Design, synthesis, and structure-activity relationship studies of l-amino alcohol derivatives as broad-spectrum antifungal agents.
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.
['Zhao|Liyu|L|', 'Tian|Linfeng|L|', 'Sun|Nannan|N|', 'Sun|Yin|Y|', 'Chen|Yixuan|Y|', 'Wang|Xinran|X|', 'Zhao|Shizhen|S|', 'Su|Xin|X|', 'Zhao|Dongmei|D|', 'Cheng|Maosheng|M|']
D000072283:A549 Cells D000605:Amino Alcohols D000935:Antifungal Agents D001232:Aspergillus fumigatus D002176:Candida albicans D041022:Candida tropicalis D020134:Catalytic Domain D003455:Cryptococcus neoformans D015195:Drug Design D004355:Drug Stability D004875:Ergosterol D006801:Humans D008826:Microbial Sensitivity Tests D011485:Protein Binding D013237:Stereoisomerism D058886:Sterol 14-Demethylase D013329:Structure-Activity Relationship
Structure-activity relationship Fluconazole-resistance CYP51 Azole antifungals