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 Sep 1;177:374-385. doi: 10.1016/j.ejmech.2019.05.047. Epub 2019 May 25.
To discover broad spectrum antifungal agents, two strategies were applied, and a novel class of l-amino alcohol derivatives were designed and synthesized. 3-F substituted compounds 14i, 14n, 14s and 14v exhibited excellent antifungal activities with broad antifungal spectra against C. albicans and C. tropicalis, with MIC values in the range of 0.03-0.06 μg/mL, and against A. fumigatus and C. neoformans, with MIC values in the range of 1-2 μg/mL. Notably, Compounds 14i, 14n, 14s and 14v also displayed moderate activities against fluconazole-resistance strains 17# and CaR that were isolated from AIDS patients. Moreover, only compounds in the S-configuration showed antifungal activity. Preliminary mechanistic studies showed that the potent antifungal activity of compound 14v stemmed from inhibition of C. albicans CYP51. Compounds 14n and 14v were almost nontoxic to mammalian A549 cells, and their stability in human plasma was excellent.
为了发现广谱抗真菌剂，我们应用了两种策略，并设计和合成了一类新型的 L-氨基醇衍生物。3-F 取代的化合物 14i、14n、14s 和 14v 对 C. albicans 和 C. tropicalis 具有优异的抗真菌活性和广泛的抗真菌谱，MIC 值在 0.03-0.06 μg/mL 范围内，对 A. fumigatus 和 C. neoformans 的 MIC 值在 1-2 μg/mL 范围内。值得注意的是，化合物 14i、14n、14s 和 14v 对从艾滋病患者中分离得到的氟康唑耐药株 17# 和 CaR 也表现出中等活性。此外，只有 S-构型的化合物表现出抗真菌活性。初步的机制研究表明，化合物 14v 的强抗真菌活性源于对 C. albicans CYP51 的抑制。化合物 14n 和 14v 对哺乳动物 A549 细胞几乎没有毒性，并且在人血浆中的稳定性非常好。
