Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry and Pharmacy, Northwest A&F University, Yangling, 712100, Shaanxi Province, China.
Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry and Pharmacy, Northwest A&F University, Yangling, 712100, Shaanxi Province, China.
Eur J Med Chem. 2019 Jul 1;173:228-239. doi: 10.1016/j.ejmech.2019.04.029. Epub 2019 Apr 14.
In continuation of our program to discover new potential antifungal agents, thirty-two neuchromenin analogues were synthesized and characterized by the spectroscopic analysis. By using the mycelium growth rate method, the target compounds were evaluated systematically for antifungal activities in vitro against six plant pathogenic fungi, and structure-activity relationships (SAR) were derived. Compounds 6b-c, and 6l showed obvious inhibition activity on each of the fungi at 50 μg/mL. For the corresponding fungi, 7 of the compounds showed average inhibition rates of >80% at 50 μg/mL; especially, compounds 6b, 6d-e, and 6i-l displayed more potent antifungal activity against A. solani than that of thiabendazole (a positive control). Moreover, compound 6c also exhibited good activity against C. lunata with EC values of 12.7 μg/mL, and the value was much superior to that of thiabendazole (EC = 59.7 μg/mL). SAR analysis showed that the presence of conjugated structure, bearing a C=C bond conjugated to the C=O group, obviously decreased the activity; the type and position of the substituted R significantly influenced the activity. Furthermore, the significantly bioactive compounds 6b-e, 6g, 6i and 6l showed very low toxicities against HL-7702, BEL-7402 and HCT-8 cells. Resistance development assay indicated that compounds 6b-e and 6l failed to induce the two tested strains of fungi to develop resistance. SEM analysis initially revealed that compound 6d may exert its antifungal effect by damaging fungal cell wall.
在我们发现新的潜在抗真菌剂的计划的延续中，合成了 32 个新色霉素类似物，并通过光谱分析进行了表征。通过采用菌丝生长速率法，系统地评估了目标化合物在体外对六种植物病原真菌的抗真菌活性，并得出了构效关系（SAR）。化合物 6b-c 和 6l 在 50μg/mL 时对每种真菌均表现出明显的抑制活性。对于相应的真菌，有 7 种化合物在 50μg/mL 时的平均抑制率>80%；特别是化合物 6b、6d-e 和 6i-l 对 A.solani 的抗真菌活性比噻菌灵（阳性对照）更强。此外，化合物 6c 对 C.lunata 也表现出良好的活性，EC 值为 12.7μg/mL，优于噻菌灵（EC=59.7μg/mL）。SAR 分析表明，共轭结构的存在，即 C=C 键与 C=O 基团共轭，明显降低了活性；取代基 R 的类型和位置对活性有显著影响。此外，具有显著生物活性的化合物 6b-e、6g、6i 和 6l 对 HL-7702、BEL-7402 和 HCT-8 细胞的毒性非常低。抗药性发展试验表明，化合物 6b-e 和 6l 未能诱导两种测试真菌菌株产生抗药性。SEM 分析初步表明，化合物 6d 可能通过破坏真菌细胞壁发挥其抗真菌作用。
