title: From antidiabetic to antifungal: discovery of highly potent triazole-thiazolidinedione hybrids as novel antifungal agents.
abstract: In an attempt to discover a new generation of triazole antifungal agents, a series of triazole-thiazolidinedione hybrids were designed and synthesized by molecular hybridization of the antifungal agent fluconazole and rosiglitazone (an antidiabetic). Most of the target compounds showed good to excellent inhibitory activity against a variety of clinically important fungal pathogens. In particular, compounds (Z)-5-(2,4-dichlorobenzylidene)-3-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)thiazolidine-2,4-dione) (15 c), (Z)-3-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-5-(furan-3-ylmethylene)thiazolidine-2,4-dione (15 j), and (Z)-3-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-5-(furan-3-ylmethylene)thiazolidine-2,4-dione (15 r) were highly active against Candida albicans, with MIC80 values in the range of 0.03-0.15 μM. Moreover, compounds 15 j and 15 r were found to be effective against four fluconazole-resistant clinical isolates; these two compounds are particularly promising antifungal leads for further optimization. Molecular docking studies revealed that the hydrogen bonding interactions between thiazolidinedione and CYP51 from C. albicans are important for antifungal activity. This study also demonstrates the effectiveness of molecular hybridization in antifungal drug discovery.
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433 (China).
authors.forename: Shanchao
authors.initials: S
authors.lastname: Wu
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: He
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Che
authors.forename: Shengzheng
authors.initials: S
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Dong
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yao
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Miao
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Wannian
authors.initials: W
authors.lastname: Zhang
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002176:Candida albicans / Q000187:drug effects / Q000378:metabolism; D025141:Drug Resistance, Fungal / Q000187:drug effects; D015725:Fluconazole / Q000494:pharmacology; D005656:Fungal Proteins / Q000737:chemistry / Q000378:metabolism; D005658:Fungi / Q000187:drug effects; D006860:Hydrogen Bonding; D007004:Hypoglycemic Agents / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D058886:Sterol 14-Demethylase / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000737:chemistry*; D014230:Triazoles / Q000737:chemistry*
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D014230:Triazoles; D015725:Fluconazole; C089946:2,4-thiazolidinedione; D058886:Sterol 14-Demethylase
keywords: Candida albicans; antifungal agents; molecular hybridization; thiazolidinedione; triazoles