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

• Published in: European journal of medicinal chemistry 1996, Vol.31 (7), p.539-546
• Main Authors: Camplo, M, Charvet-Faury, AS, Borel, C, Turin, F, Hantz, O, Trabaud, C, Niddam, V, Mourier, N, Graciet, JC, Chermann, JC, Kraus, JL
• Format: Article
• Language: English
• Subjects: 2-hydroxymethyl-5-[cytosin-1′-yl]-1,3-oxathiolane analogue; anti-HIV activity; Antibiotics. Antiinfectious agents. Antiparasitic agents; antiviral activity; Antiviral agents; Biological and medical sciences; duck hepatitis B virus; Medical sciences; Pharmacology. Drug treatments; prodrug; pyridinyl derivative; quinolinyl derivative
• ISSN: 0223-5234; 1768-3254
• 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 Na 2SS 2OO 4 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 IC 0 v values ranged from 0.1–100 μM, while the IC 0 f 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.