Vágvölgyi, M.M.VágvölgyiGirst, G.G.GirstKúsz, N.N.KúszÖtvös, S.B.S.B.ÖtvösFülöp, F.F.FülöpHohmann, J.J.HohmannServais, J.-Y.J.-Y.ServaisSeguin-Devaux, C.C.Seguin-DevauxChang, F.-R.F.-R.ChangChen, M.S.M.S.ChenChang, L.-K.L.-K.ChangHunyadi, A.A.HunyadiLI-KWAN CHANG2020-12-292020-12-29201916616596https://www.scopus.com/inward/record.url?eid=2-s2.0-85076670053&partnerID=40&md5=2288be70de74109ac150fe26bf239ee8https://scholars.lib.ntu.edu.tw/handle/123456789/535668Protoflavones, a rare group of natural flavonoids with a non-aromatic B-ring, are best known for their antitumor properties. The protoflavone B-ring is a versatile moiety that might be explored for various pharmacological purposes, but the common cytotoxicity of these compounds is a limitation to such efforts. Protoapigenone was previously found to be active against the lytic cycle of Epstein–Barr virus (EBV). Further, the 5-hydroxyflavone moiety is a known pharmacophore against HIV-integrase. The aim of this work was to prepare a series of less cytotoxic protoflavone analogs and study their antiviral activity against HIV and EBV. Twenty-seven compounds, including 18 new derivatives, were prepared from apigenin through oxidative de-aromatization and subsequent continuous-flow hydrogenation, deuteration, and/or 4′-oxime formation. One compound was active against HIV at the micromolar range, and three compounds showed significant activity against the EBV lytic cycle at the medium-low nanomolar range. Among these derivatives, protoapigenone 1′-O-isopropyl ether (6) was identified as a promising lead that had a 73-times selectivity of antiviral over cytotoxic activity, which exceeds the selectivity of protoapigenone by 2.4-times. Our results open new opportunities for designing novel potent and safe anti-EBV agents that are based on the natural protoflavone moiety. ? 2019 by the authors. Licensee MDPI, Basel, Switzerland.Antitumor; Antiviral; Barr virus; Continuous-flow chemistry; Drug discovery; Epstein; Lytic cycle; Natural product; Oxime; Protoflavonoid[SDGs]SDG3alpha tubulin; antivirus agent; apigenin; dimethyl sulfoxide; ether derivative; flavonoid; oxime derivative; protoapigenone 1' o isopropyl ether; protoapigenone derivative; proto?avone; proto?avone 4' oxime; tetrahydroprotoapigenone derivative; tetrahydroproto?avone 4' oxime; unclassified drug; antineoplastic agent; cyclohexanone derivative; diisopropyl ether; ether derivative; flavone derivative; protoapigenone; 4' oxime formation; animal cell; animal experiment; animal model; antiretroviral therapy; antiviral activity; Article; biological activity; carbon nuclear magnetic resonance; cell lysate; cell viability; chemical structure; chromatography; controlled study; cytotoxicity; deuteration; drug selectivity; drug synthesis; enantiomer; Epstein Barr virus; high performance liquid chromatography; human; human cell; hydrogenation; IC50; immunoblotting; isotope labeling; mass spectrometry; MTT assay; nonhuman; nuclear magnetic resonance; pathology; pharmacophore; proton nuclear magnetic resonance; racemic mixture; rat; reversed phase high performance liquid chromatography; structure activity relation; virus replication; chemistry; drug effect; Epstein Barr virus; nuclear magnetic resonance spectroscopy; physiology; viral phenomena and functions; Antineoplastic Agents; Cyclohexanones; Ethers; Flavones; Herpesvirus 4, Human; Humans; Magnetic Resonance Spectroscopy; Molecular Structure; Structure-Activity Relationship; Virus Physiological Phenomena; Virus Replicationjournal article10.3390/ijms20246269318423582-s2.0-85076670053