Synthesis and Antiviral Activities of Methylenecyclopropane Analogs with 6-Alkoxy and 6-Alkylthio Substitutions That Exhibit Broad-Spectrum Antiviral Activity against Human Herpesviruses

Abstract

bMethylenecyclopropane nucleosides have been reported to be active against many of the human herpesviruses. The most active compound of this class is cyclopropavir (CPV), which exhibits good antiviral activity against human cytomegalovirus (HCMV), Epstein-Barr virus, both variants of human herpesvirus 6, and human herpesvirus 8. CPV has two hydroxymethyl groups on the methylenecyclopropane ring, but analogs with a single hydroxymethyl group, such as the prototypical (S)-synguanol, are also active and exhibit a broader spectrum of antiviral activity that also includes hepatitis B virus and human immunodeficiency virus. Here, a large set of monohydroxymethyl compounds with ether and thioether substituents at the 6 position of the purine was synthesized and evaluated for antiviral activity against a range of human herpesviruses. Some of these analogs had a broader spectrum of antiviral activity than CPV, in that they also inhibited the replication of herpes simplex viruses 1 and 2 and varicellazoster virus. Interestingly, the antiviral activity of these compounds appeared to be dependent on the activity of the HCMV UL97 kinase but was relatively unaffected by the absence of thymidine kinase activity in HSV. These data taken together indicate that the mechanism of action of these analogs is distinct from that of CPV. They also suggest that they might be useful as broad-spectrum antiherpesvirus agents and may be effective in the treatment of resistant virus infections.

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

“…Valomaciclovir, a drug developed initially against varicella-zoster virus, has also shown significant activity against HHV-6 in vitro (214)(215)(216). Other antiviral compounds have demonstrated promising experimental anti-HHV-6 activity, including the nucleoside/nucleotide analogues SS2242, A-5021, cyclopropavir, and 3-deaza-HPMPA and the nonnucleoside inhibitor CMV423 (4,(217)(218)(219)(220)(221)(222). These are all still at a step of preclinical development.…”

Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: What we do and do not know

“…The results of this study are encouraging because they may indicate the effect of currently available agents for high-risk patients, but we also consider that toxicity of PFA limits the practical application of prophylaxis to the wider HCT recipient population. Many other new compounds including brincidofovir, 78,79 methylenecyclopropane analogs 81 or artesunate 82 may be available in the future for preventing HHV-6 encephalitis. A phase 2 trial showed that brincidofovir effectively prevented cytomegalovirus diseases without myelosuppression and nephrotoxicity in allo-HCT recipients.…”

“…However, many clinicians would plan for at least 3 weeks of antiviral therapy. 15 Many other compounds that are active against cytomegalovirus, including brincidofovir (CMX-001), 78,79 CMV423, 80 methylenecyclopropane analogs 81 and artesunate 82 have also been reported to inhibit HHV-6 in vitro. Administration of brincidofovir at a single dose of 2 mg/kg led to maximum plasma concentrations of 350 ng/mL 83 that sufficiently exceeds the half-maximum effective concentration of HHV-6B strain 79 without adverse events including changes in hematological or renal functions.…”

Cytomegalovirus Mutants Resistant to Ganciclovir and Cidofovir Differ in Susceptibilities to Synguanol and Its 6-Ether and 6-Thioether Derivatives

“…However, synguanol was reported in an early study to retain activity against ganciclovir-resistant mutants (6), while more recent data have indicated cyclopropavir and ganciclovir cross-resistance of some CMV UL97 variants, such as M460I and H520Q (7). Additionally, 6-alkoxy and 6-alkylthio derivatives of synguanol have been synthesized that showed improved in vitro antiviral activities against CMV and other herpesviruses (8). As with ganciclovir, the CMV UL97 kinase is involved in the initial phosphorylation of these compounds, and drug-resistant UL97 mutants have been described (9).…”

“…The MCPN analogs cyclopropavir and synguanol, and derivatives, were synthesized at Microbiotix (Worcester, MA) as described previously (8,10) and prepared as 10 mM stock solutions in dimethyl sulfoxide. CMV strain variants were derived from bacterial artificial chromosome (BAC) clones BA1, BA9, and BA33 (11,12), modified from laboratory strain AD169 by introduction of a secreted alkaline phosphatase (SEAP) reporter gene and BAC vector BeloBAC11 at gene locus US6.…”