Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, 250012, China.
The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
Eur J Med Chem. 2019 Oct 15;180:321-339. doi: 10.1016/j.ejmech.2019.07.022. Epub 2019 Jul 11.
Macrolides are widely prescribed in clinic to treat various respiratory tract infections. However, due to their inappropriate use, the prevalence of macrolide-resistant strains among clinical isolates has become a concern for public health. Therefore, novel macrolides skeleton structures against resistant pathogens are badly needed. Thus, three series of novel 15-membered 11a-azahomoclarithromycin derivatives (series A-C) with the 1, 2, 3-triazole side chain were designed and synthesized through creatively opening the ring of clarithromycin (CAM), expanding the ring properly and introducing a suitable side chain of 1, 2, 3-triazole at the C12 and C13 positions, and evaluated for their antibacterial activity. The antibacterial results indicated that compounds 38b, 38l and 38v possessed strong antibacterial activity against Staphylococcus aureus ATCC25923 (0.25 μg/mL) and Bacillus subtilis ATCC9372 (0.25 μg/mL). Furthermore, compounds 9e and 38g were found to exhibit promising potent activity (8 μg/mL) against Streptococcus pneumonia AB11 expressing the ermB and mefA genes. In addition, the determination of minimum bactericidal concentration (MBC) indicated that the most promising compounds 38b, 38l, 38v, 9e and 38g were excellent bacteriostatic agents. The bactericidal curve showed that 9e exhibited antibacterial activity through bacteriostatic mechanism. Finally, 38b, 38l and 38v were confirmed to be non-toxic to MCF-7 breast cancer cells up to a concentration of 32 μg/mL in preliminary cytotoxicity assay. In summary, 38b, 38l, 38v, 9e and 38g can be served as lead compounds to provide a new perspective for further structural optimization.
大环内酯类抗生素被广泛用于治疗各种呼吸道感染。然而，由于其使用不当，临床分离株中耐大环内酯类抗生素的菌株的流行已成为公共卫生关注的问题。因此，急需针对耐药病原体的新型大环内酯类抗生素骨架结构。因此，通过创造性地打开克拉霉素（CAM）的环，适当扩环并在 C12 和 C13 位引入合适的 1,2,3-三唑侧链，设计并合成了三种新型的 15 元 11a-氮杂克拉霉素衍生物（系列 A-C），并对其进行了抗菌活性评价。抗菌结果表明，化合物 38b、38l 和 38v 对金黄色葡萄球菌 ATCC25923（0.25μg/mL）和枯草芽孢杆菌 ATCC9372（0.25μg/mL）具有较强的抗菌活性。此外，化合物 9e 和 38g 对表达 ermB 和 mefA 基因的肺炎链球菌 AB11 表现出有前景的强效活性（8μg/mL）。此外，最低杀菌浓度（MBC）的测定表明，最有前景的化合物 38b、38l、38v、9e 和 38g 是极好的抑菌剂。杀菌曲线表明，9e 通过抑菌机制发挥抗菌活性。最后，在初步的细胞毒性测定中，38b、38l 和 38v 被证实对 MCF-7 乳腺癌细胞在 32μg/mL 浓度下无毒性。总之，38b、38l、38v、9e 和 38g 可作为先导化合物，为进一步的结构优化提供新的视角。
