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From Antidiabetic to Antifungal: Discovery of Highly Potent Triazole–Thiazolidinedione Hybrids as Novel Antifungal Agents
Author(s) -
Wu Shanchao,
Zhang Yongqiang,
He Xiaomeng,
Che Xiaoying,
Wang Shengzheng,
Liu Yang,
Jiang Yan,
Liu Na,
Dong Guoqiang,
Yao Jianzhong,
Miao Zhenyuan,
Wang Yan,
Zhang Wannian,
Sheng Chunquan
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402320
Subject(s) - antifungal , thiazolidinedione , triazole , pharmacology , drug discovery , chemistry , medicine , biology , microbiology and biotechnology , biochemistry , diabetes mellitus , endocrinology , type 2 diabetes , organic chemistry
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‐(1 H ‐1,2,4‐triazol‐1‐yl)propyl)thiazolidine‐2,4‐dione) ( 15 c ), ( Z )‐3‐(2‐(2,4‐difluorophenyl)‐2‐hydroxy‐3‐(1 H ‐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‐(1 H ‐1,2,4‐triazol‐1‐yl)propyl)‐5‐(furan‐3‐ylmethylene)thiazolidine‐2,4‐dione ( 15 r ) were highly active against Candida albicans , with MIC 80 values in the range of 0.03–0.15 μ M . 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.