title: Structural optimization of berberine as a synergist to restore antifungal activity of fluconazole against drug-resistant Candida albicans.
abstract: We have conducted systematic structural modification, deconstruction, and reconstruction of the berberine core with the aim of lowering its cytotoxicity, investigating its pharmacophore, and ultimately, seeking novel synergistic agents to restore the effectiveness of fluconazole against fluconazole-resistant Candida albicans. A structure-activity relationship study of 95 analogues led us to identify the novel scaffold of N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-(substituted phenyl)acetamides 7 a-l, which exhibited remarkable levels of in vitro synergistic antifungal activity. Compound 7 d (N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-(2-fluorophenyl)acetamide) significantly decreased the MIC₈₀ values of fluconazole from 128.0 μg mL⁻¹ to 0.5 μg mL⁻¹ against fluconazole-resistant C. albicans and exhibited much lower levels of cytotoxicity than berberine toward human umbilical vein endothelial cells.
authors.affiliation: School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, 18 Yunwan Road, Nanchang, Jiangxi 330004 (China).
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Jiang
authors.initials: J
authors.lastname: Liu
authors.forename: Maomao
authors.initials: M
authors.lastname: An
authors.forename: Shaolong
authors.initials: S
authors.lastname: Zhu
authors.forename: Yongbing
authors.initials: Y
authors.lastname: Cao
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Jiang
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Zhao
authors.forename: Zhan
authors.initials: Z
authors.lastname: Cai
authors.forename: Li
authors.initials: L
authors.lastname: Dai
authors.forename: Tingjunhong
authors.initials: T
authors.lastname: Ni
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Simin
authors.initials: S
authors.lastname: Chen
authors.forename: Changqing
authors.initials: C
authors.lastname: Wei
authors.forename: Chengxu
authors.initials: C
authors.lastname: Zang
authors.forename: Shujuan
authors.initials: S
authors.lastname: Tian
authors.forename: Jingyu
authors.initials: J
authors.lastname: Yang
authors.forename: Chunfu
authors.initials: C
authors.lastname: Wu
authors.forename: Dazhi
authors.initials: D
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.forename: Yuanying
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000081:Acetamides / Q000737:chemistry*; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001599:Berberine / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002176:Candida albicans / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004149:Dioxoles / Q000737:chemistry*; D025141:Drug Resistance, Fungal; D004357:Drug Synergism; D015725:Fluconazole / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship
chemical_list: C000590411:(N-(2-(benzo(d)(1,3)dioxol-5-yl)ethyl)-2-(2-fluorophenyl)acetamide); D000081:Acetamides; D000935:Antifungal Agents; D004149:Dioxoles; D001599:Berberine; D015725:Fluconazole
keywords: Candida albicans; antifungal agents; berberine; drug resistance; structure-activity relationships