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Twelve new cytochalasins, phomopchalasins D–O (1–3, 5–12, and 14), including one brominated (2) and two iodinated cytochalasins (3and 6), together with six known analogues (4, 13, and 15–18) were isolated from the mangrove-derived fungus Phomopsissp. QYM-13 treated with 3% NaBr or 3% KI in potato liquid medium. Their structures and absolute configurations were established by extensive spectroscopic analysis (1D and 2D NMR, HRESIMS), electronic circular dichroism calculations, and a single-crystal X-ray diffraction experiment. Compounds 3and 6represent the first iodinated cytochalasins. Compounds 2, 15, 17, and 18exhibited significant cytotoxicity against human cancer cell line MDA-MB-435 with IC50values ranging from 0.2 to 8.2 μM.

Synthetic biology is an effective way to activate silent biosynthetic gene clusters. Five new indole diterpenoids (1, 2, 5, 9, and 10), together with 10 known derivatives (3, 4, 6–8, and 11–15) were activated from Aspergillus oryzaetransformants by an exogenous P450 gene Ast Band obtained under the guidance of molecular networking. Their planar structures were determined by NMR and HR-ESI-MS. The absolute configuration of compound 1was determined by single crystal X-ray diffraction, and those of compounds 2, 5, 9, and 10were confirmed by comparing the observed ECD with the calculated ECD. HPLC analysis suggested that the BGCs of indole diterpenoids in A. oryzaewere activated by exogenous P450 gene Ast B. Compounds 1–4, 7, 8, and 11displayed strong activity against chloroquine-sensitive plasmodium strain P.f.3D7 with IC50values ranging from 0.84 to 2.9 μM. It is the first report that indole diterpenoids have potential antimalarial activity. The structure–activity relationship study showed that the linear indole diterpenoids contribute significantly to the antiparasite activity. Molecular docking studies showed that 1and positive control chloroquine were at the center of the active pocket of PfHsp90, while 11was far from the active site.