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

Peganum harmala L. is an important economic and medicinal plant. The seeds of P. harmala have a long history as traditional Chinese medicine, Uighur medicine and Mongolian medicine, which was codified within “Drug Standard of the Ministry of Health of People’s Republic of China”. Twelve structurally novel tryptamine-derived alkaloids (1−12) and eight known ones (13−20) were derived from Peganum harmala seeds. Compounds 1 and 2 were the pioneering instances of tryptamine-derived heteromers, which were constructed from tryptamine and aniline fragments with the previously unknown C-3−N-1′ linkage and C-3−C-4′ connection, respectively. Compounds 3−5 were characterized as indole-quinazoline heteromers, with an unprecedented C-3 and NH-1′ linkage between indole and quinazoline-derived fragments. Compound 6 possesses the dimerization pattern of C-C linked tryptamine-quinazoline dimer. Compound 8 is determined as a tryptamine-derived heterodimer with an unusual carbon skeleton, characterized with peculiar spiro-tricyclic ring (7) and classic bicyclic tryptamine. Compounds 9−11 are unprecedented 6/5/5/5 spiro-tetracyclic tryptamine-derived alkaloids featuring a new ring system of tryptamine-spiro-pyrrolizine. Compounds 1−3 and 6−11 were nine racemates. Compounds 2, 7, 9, 10, and 12 were characterized via X-ray crystallographic investigation. All isolates (1−20) displayed varied degrees of antiviral potency against respiratory syncytial virus (RSV). Especially, the anti-RSV activity of compound 12 (IC₅₀ = 5.01 ± 0.14 μM) is stronger than that of the positive control (ribavirin, IC₅₀ = 6.23 ± 0.95 μM), which is sufficiently confirmed by plaque reduction and immunofluorescence assays. The discovery of anti-RSV compounds from P. harmala seeds, could contribute to the advancement and use of this plant in antiviral medicinal products.