly contribute to the antioxidant capacity of quinoline derivatives through electron transfer mechanisms. Notably, each amine group has a distinct contribution to the antioxidant capacity, with the aliphatic amine displaying a potent electron donating capacity, the exo-aromatic amine showing an intermediate capacity, and the endo-aromatic amine demonstrating the least potent capacity. Our findings reveal a synergistic effect between the 4-amino-quinoline and tertiary amine in quinoline derivatives, enhancing their overall antioxidant capacity. However, the presence of the chlorine atom decreases its contribution as an electron withdrawing group. In comparison, chloroquine exhibits a higher antioxidant capacity than quinine, and their respective electron donation abilities are correlated with their pKa values. The synergistic effect between the 4-amino-quinoline and tertiary amine is particularly evident in chloroquine, surpassing the antioxidant capacity of 6-methoxy-4-methyl-quinoline moiety in quinine. Additionally, we have successfully proposed two new strategies for the development of chloroquine derivatives. Methods A theoretical study was conducted to investigate the structure-nucleophilicity and antioxidant capacity of quinoline derivatives, specifically chloroquine and quinine, through electron transfer using DFT/B3LYP/6–31 + G(d,p) methods. The HOMO values were utilized to assess nucleophilicity, while the ionization potential was indicative of electron donating capacity. To explore different aspects of the molecules, four approaches of molecular modifications were proposed: molecular fragmentation, molecular modification on amine moieties, and molecular association. These approaches aimed to provide insights into the relationships between molecular structure and nucleophilicity or antioxidant capacity. The study also involved the development of new strategies in drug design, leveraging theoretical methods to explore potential modifications and optimizations for quinoline derivatives.