Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, 475004, China.
Eur J Med Chem. 2019 Dec 1;183:111689. doi: 10.1016/j.ejmech.2019.111689. Epub 2019 Sep 13.
A series of β-azole-phenylacetone derivatives with novel structures were designed and synthesized to combat the increasing incidence of susceptible fungal infections and drug-resistant fungal infections. The antifungal activity of the synthesized compounds was assessed against five susceptible strains and five fluconazole-resistant strains. Antifungal activity tests showed that most of the compounds exhibited excellent antifungal activities against five pathogenic strains with MIC values in the range of 0.03-1 μg/mL. Compounds with R = 3-F substituted and 15o and 15ae exhibited moderate antifungal activities against fluconazole-resistant strains 17# and CaR with MIC values in the range of 1-8 μg/mL. Compounds with R = H or 2-F (such as 15a, 15o, 15p) displayed moderate to good antifungal activity against fluconazole-resistant strains 632, 901 and 904 with MIC values in the range of 0.125-4 μg/mL. Notably, 15o and 15ae exhibited antifungal activity against five susceptible strains and five fluconazole-resistant strains. Preliminary mechanistic studies showed that the potent antifungal activity of compound 15ae stemmed from inhibition of C. albicans CYP51. Compounds 15o, 15z and 15ae were nearly nontoxic to mammalian A549 cells.
我们设计并合成了一系列具有新颖结构的β-唑基-苯乙酮衍生物，以应对日益增多的敏感真菌感染和耐药真菌感染。评估了合成化合物对五种敏感菌株和五种氟康唑耐药菌株的抗真菌活性。抗真菌活性测试表明，大多数化合物对五种致病性菌株表现出优异的抗真菌活性，MIC 值在 0.03-1μg/mL 范围内。R=3-F 取代且 15o 和 15ae 的化合物对氟康唑耐药菌株 17#和 CaR 具有中等抗真菌活性，MIC 值在 1-8μg/mL 范围内。R=H 或 2-F（如 15a、15o、15p）的化合物对氟康唑耐药菌株 632、901 和 904 具有中等至良好的抗真菌活性，MIC 值在 0.125-4μg/mL 范围内。值得注意的是，15o 和 15ae 对五种敏感菌株和五种氟康唑耐药菌株均表现出抗真菌活性。初步的机制研究表明，化合物 15ae 的强效抗真菌活性源于对 C. albicans CYP51 的抑制。化合物 15o、15z 和 15ae 对哺乳动物 A549 细胞几乎没有毒性。
