Construction of antifungal dual-target (SE, CYP51) pharmacophore models and the discovery of novel antifungal inhibitors. Issue 45 (22nd August 2019)

• Record Type: Journal Article
• Authors: Dong, Yue; Liu, Min; Wang, Jian; Ding, Zhuang; Sun, Bin
• Is Part Of: RSC advances. Volume 9:Issue 45(2019)
• Page Start: 26302
• Page End: 26314
• Publication Date: 2019-08-22
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c9ra03713f
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : Fungal infections and drug-resistance are rapidly increasing with the deterioration of the external environment. Abstract : Fungal infections and drug-resistance are rapidly increasing with the deterioration of the external environment. Squalene cyclooxygenase (SE) and 14α-demethylase (CYP51) are considered to be important antifungal targets, and the corresponding pharmacophore models can be used to design and guide the discovery of novel inhibitors. Therefore, the common feature pharmacophore model (SE inhibitor) and structure-based pharmacophore model (CYP51 receptor) were constructed using different methods in this study. Then, appropriate organic fragments were selected and superimposed onto the pharmacophore features, and compounds5, 6 and8 were designed and produced by linking these organic fragments. It is noteworthy that compound8 can simultaneously match the features of both the SE and CYP51 pharmacophores. Further analysis found that these compounds exhibit a potent antifungal activity. Preliminary mechanistic studies revealed that compound8 could undergo dual-target inhibition (SE and CYP51) of Candida albicans . This study proved the rationale of pharmacophore models (SE and CYP51), which can guide the design and discovery of new antifungal inhibitors.