Design,synthesis, and SAR study of 3-(benzo[d][1,3]dioxol-5-yl)-N-benzylpropanamide as novel potent synergists against fluconazole-resistant Candida albicans |
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| Institution: | 1. Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China;2. Center of New Drug Research, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China;3. School of Pharmacy, Fujian University of Traditional Chinese Medicine, 1 Qiuyang Road, Fuzhou 350112, China;1. Key Laboratory of Biotechnology of Antibiotics, The National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, No. 1 Tian Tan Xi Li, Beijing 100050, PR China;2. Shen Yang Tonglian Group Co., Ltd., Dadong District, Shen Yang 110042, PR China;1. School of Chinese Herbal Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, People''s Republic of China;2. First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, People''s Republic of China;3. Guangzhou Pi & Pi Technology Inc, Guangzhou 510006, People''s Republic of China;1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China;2. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China;3. College of Chemistry and Molecular Engineering, East China Normal University, 3663 North of Zhongshan Road, Shanghai 200062, PR China;1. State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China;2. Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK |
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| Abstract: | Based on our previous discovery and SAR study on the lead compounds 7d, 5 and berberine which can significantly enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans, a series of 3-(benzod]1,3]dioxol-5-yl)-N-(substituted benzyl)propanamides were designed, synthesized, and evaluated for their in vitro synergistic activity in combination with fluconazole. The series 2a–f were designed by replacing the amide moiety of the lead compound 7d with retro-amide moiety, and compounds 2a and 2b showed more activity than the lead 7d. Furthermore, introducing biphenyl moiety into series 2d–f afforded series 3a–r, most of which exhibited significantly superior activity to the series 2d–f. Especially, compound 3e, at a concentration of 1.0 µg/ml, can enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans from 128.0 µg/ml to 0.125–0.25 µg/ml. A clear SAR of the compounds is discussed. |
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| Keywords: | Fluconazole Synergistic Antifungal activity Structure-activity relationship Synthesis |
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