Cell culture replication of herpes simplex virus and, or human cytomegalovirus is inhibited by 3,7-dialkoxylated, 1-hydroxyacridone derivatives.
The synthetic acridone compound, 5-chloro-1,3-dihydroxyacridone inhibits herpes simplex virus (HSV) replication by inducing the formation of defective viral (B-type) capsids [Antiviral Res. 53 (2002) 113]. In this report, synthetic elaboration of the 1-hydroxyacridone scaffold coupled with antiviral testing led to the identification of 3,7-dimethoxy-1-hydroxy-acridone (2) as an inhibitor of low multiplicity human cytomegalovirus (HCMV) infection (ED(50) value of 1.4 microM (0.5 microg/ml); greater than 35-fold selectivity). Compound 2 was inactive against HSV replication and the efficacy as an anti-HCMV agent at higher viral loads was only apparent if host cells were replicated in the presence of the compound prior to infection. Interestingly, the 3,5-dimethoxy regioisomer inhibited cell replication (mean CC(50) 33 microM) and was inactive as a selective anti-herpes agent. A limited parallel synthesis and testing of ten 3,7-dialkoxylated compounds closely related to compound 2 led to the discovery of the 3-ethoxy-, 3-propoxy-, 3-isopropoxy- and 3-allyloxy-derivatives as dual inhibitors of both HSV and HCMV (selectivity of the 3-allyloxy analog was greater than 10- and 36-fold, respectively). The 3-benzyloxy-derivative was active (ED(50) value of 6.9 microM) against HCMV only. Moreover, the corresponding C-7 variable alkoxylated parallel series were either weakly active or inactive antiviral agents suggesting an apparent requirement for a C-7 methoxy substituent in the active structure. Exploratory mode of action studies showed that dual inhibitors were most active against a low multiplicity HSV infection and potent inhibition of viral release likely contributed to this. Furthermore, suppression of late viral protein synthesis by dual inhibitors did not correlate with anti-HSV activity. On the basis of the present findings, the 1-hydroxyacridone scaffold is further expanded as a useful template for the discovery of investigational anti-herpes agents. As a group, the active 3,7-dialkoxylated compounds likely have diverse mechanisms of action, consequently they are of potential medicinal interest.
Lowden
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Division of Medicinal Chemistry and Natural Products, School of Pharmacy, CB# 7630, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Bastow
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D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D003587:Cytomegalovirus / Q000187:drug effects / Q000502:physiology*; D003588:Cytopathogenic Effect, Viral; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests / Q000379:methods; D018139:Simplexvirus / Q000187:drug effects / Q000502:physiology*; D013329:Structure-Activity Relationship; D014709:Vero Cells; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000187:drug effects / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
C478578:3,7-dimethoxy-1-hydroxyacridone; C411209:5-chloro-1,3-dihydroxyacridone; D000166:Acridines; D000998:Antiviral Agents; D014764:Viral Proteins