Synthesis and antiviral activity of N-4'-dihydropyridinyl and dihydroquinolinylcarbonyl-2-hydroxymethyl-5-[cytosin-1'-yl]-1, 3-oxathiolane derivatives against human immunodeficiency virus and duck hepatitis B virus

Article abstract of DOI:10.1016/0223-5234(96)89550-X

Dihydropyridine and dihydroquinoline derivatives of 2-hydroxymethyl-5-[cytosin-1'-yl]-1,3-oxathiolane ((±)-3TC) have been prepared. The N-4-nicotinate or the N-4-quinoline-carboxylate amides were obtained by reacting nicotinic or quinolinecarboxylic acids with (±)-3TC in the presence of DCC and HOBT. These derivatives were converted into their corresponding N-methylpyridinium and N-methyl quinolinium salts by treatment with MeI in acetone. Reduction of the latter with Na₂S₂O₄ gave dihydropyridine and dihydroquinoline compounds. The N-4-trifluorotoluidinonicotinate derivative was obtained from the coupling of niflumic acid and (±)-3TC using BOP and DIEA. The anti-HIV-1 activities of seven derivatives were determined in MT-4 infected cell cultures. Of these compounds, the IC₅₀ values ranged from 0.1-100 μM, while the IC₅₀ for (±)-3TC was 0.1 μM. The anti-HBV activities were determined in infected duck hepatocytes. Anti-HBV activities of the (±)-3TC derivatives were half that of the parent drug (±)-3TC. The lipophilicity (partition coefficients) of these compounds were determined. The dihydroquinoline prodrugs had greater lipophilicity than the dihydropyridine analogues.