Antiviral Research 72 (2006) 60–67 Antiviral properties of new arylsulfone derivatives with activity against human betaherpesviruses Lieve Naesens a,∗ , Chad E. Stephens b,1 , Graciela Andrei a , Arianna Loregian c , Leen De Bolle a , Robert Snoeck a , J. Walter Sowell b , Erik De Clercq a a Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium b College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA c Department of Histology, Microbiology and Medical Biotechnologies, University of Padua, 35121 Padua, Italy Received 29 November 2005; accepted 28 March 2006 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 ≥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. © 2006 Published by Elsevier B.V. Keywords: Cytomegalovirus; Human herpesvirus 6; Betaherpesvirus; Antiviral; Arylsulfone derivative 1. Introduction The availability of more than eight antiherpetic drugs allows control of human herpesvirus infections in various clinical set- tings (Coen and Schaffer, 2003). Considerable progress has been achieved in the therapy of life-threatening manifestations of herpesvirus reactivation in immunocompromised patients, such as transplant recipients undergoing immunosuppressive therapy. Ganciclovir (GCV) and, to a lesser extent, foscar- net, are the standard drugs for preemptive therapy of human cytomegalovirus (HCMV) infections in transplant recipients (Nichols and Boeckh, 2000). The value of ganciclovir or fos- carnet treatment in transplant recipients showing clinical signs ∗ Corresponding author. Tel.: +32 16 337345; fax: +32 16 337340. E-mail address: lieve.naesens@rega.kuleuven.ac.be (L. Naesens). 1 Present address: Department of Chemistry and Physics, Augusta State Uni- versity, Augusta, GA 30904, USA. from human herpesvirus 6 (HHV-6) reactivation remains to be fully established (Zerr et al., 2002, 2005; De Bolle et al., 2005). Since HCMV reactivation in solid organ recipients can be enhanced by the other two betaherpesviruses HHV-6 and human herpesvirus 7 (HHV-7) (Mendez et al., 2001), antivi- ral drugs with activity against all three betaherpesviruses are to be preferred. Unfortunately, long-term administration of ganci- clovir or foscarnet can lead to severe toxicity or emergence of drug-resistant virus strains (Nichols and Boeckh, 2000). There- fore, the need remains for new antiherpetic drugs (preferably with non-nucleoside structure) that combine efficacy and safety with a novel mechanism of action, thus excluding the possi- bility of cross-resistance with existing therapeutics (Wathen, 2002). We previously reported on the synthesis and antiviral and antitumor activities of a series of new diarylsulfone derivatives (Stephens et al., 2001). While their anti-human immunodefi- ciency virus type 1 (HIV-1) activity may be based on inhibition of the HIV-1 reverse transcriptase (RT), in analogy to structurally 0166-3542/$ – see front matter © 2006 Published by Elsevier B.V. doi:10.1016/j.antiviral.2006.03.013