Discovery of Novel α,β-Unsaturated Amide Derivatives as Candidate Antifungals to Overcome Fungal Resistance.

In our previous study, coumarin-containing CYP51 inhibitor demonstrated potent antiresistance activity. However, compound demonstrated unsatisfied metabolic stability, necessitating modifications to overcome these limitations. In this study, α,β-unsaturated amides were used to replace the unstable coumarin ring, which increased metabolic stability by four times while maintaining antifungal activity, including activity against resistant strains. Subsequently, the sterol composition analysis and morphological observation experiments indicated that the target of these novel compounds is lanosterol 14α-demethylase (CYP51). Meanwhile, biofilm growth was inhibited and resistance genes (, , , and ) expression was downregulated to find out how the antiresistance works. Importantly, compound demonstrated the capacity to stimulate reactive oxygen species, thus displaying potent fungicidal activity. Moreover, exhibited encouraging effectiveness in vivo following intraperitoneal administration. Additionally, the most potent compound showed satisfactory pharmacokinetic properties and low toxicity. These α,β-unsaturated amide derivatives, particularly , are potential candidates for treating azole-resistant candidiasis.