Design, synthesis, antiviral and cytostatic activity of ω-(1H-1,2,3-triazol-1-yl)(polyhydroxy)alkylphosphonates as acyclic nucleotide analogues

The efficient synthesis of a new series of polyhydroxylated dibenzyl ω-(1H-1,2,3-triazol-1-yl)alkylphosphonates as acyclic nucleotide analogues is described starting from dibenzyl ω-azido(polyhydroxy)alkylphosphonates and selected alkynes under microwave irradiation. Selected O,O-dibenzylphosphonate acyclonucleotides were transformed into the respective phosphonic acids. All compounds were evaluated in vitro for activity against a broad variety of DNA and RNA viruses and for cytostatic activity against murine leukemia L1210, human T-lymphocyte CEM and human cervix carcinoma HeLa cells. Compound (1S,2S)-16b exhibited antiviral activity against Influenza A H3N2 subtype (EC50 = 20 μM—visual CPE score; EC50 = 18 μM—MTS method; MCC >100 μM, CC50 >100 μM) in Madin Darby canine kidney cell cultures (MDCK), and (1S,2S)-16k was active against vesicular stomatitis virus and respiratory syncytial virus in HeLa cells (EC50 = 9 and 12 μM, respectively). Moreover, compound (1R,2S)-16l showed activity against both herpes simplex viruses (HSV-1, HSV-2) in HEL cell cultures (EC50 = 2.9 and 4 μM, respectively) and feline herpes virus in CRFK cells (EC50 = 4 μM) but at the same time it exhibited cytotoxicity toward uninfected cell (MCC ⩾ 4 μM). Several other compounds have been found to inhibit proliferation of L1210, CEM as well as HeLa cells with IC50 in the 4–50 μM range. Among them compounds (1S,2S)- and (1R,2S)-16l were the most active (IC50 in the 4–7 μM range).

Compound (1S,2S)-16b exhibited antiviral activity against Influenza A H3N2 subtype (EC50 = 20 μM—visual CPE score; EC50 = 18 μM—MTS method; MCC >100 μM, CC50 >100 μM) in Madin Darby canine kidney cell cultures (MDCK), and (1S,2S)-16k against vesicular stomatitis virus and respiratory syncytial virus in HeLa cells (EC50 = 9 and 12 μM, respectively). Moreover, (1R,2S)-16l showed activity against both herpes simplex viruses (HSV-1, HSV-2) in HEL cell cultures (EC50 = 2.9 and 4 μM, respectively) and feline herpes virus in CRFK cells (EC50 = 4 μM) but at the same time it exhibited cytotoxicity toward uninfected cell (MCC ⩾ 4 μM). Several compounds (1S,2S)-16i–l and (1R,2S)-16f–l inhibited proliferation of L1210, CEM as well as HeLa cells with IC50’s in the 4–50 μM range.Figure optionsDownload as PowerPoint slide