title: Discovery of new imidazole derivatives containing the 2,4-dienone motif with broad-spectrum antifungal and antibacterial activity.
abstract: 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.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
authors.forename: Chunli
authors.initials: C
authors.lastname: Liu
authors.affiliation: Radioimmunology and Clinical Laboratory, Luwan Branch, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200020, China.
authors.forename: Ce
authors.initials: C
authors.lastname: Shi
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China. maofei6517@163.com.
authors.forename: Fei
authors.initials: F
authors.lastname: Mao
authors.affiliation: Humanwell Healthcare (Group) Co, Ltd., 666 Gaoxin Road, East Lake High-Tech Development Zone, Wuhan 430075, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Radioimmunology and Clinical Laboratory, Luwan Branch, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200020, China.
authors.forename: Jinyan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Radioimmunology and Clinical Laboratory, Luwan Branch, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200020, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Wei
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Radioimmunology and Clinical Laboratory, Luwan Branch, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200020, China.
authors.forename: Mingjie
authors.initials: M
authors.lastname: Xiang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China. jianli@ecust.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality; D060326:Chemistry Techniques, Synthetic; D005260:Female; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality; D013210:Staphylococcus / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D007093:Imidazoles; C029899:imidazole