Structure-antiviral activity relationship in the series of pyrimidine and purine N-[2-(2-phosphonomethoxy)ethyl] nucleotide analogues. 1. Derivativessubstituted at the carbon atoms of the base

A series of dialkyl esters of purine and pyrimidine N-[2-(phosphonomethoxy) ethyl] derivatives substituted at position 2, 6, or 8 of the purine base or position 2, 4, or 5 of the pyrimidine base were prepared by alkylation of the appropriate heterocyclic base with 2-chloroethoxymethylphosphonate dies ter in the presence of sodium hydride, cesium carbonate, or 1,8-diazabicycl o-[5,4,0]undec-7-ene (DBU) in dimethylformamide. Additional derivatives wer e,obtained by the transformations of the bases in the suitably modified int ermediates bearing reactive functions at the base moiety. The diesters were converted to the corresponding monoesters by sodium azide treatment, while the free acids were obtained from the diester by successive treatment with bromotrimethylsilane and hydrolysis. None of the PME derivatives in the py rimidine series, their 6-aza or 3-deaza analogues, exhibited any activity a gainst DNA viruses or retroviruses tested,except for the 5-bromocytosine de rivative. Substitution of the adenine ring in PMEA at position 2 by Cl, F, or OH group decreased the activity against all DNA viruses tested. PMEDAP w as highly active against HSV-1, HSV-8, and VZV in the concentration range ( EC50) of 0.07-2 mu g/mL. Also the 2-amino-6-chloropurine derivative was str ongly active (EC50 = 0.1-0.4 mu g/mL) against herpes simplex viruses and (E C50 = 0.006-0.3 mu g/mL) against CMV and VZV. PMEG was the most active comp ound of the whole series: against DNA viruses (EC50 similar to 0.01-0.02 mu g/mL), though it exhibited significant toxicity against the host cells. Th e base-modified compounds did not show any appreciable activity against DNA viruses except for 7-deazaPMEA (IC50 similar to 7.5 mu g/mL) against HIV-1 and MSV. The neutral.(diisopropyl, diisooctyl) diesters of PMEA were activ e against CMV and VZV, while the corresponding monoesters were inactive. Th e diisopropyl ester of the 2-chloroadenine analogue of PMEA showed substant ially (10-100x) higher activity against CMV and VZV than the parent phospho nate. Also, the diisopropyl and diisooctyl ester of PMEDAP inhibited CMV si nd VZV, but esterification of the phosphonate residue did not improve the a ctivity against either MSV or. HIV.