l-Tryptophan Induces a Marine-Derived Fusarium sp. to Produce Indole Alkaloids with Activity against the Zika Virus.

The effects of l-tryptophan supplementation on secondary metabolite production in the marine-derived fungus Fusarium sp. L1 were investigated by culturing the fungus in GPY medium with and without the amino acid. HPLC analysis of the products showed distinct metabolite profiles between the two cultures. The 1H NMR spectrum of the EtOAc extract of the culture supplemented with l-tryptophan displayed a series of characteristic aromatic proton signals (δH 6.50-8.50) and NH signals (δH 10.50-11.50) that were not observed in those from cultures not supplemented with l-tryptophan. Subsequently, 23 distinct indole alkaloids, including six new compounds, fusaindoterpenes A and B (1 and 2), fusariumindoles A-C (3-5), and (±)-isoalternatine A (6), together with 17 known compounds, were obtained from this culture. Fusaindoterpene A (1) contains a 6/9/6/6/5 heterocyclic system. Their chemical structures were determined by analysis of HRMS, NMR spectroscopy, optical rotation calculation, ECD calculation, and single-crystal X-ray diffraction data. Compounds 2, 9, and 15 displayed inhibitory activity against the Zika virus (ZIKV) in a standard plaque assay with EC50 values of 7.5, 4.2, and 5.0 µM, respectively, while not showing significant cell cytotoxicity against the A549 adenocarcinomic human alveolar basal epithelial cell line.