Synthesis and the Biological Activity of Phosphonylated 1,2,3-Triazolenaphthalimide Conjugates.

A novel series of diethyl {4-[(5-substituted-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)-methyl]-1H-1,2,3-triazol-1-yl}alkylphosphonates designed as analogues of amonafide was synthesized. All phosphonates were assessed for antiviral activity against a broad range of DNA and RNA viruses and several of them showed potency against varicella-zoster virus (VZV) [EC50 (50% effective concentration) = 27.6-91.5 µM]. Compound 16b exhibited the highest activity against a thymidine kinase-deficient (TK-) VZV strain (EC50 = 27.59 µM), while 16d was the most potent towards TK⁺ VZV (EC50 = 29.91 µM). Cytostatic properties of the compounds 14a-i-17a-i were studied on L1210, CEM, HeLa and HMEC-1 cell lines and most of them were slightly cytostatic for HeLa [IC50 (50% inhibitory concentration) = 29-130 µM] and L1210 cells [IC50 (50% inhibitory concentration) = 14-142 µM].

Phosphonylated Acyclic Guanosine Analogues with the 1,2,3-Triazole Linker.

A novel series of {4-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-1H-1,2,3-triazol-1-yl}alkylphosphonates and {4-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-1H-1,2,3-triazol-1-yl}alkylphosphonates as acyclic analogues of guanosine were synthesized and assessed for antiviral activity against a broad range of DNA and RNA viruses and for their cytostatic activity toward three cancerous cell lines (HeLa, L1210 and CEM). They were devoid of antiviral activity; however, several phosphonates were found slightly cytostatic against HeLa cells at an IC50 in the 80-210 µM range. Compounds (1R,2S)-17k and (1S,2S)-17k showed the highest inhibitory effects (IC50=15-30 µM) against the proliferation of murine leukemia (L1210) and human T-lymphocyte (CEM) cell lines.

Design, synthesis and antiviral evaluation of novel acyclic phosphonate nucleotide analogs with triazolo[4,5-b]pyridine, imidazo[4,5-b]pyridine and imidazo[4,5-b]pyridin-2(3H)-one systems.

A new series of phosphonylated triazolo[4,5-b]pyridine (1-deaza-8-azapurine), imidazo[4,5-b]pyridine (1-deazapurine) and imidazo[4,5-b]pyridin-2(3H)-one (1-deazapurin-8-one) were synthesized from 2-chloro-3-nitropyridine and selected diethyl É·-aminoalkylphosphonates followed by reduction of the nitro group and cyclization. In the final step O,O-diethylphosphonates were transformed into the corresponding phosphonic acids. All synthesized compounds were evaluated in vitro for inhibitory activity against a broad variety of DNA and RNA viruses and their cytotoxic potencies were also established. Compound 12f showed marginal activity against cytomegalovirus Davis strain (EC50 = 76.47 µM) in human embryonic lung (HEL) cells while compounds 10g (EC50 = 52.53 µM) and 12l (EC50 = 61.70 µM) were minimally active against the varicella-zoster virus Oka strain in HEL cells. Compounds under investigation were not cytotoxic at the maximum concentration evaluated (100 µM).

The synthesis, antiviral, cytostatic and cytotoxic evaluation of a new series of acyclonucleotide analogues with a 1,2,3-triazole linker.

The efficient synthesis of a new series of acyclonucleotide analogues with a 1,2,3-triazole linker is described starting from diethyl azidomethyl-, 2-azidoethyl-, 3-azidopropyl-, 4-azidobutyl-, 2-azido-1-hydroxyethyl-, 3-azido-2-hydroxypropyl- and 3-azido-1-hydroxypropylphosphonates and selected alkynes under microwave irradiation. Several O,O-diethylphosphonate 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 cytostatic activity against murine leukaemia L1210, human T-lymphocyte CEM and human cervix carcinoma HeLa cells. Acyclonucleotide 22e exhibited activity against both herpes simplex viruses (HSV-1, HSV-2) in HEL cell cultures (EC50 = 17 µM) and feline herpes virus (EC50 = 24 µM) in CRFK cell cultures, while compounds 20k, 21k, 22k and 23k preferentially inhibited proliferation of human T-lymphocyte CEM cells at IC50 in the 2.8-12 µM range.