Synthesis and in vitro Biological Evaluation of Novel Thymidine Analogs Containing 1H-1,2,3-Triazolyl, 1H-Tetrazolyl, and 2H-Tetrazolyl Fragments

3 '-Azidothymidine (AZT) reacts with 1-propargyl-5-R-1H- and 2-propargyl-5-R-2H-tetrazoles (R=H, Me, CH2COOEt, CH2CON(CH3)(2), Ph, 2-CH3-C6H4, or 4-NO2-C6H4) via the Cu(I)-catalyzed asymmetric [3+2] cycloaddition to give 3 '-modified thymidine analogs incorporating 1H-1,2,3-triazolyl, 1H-, and 2H-tetrazolyl fragments in 41-76% yield. The structures of the obtained compounds have been elucidated by means of HRESI+-MS, H-1 and C-13{H-1} NMR, and single crystal X-ray diffraction {for 3 '-[4-(1H-5-N,N-dimethylaminocarbonylmethyltetrazol-1-yl)-1H-1,2,3-triazol-1-yl]thymidine 10d}. In vitro biological evaluation of the prepared compounds has been performed; they have exhibited low activity against phenotypic HIV-1(899A). Moderate anti-influenza activity against influenza virus A/Puerto Rico/8/34 (H1N1) strain has been observed in the cases of 3 '-(4-(1H-tetrazol-1-ylmethyl)-1H-1,2,3-triazol-1-yl)thymidine 10a (IC50 39.6 mu g/mL), 3 '-(4-(2H-5-ethoxycarbonyltetrazol-2-ylmethyl)-1H-1,2,3-triazol-1-yl)thymidine 11c (IC50 31.6 mu g/mL), and 3 '-(4-(2H-5-(4-nitrophenyl)-tetrazol-2-ylmethyl)-1H-1,2,3-triazol-1-yl)thymidine 11g (IC50 46.4 mu g/mL). The tested compounds possess very low cytotoxicity towards MDCK and MT4 cells as well as tumor human cervical carcinoma HeLa and promyelocytic leukemia HL-60 cells. [GRAPHICS] .