Antiviral properties of a series of 1,6-naphthyridine and 7,8-dihydroisoquinoline derivatives exhibiting potent activity against human cytomegalovirus

A series of 1,6-naphthyridine (L. Chan, H. Jin, T. Stefanac, J. F. Lavallee , G. Falardeau, W. Wang, J. Bedard, S. May, and L. Yuen, J. Med. Chem. 42:3 023-3025, 1999) and isoquinoline (L. Chan, H. Jin, T. Stefanac, W. Wang, J. F. Lavallee, J. Bedard, and S. May, Bioorg. Med. Chem. Lett. 9:2583-2586, 1999) analogues exhibiting a high level of anti-human cytomegalovirus (HCMV ) activity were investigated in a series of studies aimed at better underst anding the mechanism of action of some representatives of this class of com pounds. In vitro antiviral profiling revealed that these compounds were act ive against a narrow spectrum of viruses, essentially the human herpesvirus es and type 2 rhinovirus. In HCMV assays, a 39- to 223-fold lower 50% inhib itory concentration was obtained for compound Al than for ganciclovir again st strains AD 169 and Towne. In addition, ganciclovir, fos carnet, cidofovi r, and BDCRB (2-bromo-5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole)-res istant HCMV strains remained susceptible to 1,6-naphthyridines and 7,8-dihy droisoquinolines tested in this study, supporting the view that a novel mec hanism of action could be involved. Drug combination studies showed a small but significant synergistic antiviral effect between compound B2 and ganci clovir. Cytotoxicity profiling of representative compounds under various ce ll growth conditions indicated a generally similar cytotoxic effect, relati ve to ganciclovir, in log-phase growing cells. However, in stationary cells , a relatively higher level of toxicity was observed than that for control compound. Effect of time of drug addition showed that the anti-HCMV activit y of compound A1, ganciclovir, and cidofovir was lost at approximately the same time (72 h postinfection), indicating that the compound,vas affecting events at the early and late stage of virus replication. This interpretatio n is also supported by reduction of de novo synthesis of pp65 tegument prot ein and lack of any effect of the compound on viral adsorption. A reduction of the HCMV enhancer-promoter-directed luciferase expression was also obse rved in a stably transfected cell line when compound A1 was present at rela tively high concentrations.