New Quinoline Derivatives as Potential Multitherapeutic Agents: A Facile Synthesis <i>via</i> an Epoxide Ring Opening Reaction, Characterization, DFT Calculations, and Molecular Docking

Abstract A mixture of three newly synthesized quinoline derivatives, namely 1‐(5‐bromo‐2,6‐dimethoxyquinolin‐3‐yl)ethane‐1,2‐diol ( 6 ), 2‐bromo‐2‐(5‐bromo‐2,6‐dimethoxyquinolin‐3‐yl)ethan‐1‐ol ( 7 ), and 1‐(5‐bromo‐2,6‐dimethoxyquinolin‐3‐yl)‐2‐hydroxyethyl nitrate ( 8 ) were prepared by treating 2,6‐dimethoxy‐3‐oxiranylquinoline ( 5 ) with cerium(IV) ammonium nitrate (CAN) in the presence of N ‐bromosuccinimide (NBS). The compounds were fully characterized by FT‐IR, 1 H, 13 C‐NMR, and HRMS. Their molecular structures were optimized by DFT/B3LYP/6–311++G( d , p ) and discussed in comparison with experimental closely‐related molecules, namely 2,6‐dimethoxyquinoline‐3‐carbonitrile (DQC). The results obtained are in good agreement with the X‐ray data and the optimized geometry of DQ. The effect of the substituents’ groups on the quinoline ring in 5 – 8 was thoroughly analyzed. The evaluation of the frontier molecular orbitals showed that the HOMOs are localized on the quinoline ring, the oxygen and bromine atoms, whereas all LUMOs are situated on the quinoline ring. Furthermore, a natural population analysis (NPA) was conducted and therefore the natural atomic charges in 5 – 8 were discussed. The computed global reactivity descriptors presented promising biological properties of 5 – 8 , hence their endorsement with molecular docking simulations against Staphylococcus aureus topoisomerase II gyrase A, Escherichia coli topoisomerase II DNA gyrase B, Candida albicans dihydrofolate reductase, human DNA topoisomerase I, and cyclooxygenase‐2 (COX2). The results showed the presence of H‐bonds, hydrophobic contacts, and π∙∙∙π stacking, which resulted in a potential antimicrobial, antitumor, and anti‐inflammatory efficiency of 5 – 8 .