Discovery of New Imidazole Derivatives Containing the 2,4-Dienone Motif with Broad-Spectrum Antifungal and Antibacterial Activity
Chunli Liu,
Ce Shi,
Fei Mao,
Yong Xu,
Jinyan Liu,
Bing Wei,
Jin Zhu,
Mingjie Xiang,
Jian Li
Affiliations
Chunli Liu
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China
Ce Shi
Radioimmunology and Clinical Laboratory, Luwan Branch, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200020, China
Fei Mao
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China
Yong Xu
Humanwell Healthcare (Group) Co, Ltd., 666 Gaoxin Road, East Lake High-Tech Development Zone, Wuhan 430075, China
Jinyan Liu
Radioimmunology and Clinical Laboratory, Luwan Branch, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200020, China
Bing Wei
Radioimmunology and Clinical Laboratory, Luwan Branch, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200020, China
Jin Zhu
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China
Mingjie Xiang
Radioimmunology and Clinical Laboratory, Luwan Branch, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200020, China
Jian Li
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China
A compound containing an imidazole moiety and a 2,4-dienone motif with significant activity toward several fungi was discovered in a screen for new antifungal compounds. Then, a total of 26 derivatives of this compound were designed, synthesized and evaluated through in vitro and in vivo antifungal activity assays. Several compounds exhibited improved antifungal activities compared to the lead compound. Of the derivatives, compounds 31 and 42 exhibited strong, broad-spectrum inhibitory effects toward Candida spp. In particular, the two derivatives exhibited potent antifungal activities toward the fluconazole-resistant isolate C. albicans 64110, with both having MIC values of 8 µg/mL. In addition, they had significant inhibitory effects toward two Gram-positive bacteria, Staphylococcus aureus UA1758 (compound 31: MIC = 8 µg/mL; compound 42: MIC = 4 µg/mL) and Staphylococcus epidermidis UF843 (compound 31: MIC = 8 µg/mL; compound 42: MIC = 8 µg/mL). The results of an animal experiment indicated that both compounds could improve the survival rate of model mice infected with ATCC 90028 (fluconazole-susceptible isolate). More importantly, the two compounds exhibited notable in vivo effects toward the fluconazole-resistant C. albicans isolate, which is promising with regard to the clinical problem posed by fluconazole-resistant Candida species.
