School of Pharmacy, Nantong University, Nantong 226001, China.
Department of Dermatology and Venereology, Affiliated Hospital of Nantong University, Nantong 226001, China.
Med Chem. 2020;16(3):413-421. doi: 10.2174/1573406415666190708145639.
In the past century, many phenazines were isolated from the marine microorganism, and some of these phenazines possessed potent antibacterial activities. We found that a few of the synthesized 4-substituted phenazines could block the infectivity of chlamydiae without host cell toxicity.
The aim of this study was to design and synthesize two series of novel 3-substituted phenazines to find novel antichlamydial agents.
The 3-substituted phenazines were synthesized via Buchwald-Hartwig cross coupling reaction and Suzuki reaction from 3-bromo-1-methoxyphenazine. The antichlamydial activity of these synthesized compounds was evaluated by determining their effect on the yield of infectious progeny EBs. Cytotoxicity of these compounds on host cells was assessed by the treatment of uninfected HeLa cells using WST-1 method.
Most of the 3-substituted phenazines possessed potent antichlamydial activity with IC50 values from 0.15 to 12.08 μM against Chlamydia trachomatis L2, C. muridarum MoPn and C. pneumoniae AR39. Among them, 7d and 9a exhibited better antichlamydial activity with IC50 values from 0.20 to 1.01 μM while they have no apparent cytotoxicity to host cells. Biological assay disclosed that both 7d and 9a inhibited chlamydial infection by reducing elementary body infectivity and disturbing chlamydial growth during the whole chlamydial developmental cycle.
Our findings suggested that 3-substituted phenazine derivatives might be a promising class of therapeutic agents for chlamydial infections. More effective phenazines with low toxicity could be acquired through further chemical modification on C-3 position rather than C-4 position of phenazine.
在过去的一个世纪中，许多吩嗪类化合物从海洋微生物中分离出来，其中一些吩嗪类化合物具有很强的抗菌活性。我们发现，一些合成的 4-取代吩嗪类化合物可以在没有宿主细胞毒性的情况下阻断衣原体的感染力。
本研究旨在设计和合成两个系列的新型 3-取代吩嗪类化合物，以寻找新型抗衣原体药物。
通过 Buchwald-Hartwig 交叉偶联反应和 Suzuki 反应，从 3-溴-1-甲氧基吩嗪合成 3-取代吩嗪类化合物。通过测定对感染性后代 EBs 产量的影响来评估这些合成化合物的抗衣原体活性。通过 WST-1 法用未感染的 HeLa 细胞处理来评估这些化合物对宿主细胞的细胞毒性。
大多数 3-取代吩嗪类化合物对沙眼衣原体 L2、鼠衣原体 MoPn 和肺炎衣原体 AR39 具有很强的抗衣原体活性，IC50 值为 0.15-12.08 μM。其中，7d 和 9a 表现出更好的抗衣原体活性，IC50 值为 0.20-1.01 μM，同时对宿主细胞无明显细胞毒性。生物学测定表明，7d 和 9a 通过降低原体感染力和干扰衣原体整个发育周期中的生长来抑制衣原体感染。
我们的研究结果表明，3-取代吩嗪衍生物可能是一种有前途的治疗衣原体感染的药物。通过对吩嗪 C-3 位而不是 C-4 位进行进一步的化学修饰，可以获得更有效且毒性更低的吩嗪类化合物。
