Qin Yinhui, Sun Min, Zhang Na, Yang Yan, Ma Peizhi
Department of Pharmacy, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou 450003, Henan, China.
Department of Pharmacy, People's Hospital of Rizhao, Rizhao 276826, China.
Bioorg Chem. 2022 Oct;127:106020. doi: 10.1016/j.bioorg.2022.106020. Epub 2022 Jul 9.
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.
细菌感染仍然是威胁人类健康的疾病之一，并且细菌耐药性在全球范围内广泛存在。因此，目前根除细菌很大程度上依赖于抗菌药物的发现。在此，我们通过描述在4''-位和11-OH位引入1,2,3-三唑部分的新型克拉霉素衍生物的设计、合成及评估，揭示了一种开发14元大环内酯类抗生素的新方法。利用化学合成制备了35种克拉霉素衍生物，并对它们的抗菌特性进行了分析。我们发现化合物8e - 8h、8l - 8o、8v和19d对粪肠球菌ATCC29212的抗菌活性与阿奇霉素相当。此外，与阿奇霉素和克拉霉素相比，化合物8c、8d、8n和8o对鲍曼不动杆菌ATCC19606的抗菌活性略有提高（2倍）。另外，化合物8e、8f、8h、8l和8v对金黄色葡萄球菌ATCC43300、金黄色葡萄球菌PR和肺炎链球菌ER - 2表现出优异的抗菌活性。这些化合物的活性通常比阿奇霉素高64至128倍，比克拉霉素高32至128倍。分子对接结果表明，化合物8f可能通过氢键、疏水、静电或π-π堆积相互作用与核苷酸残基A752结合。预测的ClogP数据表明，较高的ClogP值（>6.65）增强了化合物8e、8f、8h、8l和8v等的抗菌活性。最低杀菌浓度的测定表明，大多数受试化合物为抑菌剂。从该杀菌动力学研究中，我们可以得出结论，化合物8f对金黄色葡萄球菌ATCC43300的增殖具有浓度和时间依赖性作用。最后，细胞毒性试验结果表明，化合物8f在有效抗菌浓度下无毒性。
