Department of Chemistry, Umeå University, Sweden.
J Antibiot (Tokyo). 2012 Aug;65(8):397-404. doi: 10.1038/ja.2012.43. Epub 2012 Jun 6.
Salicylidene acylhydrazides belong to a class of compounds shown to inhibit bacterial type III secretion (T3S) in pathogenic Gram-negative bacteria. This class of compounds also inhibits growth and replication of Chlamydiae, strict intracellular bacteria that possess a T3S system. In this study a library of 58 salicylidene acylhydrazides was screened to identify inhibitors of Chlamydia growth. Compounds inhibiting growth of both Chlamydia trachomatis and Chlamydophila pneumoniae were tested for cell toxicity and seven compounds were selected for preliminary pharmacokinetic analysis in mice using cassette dosing. Two compounds, ME0177 and ME0192, were further investigated by individual pharmacokinetic analysis. Compound ME0177 had a relatively high peak plasma concentration (C(max)) and area under curve and therefore may be considered for systemic treatment of Chlamydia infections. The other compound, ME0192, had poor pharmacokinetic properties but the highest anti-chlamydial activity in vitro and therefore was tested for topical treatment in a mouse vaginal infection model. ME0192 administered vaginally significantly reduced the infectious burden of C. trachomatis and the number of infected mice.
水杨醛酰腙类化合物属于一类被证明能抑制致病性革兰氏阴性菌的 III 型分泌系统（T3S）的化合物。这类化合物还能抑制衣原体的生长和复制，而衣原体是一种严格的细胞内细菌，具有 T3S 系统。在这项研究中，筛选了一个 58 种水杨醛酰腙的文库，以鉴定抑制衣原体生长的抑制剂。对同时抑制沙眼衣原体和肺炎衣原体生长的化合物进行了细胞毒性测试，并选择了 7 种化合物进行小鼠体内药代动力学分析，采用盒式给药。两种化合物 ME0177 和 ME0192 进一步进行了个体药代动力学分析。化合物 ME0177 具有相对较高的血浆峰浓度（C(max)）和曲线下面积，因此可能被考虑用于系统治疗衣原体感染。另一种化合物 ME0192 的药代动力学特性较差，但在体外具有最高的抗衣原体活性，因此在小鼠阴道感染模型中测试了其局部治疗效果。阴道给予 ME0192 可显著降低沙眼衣原体的感染负荷和感染小鼠的数量。
