Synthesis, Antibacterial Properties and Molecular Docking Studies of Nitrogen Substituted 9-(((4X-But-2-ynyloxy)methyl)-1,2,3-triazolyl)–Cinchona Alkaloid Conjugates

The year 2024 marked the 80th anniversary of Woodward's total synthesis of quinine. Quinine is a natural alkaloid from the bark of the cinchona tree that has been used for years as an antimalarial drug. The antibacterial effect of quinine salts has also been regarded. With this in mind, a series of original 9-deoxycinchone alkaloid derivatives bearing a dialkylamino- or heterocyclic moiety at the 4 position of the 9-(((4-X-but-2-ynyloxy)methyl)-1,2,3-triazolyl)-substituent was synthesized. The copper-catalyzed three-component A³-coupling reaction of 9-(((4-prop-2-ynyloxy)methyl)-1,2,3-triazolyl)- substituted cinchona alkaloid derivatives with secondary amines and formaldehyde was the main route of synthesis. The present study attempted to examine the antibacterial properties of 9-substituted 9-desoxyquinine-derived compounds and their antibacterial activity against pathogenic bacterial strains, e.g., <i>Staphylococcus aureus</i>, <i>Bacillus subtillis</i>, <i>Bacillus cereus</i>, and <i>Escherichia coli</i>. The difference in the antibacterial activity profile of diastereoisomeric 9-(((4-X-but-2-ynyloxy)methyl)-1,2,3-triazolyl)-substituted derivatives of cinchona alkaloids indicated the importance of the nature of nitrogen substituents in the molecules. In a concentration-dependent pattern, (9<i>R</i>)- and (9<i>S</i>)- (((4-asocan-1yl)-but-2-ynyl-oxy)methyl)-1,2,3-triazolyl)-substituted compounds demonstrated considerable biofilm-inhibitory efficacy against the <i>S. aureus</i> bacterial strain. A detailed study of the molecular interactions with the targeted protein MurB was performed using docking simulations, and the obtained results are quite promising.