Maternal and Child Health Hospital of Xuzhou Medical University, Jiangsu Province, China.
School of Pharmacy, Xuzhou Medical University, Jiangsu Province, China.
Curr Top Med Chem. 2021;21(27):2474-2482. doi: 10.2174/1568026621666211013125551.
Methicillin-resistant S. aureus (MRSA) has already tormented humanity and the environment for a long time and is responsible for many difficult-to-treat infections. Unfortunately, there are limited therapeutic options, and MRSA isolates with complete resistance to vancomycin, the first-line drug for the treatment of MRSA infections, have already emerged in recent years. Moxifloxacin retained activity against mutant bacterial strains with various levels of fluoroquinolones resistance and had a lower potential to select for resistant mutants. Isatin is a versatile structure, and its derivatives are potent inhibitors of many enzymes and receptors. The fluoroquinolone- isatin derivatives demonstrated excellent antibacterial activity against both drug-sensitive and drug-resistant organisms. The structure-activity relationship elucidated that incorporation of 1,2,3-triazole moiety into the C-7 position of fluoroquinolone skeleton was favorable to the antibacterial activity. Accordingly, fluoroquinolone derivatives with isatin and 1,2,3-triazole fragments at the side chain on the C-7 position are promising candidates to fight against drug-resistant bacteria.
To explore more active moxifloxacin derivatives to fight against MRSA and enrich the structure-activity relationships.
The synthesized moxifloxacin derivatives 7a-i and 14a-f were evaluated for their antibacterial activity against a panel of MRSA strains by means of standard two-fold serial dilution method.
The majority of the synthesized moxifloxacin derivatives were active against most of the tested MRSA strains with MIC values in a range of 1 to 64 μg/mL. The mechanistic investigations revealed that topoisomerase IV was one of the targets for antibacterial activity.
These derivatives are useful scaffolds for the development of novel topoisomerase IV inhibitors.
耐甲氧西林金黄色葡萄球菌（MRSA）长期以来一直折磨着人类和环境，导致许多难以治疗的感染。不幸的是，治疗选择有限，近年来已经出现了对万古霉素（治疗 MRSA 感染的一线药物）完全耐药的 MRSA 分离株。莫西沙星对具有不同水平氟喹诺酮耐药性的突变菌仍具有活性，并且选择耐药突变体的潜力较低。靛红是一种多功能结构，其衍生物是许多酶和受体的有效抑制剂。氟喹诺酮-靛红衍生物对敏感和耐药的细菌均表现出极好的抗菌活性。构效关系研究表明，在氟喹诺酮骨架的 C-7 位置引入 1,2,3-三唑片段有利于抗菌活性。因此，在 C-7 位置的侧链上带有靛红和 1,2,3-三唑片段的氟喹诺酮衍生物是对抗耐药菌的有前途的候选药物。
探索更有效的莫西沙星衍生物来对抗 MRSA 并丰富构效关系。
采用标准两倍连续稀释法评估合成的莫西沙星衍生物 7a-i 和 14a-f 对一系列 MRSA 菌株的抗菌活性。
大多数合成的莫西沙星衍生物对大多数测试的 MRSA 菌株均具有活性，MIC 值在 1 至 64 μg/mL 范围内。机制研究表明拓扑异构酶 IV 是抗菌活性的靶标之一。
这些衍生物是开发新型拓扑异构酶 IV 抑制剂的有用支架。
