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 compounds 5, 6 and 8 were designed and produced by linking these organic fragments. It is noteworthy that compound 8 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 compound 8 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.
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