Design, synthesis, and evaluation of caffeic acid amides as synergists to sensitize fluconazole-resistant Candida albicans to fluconazole

• Published in: Bioorganic & medicinal chemistry letters Vol. 25; no. 1; pp. 34 - 37
• Main Authors: Dai, Li, Zang, Chengxu, Tian, Shujuan, Liu, Wei, Tan, Shanlun, Cai, Zhan, Ni, Tingjunhong, An, Maomao, Li, Ran, Gao, Yue, Zhang, Dazhi, Jiang, Yuanying
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.01.2015; Elsevier
• Subjects: Amides - administration & dosage; Amides - chemistry; Caffeic acid; Caffeic Acids - administration & dosage; Caffeic Acids - chemistry; Candida albicans; Candida albicans - drug effects; Candida albicans - physiology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Design; Drug Evaluation, Preclinical - methods; Drug Resistance, Fungal - drug effects; Drug Resistance, Fungal - physiology; Drug Synergism; Fluconazole - administration & dosage; Fluconazole - chemistry; Fluconazole-resistant Candida albicans; Life Sciences & Biomedicine; Microbial Sensitivity Tests - methods; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Structure–activity relationship; Synergistic activity; Synergistic activity; Fluconazole-resistant Candida albicans; Caffeic acid; Structure–activity relationship; IN-VITRO; Structure-activity relationship; ANTIFUNGAL ACTIVITY; BERBERINE
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.11.022

A series of caffeic acid amides 3–13 were designed and synthesized through scaffold hopping from berbeine and 2, and their synergistic activity with fluconazole against fluconazole-resistant Candida albicans was evaluated in vitro. The title caffeic acid amides 3–30 except 26 exhibited potent activity. The SAR study indicates that the dihydroxyl groups and the amido group in the caffeic acid amides are the important pharmacophores. [Display omitted] A series of caffeic acid amides were designed, synthesized, and their synergistic activity with fluconazole against fluconazole-resistant Candida albicans was evaluated in vitro. The title caffeic acid amides 3–30 except 26 exhibited potent activity, and the subsequent SAR study was conducted. Compound 3, 5, 21, and 34c, at a concentration of 1.0μg/ml, decreased the MIC80 of fluconazole from 128.0μg/ml to 1.0–0.5μg/ml against the fluconazole-resistant C. albicans. This result suggests that the caffeic acid amides, as synergists, can sensitize drug-resistant fungi to fluconazole. The SAR study indicated that the dihydroxyl groups and the amido groups linking to phenyl or heterocyclic rings are the important pharmacophores of the caffeic acid amides.