Biol. Pharm. Bull. 29(9) 1843—1847 (2006)

pes virus family and is transmitted via direct contact in all areas of world. In Japanese population, seropositivity for HCMV is higher. After primary infection, this virus causes latent infection in lineage-committed myeloid cells, including progenitors that give rise to granulocytes, macrophages, and dendritic cells. Pathogenesis of HCMV disease is directly linked to the immune status of the host. That is, although this virus poses little risk to healthy persons, immunocompromised persons, notably AIDS patients and organ transplant recipients are susceptible to HCMV-related pathologies. There are currently several approved anti-HCMV drugs, ganciclovir (GCV), foscarnet, cidofovir, fomivirsen, and valganciclovir in U.S.A. GCV is exclusively used for the treatment of HCMV in Japan. GCV suffers limitations, however, including toxic side effects (bone marrow toxicity and nephrotocixity) and poor bioavailability. In addition, GCVresistant virus mutants can emerge more likely since the compound acts upon HCMV-specific DNA polymerase. Thus, in order to overcome these disadvantages of GCV for treating HCMV infections, other promising drug candidates having activity against HCMV, and mechanism of action different from GCV are needed. Combination therapy with synergistically active antiviral agents that target different viral replication stages may provide several advantages over single-agent treatment, such as greater potency, superior clinical efficacy, reduction of the drug dosages needed, reduction of toxicity and side effects, reduction of the emergence of drug-resistant mutants, and greater cost-effectiveness. Several reports address the antiHCMV activity of drug combinations. Combinations of GCV with human interferons, a polyamine synthesis inhibitor, foscarnet, 4,6-dibenzamidopyrazolo[3,4-d]pyrimidine, or a ribonucleotide reductase inhibitor were synergistic for HCMV replication. We recently reported on a novel antiviral chromene derivative (1) (Chart 1). The compound is derived from the plastoquinones isolated from the brown alga, Sargassum micracanthum, and shows potent and selective inhibition of HCMV replication in vitro. Among the chromene-related compounds, calanolide A containing the ring of chromene has reported to be an anti-human immunodeficiency virus (HIV) compound isolated from a tropical tree, Calophyllum lanigerum, and to function as an HIV-1-specific reverse transcriptase inhibitor. There has been so far no report on anti-HCMV action of chromenes. In the present study, we first elucidated the anti-HCMV target(s) of 1 under the various experimental conditions. Based on the findings that the compound inhibited HCMV replication in a different manner from that of GCV, we also evaluated combination therapy to determine whether the combined use of 1 and GCV reduced HCMV replication additively or synergistically in an in vitro situation.