Structurally diverse alkaloids produced by Aspergillus creber EN-602, an endophytic fungus obtained from the marine red alga Rhodomela confervoides

[Display omitted] •Three new diketopiperazines were isolated from Aspergillus creber EN-602.•Compounds 1, 2, and 4 exhibited inhibitory activity against ACE in vitro.•Compounds 5 and 6 inhibited various aquatic bacteria in assay.•The intermolecular interaction of compounds 1–6 with ACE was investigated. Thirteen alkaloids, which include three new diketopiperazines, namely, 3-hydroxyprotuboxepin K (4), 3,15-dehydroprotuboxepin K (5), and versiamide A (6), together with ten known alkaloid derivatives (1–3 and 7–13), were isolated from the marine red algal-derived fungus Aspergillus creber EN-602. Versiamide A (6) represents the first example of a naturally occurring quinazolinone alkaloid with a diketopiperazine ring that is derived from phenylalanine (Phe) and leucine (Leu). The structures of these compounds were elucidated by detailed interpretation of their 1D/2D NMR spectroscopic and mass spectrometric data, while the absolute configurations of compounds 1–6 were established on the basis of X-ray crystallographic analysis and time-dependent density functional (TDDFT) calculations of the ECD spectra. Compounds 1, 2, and 4 exhibited inhibitory activity against the angiotensin converting enzyme (ACE) with IC50 values of 11.2, 16.0, and 22.4 μM, respectively, and compounds 5 and 6 inhibited various aquatic bacteria with MIC values that ranged from 8 to 64 μg/mL. The intermolecular interactions and potential binding sites between compounds 1–6 and ACE were investigated via molecular docking simulations.