Diversity-oriented synthesis of pyrazoles derivatives from flavones and isoflavones leads to the discovery of promising reversal agents of fluconazole resistance in Candida albicans

• Published in: Bioorganic & medicinal chemistry letters Vol. 28; no. 9; pp. 1545 - 1549
• Main Authors: Cui, Chang-Yi, Liu, Jun, Zheng, Hong-Bo, Jin, Xue-Yang, Zhao, Xiao-Yu, Chang, Wen-Qiang, Sun, Bin, Lou, Hong-Xiang
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.05.2018; Elsevier
• Subjects: 3,4-Diaryl pyrazoles; 3,5-Diaryl pyrazoles; Antifungal; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Candida albicans; Candida albicans - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Discovery; Drug Resistance, Fungal - drug effects; Flavones - chemistry; Flavones - pharmacology; Fluconazole - chemistry; Fluconazole - pharmacology; Isoflavones - chemistry; Isoflavones - pharmacology; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Resistance; Science & Technology; Structure-Activity Relationship; Candida albicans; Resistance; 3,5-Diaryl pyrazoles; 3,4-Diaryl pyrazoles; Antifungal
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2018.03.066

[Display omitted] Diversity-oriented synthesis of derivatives of natural products is an important approach for the discovery of novel drugs. In this paper, a series of novel 3,4-diaryl-1H-pyrazoles and 3,5-diaryl-1H-pyrazoles derivatives were synthesized through the one-pot reaction of flavones and isoflavones with the hydrazine hydrate and substituted hydrazine hydrate. Some of these novel compounds exhibited antifungal effects against Candida albicans SC5314, and displayed more potent inhibitory activities against the efflux-pump-deficient strain DSY654. In addition, compounds 25, 28 and 32a displayed outstanding reversal activity of azole resistance against clinical azole-resistant Candida albicans in combination with fluconazole (FLC), with FICI values ranging from 0.012 to 0.141. The preliminary structure-activity relationship (SAR) of these compounds was also discussed. In conclusion, this study provides several novel agents that displayed potent antifungal activities alone or together with fluconazole, which makes progress for development of antifungal drugs.