Structurally novel tryptamine-derived alkaloids from the seeds of Peganum harmala and their antiviral activities against respiratory syncytial virus

Peganum harmala L. (P. harmala) is a significant economic and medicinal plant. The seeds of P. harmala have been extensively utilized in traditional Chinese medicine, Uighur medicine, and Mongolian medicine, as documented in the Drug Standard of the Ministry of Health of China. Twelve novel tryptamine-derived alkaloids (1−12) and eight known compounds (13−20) were isolated from P. harmala seeds. Compounds 1 and 2 represent the first reported instances of tryptamine-derived heteromers, comprising tryptamine and aniline fragments with previously undocumented C-3−N-1′ linkage and C-3−C-4′ connection, respectively. Compounds 3−5 were identified as indole-quinazoline heteromers, exhibiting a novel C-3 and NH-1′ linkage between indole and quinazoline-derived fragments. Compound 6 demonstrates the dimerization pattern of C-C linked tryptamine-quinazoline dimer. Compound 8 represents a tryptamine-derived heterodimer with a distinctive carbon skeleton, featuring an unusual spiro-tricyclic ring (7) and conventional bicyclic tryptamine. Compounds 9−11 constitute novel 6/5/5/5 spiro-tetracyclic tryptamine-derived alkaloids presenting a unique ring system of tryptamine-spiro-pyrrolizine. Compounds 1−3 and 6−11 were identified as racemates. Compounds 2, 7, 9, 10, and 12 were confirmed via X-ray crystallographic analysis. All isolated compounds (1−20) exhibited varying degrees of antiviral efficacy against respiratory syncytial virus (RSV). Notably, the anti-RSV activity of compound 12 (IC₅₀ 5.01 ± 0.14 μmol·L⁻¹) surpassed that of the positive control (ribavirin, IC₅₀ 6.23 ± 0.95 μmol·L⁻¹), as validated through plaque reduction and immunofluorescence assays. The identification of anti-RSV compounds from P. harmala seeds may enhance the development and application of this plant in antiviral therapeutic products.