4-Acyl-5-aminoimidazole Alkaloids from a Marine-Derived Streptomyces sp. OUCMDZ-944

Thirteen new 4-acyl-5-amino-1H-imidazole alkaloids (1-13) were identified from cultures produced by the marine-derived Streptomyces sp. OUCMDZ-944 using feature-based molecular networking (FBMN)-guided isolation. Notably, compounds 1 and 2 were identified as phenyl-containing derivatives, specifically 5-amino-4-phenylpropionylimidazole (1) and 5-amino-4-phenylbutyrylimidazole (2). Ten isolates (4-13) are hydroxylated, with compound 13 being identified as a novel dimeric analogue. Furthermore, five methylated derivatives, 1a, 4a, 4b, 17a, and 17b, were synthesized. In an in vitro depression model, compounds 1, 4, 4a, 4b, 8, 16, and 17b were found to significantly reduce IL-1β levels, while compounds 1, 1a, 4b, and 10 notably reversed the corticosterone-induced decrease in brain-derived neurotrophic factor (BDNF) expression, suggesting a potential antidepressant-like activity. In the zebrafish anxiety model, compounds 1, 1a, 4b, 16, and 17b significantly enhanced spontaneous locomotor activity, reduced thigmotaxis behavior, and increased time spent in the inner zone under various lighting conditions, demonstrating clear anxiolytic-like effects. These five compounds were identified as promising lead candidates with dual anxiolytic and antidepressant potential.