Hop bitter acids from the pistillate flower of Humulus lupulus L. and their anti-inflammatory and anti-dengue virus activities

Abstract

Nine undescribed hop bitter acids, humulupulones A–I (1–9), along with three known ones (10–12) were isolated from the pistillate flower of Humulus lupulus L. (hops). Structurally, compounds 1 and 2 possess an unprecedented nitrogen-containing skeleton in α-acids, and this is the first time that nitrogen has replaced oxygen at the same position, thereby forming a new skeleton consisting of a fused α-acid and a dimethyl-substituted pyridine. Compound 3 is a rare pyridine-2,4-dione derivative simultaneously incorporating prenyl and isopropyl moieties. Compounds 7–10 were separated into four pairs of enantiomers by chiral HPLC separation. Their structures were unambiguously established by comprehensive spectroscopic analysis, X-ray crystallography, and ECD calculations. Moreover, compounds 2, 4, and 7 exhibited significant anti-inflammatory activities in the CuSO₄-induced zebrafish inflammation model. Compounds 4, 5, 7–10 and 12 possessed significant anti-dengue virus (DENV) activities at the viral adsorption and entry stages with IC₅₀ values ranging from 0.29 μM to 70.09 μM, while compounds 7, 10, and 11 exerted anti-DENV activities at the viral replication stage with IC₅₀ values of 71.47 ± 7.30, 19.36 ± 6.77, and 16.18 ± 3.49 μM, respectively.