Synthesis and biological evaluation of antibacterial activity of novel clarithromycin derivatives incorporating 1,2,3-triazole moieties at the 4″- and 11-OH positions

Abstract

Bacterial infection is still one of the diseases that threaten human health, and bacterial drug resistance is widespread worldwide. As a result, their eradication now largely relies on antibacterial drug discovery. Here, we reveal a novel approach to the development of 14-membered macrolide antibiotics by describing the design, synthesis, and evaluation of novel clarithromycin derivatives incorporating 1,2,3-triazole moieties at the 4″- and 11-OH positions. Using chemical synthesis, 35 clarithromycin derivatives were prepared, and their antibacterial properties were profiled. We found that compounds 8e-8h, 8l-8o, 8v, and 19d were as potent as azithromycin against Enterococcus faecalis ATCC29212. Furthermore, compounds 8c, 8d, 8n, and 8o showed slightly improved antibacterial activity (2-fold) against Acinetobacter baumannii ATCC19606 when compared with azithromycin and clarithromycin. In addition, compounds 8e, 8f, 8h, 8l, and 8v exhibited excellent antibacterial activity against Staphylococcus aureus ATCC43300, Staphylococcus aureus PR, and Streptococcus pneumoniae ER-2. These compounds were generally 64- to 128-fold more active than azithromycin, and 32- to 128-fold more active than clarithromycin. The results of molecular docking indicated that compound 8f may bind to the nucleotide residue A752 through hydrogen-bonding, hydrophobic, electrostatic, or π-π stacking interactions. The predicted ClogP data suggested that higher values of ClogP (>6.65) enhanced the antibacterial activity of compounds such as 8e, 8f, 8h, 8l, and 8v. The determination of the minimum bactericidal concentration showed that most of the tested compounds were bacteriostatic agents. From this study of bactericidal kinetics, we can conclude that compound 8f had a concentration- and time-dependent effect on the proliferation of Staphylococcus aureus ATCC43300. Finally, the results of the cytotoxicity assay showed that compound 8f exhibited no toxicity at the effective antibacterial concentration.