苯腙类果糖-1,6-二磷酸醛缩酶新型抑制剂的合成及其抗真菌活性研究(英文)

白色念珠菌果糖-1,6-二磷酸醛缩酶 (CaFBA-II)被认为是开发新型抗真菌药物的一个潜在新靶标.本课题组前期的研究中报道了β-酰腙-α， γ-二羰基化合物对CaFBA-II具有一定的抑制活性.在本研究中，几类苯腙类化合物被发现可以高效抑制CaFBA-II.实验结果显示，R2位上引入NO2有利于提高化合物的酶体活性，尤其是同时在R3位置引入磺酸基后，化合物2g的CaFBA-II抑制活性达到了亚纳摩尔级别(IC50＝200 nmol·L－1).以化合物2g为代表，运用分子动力学模拟(MD)和DOX方法，对化合物2g与CaFBA-II的结合模式也进行了系统研究.值得注意的是，本研究中设计的大多数苯腙类化合物都对白色念珠菌具有一定的抗真菌活性(MIC80＝16～64 μg · mL－1).因而表明以苯腙类化合物为药物先导结构进行优化改造是设计开发新型抗真菌药物的一条可行途径.

Synthesis and antifungal activities of phenylhydrazono derivatives as the novel fructose-1,6-bisphosphate aldolase inhibitors

Fructose-1， 6-bisphosphate aldolase from C. albicans (CaFBA-II) is an attractive new target for the discovery of drugs to combat invasive fungal infection. Our previous study demonstrated that β-arylhydrazono-α， γ-dicarbonylderivatives exhibit moderate inhibitory against CaFBA-II. Herein， several new phenylhydrazono derivatives were found to potently inhibit CaFBA-II. The experimental results show that the NO2 group in the R2 position is favorable， but COOH， SO3H and halogen atom are unfavorable for their CaFBA-II inhibitory activities. Especially， when the R3 was substituted by sulfonic acid group， compound 2g possessed the highest inhibitory activity (IC50＝200 nmol·L－1). Furthermore， compound 2g were selected as representative molecule， the binding mode of 2g and the surrounding residues in the active site of CaFBA-II were elucidated by jointly using DOX methods and molecular dynamics (MD) simulations. Notably， antifungal experiments demonstrate that most of our designed compounds possess moderate inhibitory activities (MIC80＝16-64 μg · mL－1) against C. albicans. The present results suggest that the phenylhydrazono derivatives can be used as the lead compounds of novel drugs against fungal pathogens of humans in the future.