Natural phytoalexins inspired the discovery of new biphenyls as potent antifungal agents for treatment of invasive fungal infections

With the aim of discovering novel and effective antifungal agents derived from natural sources, a series of new biphenyls based on natural biphenyl phytoalexins were designed, synthesized and evaluated for their antifungal activities against four invasive fungi. By modifying the two benzene rings of noraucuparin, a well-known biphenyl phytoantitoxin, some promising compounds with remarkable antifungal activity were discovered. Notably, compounds 23a, 23e and 23h exhibited potent activities and a broad antifungal spectrum with low MICs of 0.25-16 mu g/mL, which were 8-256-fold more potent than that of the lead compound noraucuparin. Particularly, they displayed comparable potency to the positive control amphotericin B against Cryptococcus neoformans. Some interesting structure-activity relationships have also been discussed. Preliminary mechanism studies revealed that compound 23h might achieve its rapid fungicidal activity by disrupting the fungal cell membrane. Moreover, compound 23h exhibited significant inhibition against some virulence factors of Cryptococcus neoformans, low toxicity to normal human cells, as well as favorable pharmacokinetic and drug-like properties. The above results evidenced that the development of new antifungal candidates derived from natural phytoalexins was a bright and promising strategy.

Automated summary

In this study, a series of new biphenyl compounds based on natural biphenyl phytoalexins were designed, synthesized, and evaluated for their antifungal activities against four invasive fungi. Promising compounds with remarkable antifungal activity were discovered through modifying the two benzene rings of a well-known biphenyl phytoantitoxin. Notably, compounds 23a, 23e, and 23h exhibited potent activities and a broad antifungal spectrum, with low minimum inhibitory concentrations (MICs) and comparable potency to the positive control amphotericin B against Cryptococcus neoformans. Preliminary mechanism studies suggested that compound 23h exerts its rapid fungicidal activity by disrupting the fungal cell membrane. Moreover, compound 23h displayed significant inhibition against virulence factors of Cryptococcus neoformans, low toxicity to normal human cells, and favorable pharmacokinetic and drug-like properties. These results highlight the bright and promising strategy of developing new antifungal candidates derived from natural phytoalexins.