(Z)- and (E)-2-(hydroxymethylcyclopropylidene)methylpurines and pyrimidines as antiviral agents

Several Z- and E-methylenecyclopropane nucleoside analogues were synthesized and tested for antiviral activity in vitro against human and murine cytomegalovirus (HCMV, MCMV), Epstein-Barr virus (EBV), varicella tester vii us (VZV), hepatitis B virus (HBV), herpes simplex virus types 1 and 2 (HSV-1, HSV-2), human herpesvirus 6 (HHV-6) and human immunodeficiency virus type 1 (HIV-1). The Z-2-amino-6-cyclopropylaminopurine analogue was the most effective agent against HCMV (EC50 or EC90 0.4-2 mu M) followed by syncytol and the Z-2,6-diaminopurine analogues (EC50 or EC90 3.4-29 and 11-24 mu M, respectively). The latter compound was also a strong inhibitor of MCMV (EC50 0.6 mu M). Syncytol was the most potent against EBV (EC50 <0.41 and 2.5 mu M) followed by the Z-2,6-diaminopurine (EC50 1.5 and 6.9 mu M) and the Z-2-amino-6-cyclopropyl-aminopurine derivative (EC50 11.8 mu M). Syncytol was also most effective against VZV (EC50 3.6 mu M). Activity against HSV-1, HSV-2 and HHV-6 was generally lower; synthymol had an EC50 of 2 mu M against HSV-1 (ELISA) and 1.3 mu M against EBV in Daudi cells but was inactive in other assays. The 2-amino-6-cyclopropylamino analogue displayed EC,, values between 215 and >74 mu M in HSV-1 and HSV-2 assays. 2-Amino-6-cyclopropylaminopurine and 2,6-diaminopurine derivatives were effective against HBV (EC50 and 10 mu M, respectively), whereas none of the analogues inhibited HIV-1 at a higher virus load. Syncytol and the E isomer were equipotent against EBV in Daudi cells but the E isomer was much less effective in DNA hybridization assays. The E-2,6-diaminopurine analogue and E isomer of synthymol were devoid of antiviral activity.