Fungal infections have become a serious medical problem due to the high infection rate and the frequent emergence of drug resistance. Squalene epoxidase (SE) and 14α-demethylase (CYP51) are considered as the important antifungal targets, they can show the synergistic effect on antifungal therapy. In the study, a series of active fragments were screened through the method of De Novo Link, and these active fragments with the higher Ludi_Scores were selected, which can show the obvious binding ability with the dual targets (SE, CYP51). Subsequently, three series of target compounds with naphthyl amide scaffolds were constructed by connecting these core fragments, and their structures were synthesized. Most of compounds showed the antifungal activity in the treatment of pathogenic fungi. It was worth noting that compounds 10b-5 and 17a-2 with the excellent broad-spectrum antifungal properties also exhibited the obvious antifungal effects against drug-resistant fungi. Preliminary mechanism study has proved these target compounds can block the biosynthesis of ergosterol by inhibiting the activity of dual targets (SE, CYP51). Furthermore, target compounds 10-5 and 17a-2 with low toxicity side effects also demonstrated the excellent pharmacological effects in vivo. The molecular docking and ADMET prediction were performed, which can guide the optimization of subsequent lead compounds.

由于高感染率和频繁出现的耐药性，真菌感染已成为严重的医学问题。角鲨烯环氧酶（SE）和14α-脱甲基酶（CYP51）被认为是重要的抗真菌靶标，它们可以在抗真菌治疗中发挥协同作用。本研究通过De Novo Link方法筛选了一系列活性片段，并筛选出具有较高Ludi_Scores的活性片段，这些片段均显示出与双靶标（SE，CYP51）的明显结合能力。随后，通过连接这些核心片段，构建了带有萘基酰胺骨架的三个系列目标化合物，并合成了它们的结构。大多数化合物在病原真菌的治疗中均显示出抗真菌活性。值得注意的是具有优良的广谱抗真菌特性的10b-5和17a-2也表现出明显的抗药性真菌抗真菌作用。初步机理研究证明，这些靶标化合物可通过抑制双重靶标（SE，CYP51）的活性来阻断麦角甾醇的生物合成。此外，具有低毒性副作用的目标化合物10-5和17a-2在体内也显示出优异的药理作用。进行了分子对接和ADMET预测，可以指导后续先导化合物的优化。