title: Development of flavonoid-based inverse agonists of the key signaling receptor US28 of human cytomegalovirus.
abstract: A series of 31 chalcone- and flavonoid-based derivatives were synthesized in good overall yields and screened for their inverse agonist activity on the US28 receptor of human cytomegalovirus (HCMV). With one exception (e.g., 2-(5-bromo-2-methoxyphenyl)-3-hydroxy-4H-chromen-4-one), halogen-substituted flavonoids were typically more potent inverse agonists than their related hydro derivatives. While toxicity could be used to partially explain the inverse agonist activity of some members of the series, 5-(benzyloxy)-2-(5-bromo-2-methoxyphenyl)-4H-chromen-4-one (11b) acted on the US28 receptor as a nontoxic, inverse agonist. The full inverse agonism (efficacy, -89%) and potency (EC50 = 3.5 μM) observed with flavonoid 11b is especially important as it provides both a new tool to study US28 signaling and a potential platform for the future development of HCMV-targeting drugs.
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich Alexander University, Erlangen 91052, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Kralj
authors.forename: Mai-Thao
authors.initials: MT
authors.lastname: Nguyen
authors.forename: Nuska
authors.initials: N
authors.lastname: Tschammer
authors.forename: Nicolette
authors.initials: N
authors.lastname: Ocampo
authors.forename: Quinto
authors.initials: Q
authors.lastname: Gesiotto
authors.forename: Markus R
authors.initials: MR
authors.lastname: Heinrich
authors.forename: Otto
authors.initials: O
authors.lastname: Phanstiel
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003587:Cytomegalovirus / Q000187:drug effects*; D055808:Drug Discovery; D054314:Drug Inverse Agonism; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D019707:Receptors, Chemokine / Q000819:agonists*; D014764:Viral Proteins / Q000819:agonists*
chemical_list: D000998:Antiviral Agents; D005419:Flavonoids; D019707:Receptors, Chemokine; C411191:US28 receptor, Cytomegalovirus; D014764:Viral Proteins