title: Antiviral properties of new arylsulfone derivatives with activity against human betaherpesviruses.
abstract: Based on our previous experience with arylsulfone derivatives displaying antiherpetic activity, we synthesized several analogues in which the sulfonyl group is part of a bicyclic structure. The benzene-fused derivative 2H-3-(4-chlorophenyl)-3,4-dihydro-1,4-benzo-thiazine-2-carbonitrile 1,1-dioxide and its thiophene-fused analogue were shown to have favorable activity and selectivity against the betaherpesviruses human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6) and 7 (HHV-7). The benzene-fused derivative retained its anti-HCMV activity when evaluated against virus strains resistant to foscarnet, ganciclovir, and/or cidofovir. The compound conferred >or=95% inhibition of viral DNA synthesis in HHV-6-infected cells. RT-PCR analysis of immediate-early, early and late gene products revealed that this arylsulfone compound acts at a step preceding late gene expression, and coinciding with the inhibition exerted by foscarnet. No inhibitory effect was seen in an enzyme assay for DNA elongation catalyzed by the HCMV or HHV-6 DNA polymerase catalytic subunit. The arylsulfone derivatives had no effect on the functional interaction between the catalytic subunit of HCMV DNA polymerase and its accessory protein, nor did they disrupt the physical interaction between the two proteins. We conclude that these arylsulfone derivatives represent new betaherpesvirus inhibitors with a novel mode of action that results in indirect inhibition of viral DNA synthesis.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. lieve.naesens@rega.kuleuven.ac.be
authors.forename: Lieve
authors.initials: L
authors.lastname: Naesens
authors.forename: Chad E
authors.initials: CE
authors.lastname: Stephens
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.forename: Arianna
authors.initials: A
authors.lastname: Loregian
authors.forename: Leen
authors.initials: L
authors.lastname: De Bolle
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
authors.forename: J Walter
authors.initials: JW
authors.lastname: Sowell
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects* / Q000235:genetics; D004279:DNA, Viral / Q000096:biosynthesis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D017245:Foscarnet / Q000494:pharmacology; D015654:Herpesvirus 6, Human / Q000187:drug effects / Q000235:genetics; D016199:Herpesvirus 7, Human / Q000187:drug effects; D006801:Humans; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D013450:Sulfones; D017245:Foscarnet