PDF(Pubmed)
Abstract：
A series of hybrid compounds with triazole and thiazolidine nuclei connected by a linker has been synthesized and extensively studied. Various synthetic methods for the target compounds have been tested. A microbiological assessment of the obtained compounds was carried out on strains of pathogenic fungi C. albicans, C. non-albicans, multidrug-resistant C. auris, Rhizopus arrhizus, Aspergillus spp. and some dermatophytes and other yeasts. The lowest obtained MIC values for target compounds lie between 0.003 µg/mL and 0.5 µg/mL and therefore the compounds are not inferior or several times better than commercial azole drugs. The length of the acylpiperazine linker has a limited effect on antifungal activity. Some bioisosteric analogues were tested in microbiological analysis, but turned out to be weaker than the leader in activity. The highest activity was demonstrated by a compound with para-chlorobenzylidene substituent in the thiazolidine fragment. Molecular modelling was used to predict binding modes of synthesized molecules and rationalize experimentally observed SAR. The leader compound is twice more effective in inhibiting the formation of germ tubes by Candida albicans yeast cells compared to voriconazole. An increased level of Pdr5, an azoles drug efflux pump was observed, but the increase is lower than that caused by azoles. The results can be useful for further development of more powerful and safe antifungal agents.
摘要：
已经合成并广泛研究了一系列具有通过接头连接的三唑和噻唑烷核的杂化化合物。已经测试了用于目标化合物的各种合成方法。对病原真菌白色念珠菌菌株进行了所得化合物的微生物学评估，C.非白色念珠菌,多药耐药金黄色葡萄球菌，阿耳根霉,曲霉属。还有一些皮肤癣菌和其他酵母.目标化合物的最低MIC值介于0.003µg/mL至0.5µg/mL之间，因此该化合物并不比市售唑类药物差或好几倍。酰基哌嗪接头的长度对抗真菌活性的影响有限。在微生物分析中测试了一些生物等排类似物，但结果却比活动的领导者弱。在噻唑烷片段中具有对氯亚苄基取代基的化合物证明了最高的活性。分子建模用于预测合成分子的结合模式，并使实验观察到的SAR合理化。与伏立康唑相比，前导化合物在抑制白色念珠菌酵母细胞形成胚管方面的有效性提高了两倍。观察到唑类药物外排泵Pdr5水平升高，但是增加的幅度低于唑类。该结果可用于进一步开发更有效和安全的抗真菌剂。
