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

Abstract

3'-Azidothymidine (AZT) reacts with 1-propargyl-5-R-1<i>H</i>- and 2-propargyl-5-R-2<i>H</i>-tetrazoles (R = H, Me, CH₂COOEt, CH₂CON(CH₃)₂, Ph, 2-CH₃-C₆H₄, or 4-NO₂-C₆H₄) <i>via</i> the Cu(I)-catalyzed asymmetric [3 + 2] cycloaddition to give 3'-modified thymidine analogs incorporating 1<i>H</i>-1,2,3-triazolyl, 1<i>H</i>-, and 2<i>H</i>-tetrazolyl fragments in 41-76% yield. The structures of the obtained compounds have been elucidated by means of HRESI⁺-MS, ¹H and ¹³ C{¹H} NMR, and single crystal X-ray diffraction {for 3'-[4-(1<i>H</i>-5-<i>N</i>,<i>N</i>-dimethylaminocarbonylmethyltetrazol-1-yl)-1<i>H</i>-1,2,3-triazol-1-yl]thymidine <b>10d</b>}. <i>In vitro</i> 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-(1<i>H</i>-tetrazol-1-ylmethyl)-1<i>H</i>-1,2,3-triazol-1-yl)thymidine <b>10a</b> (IC₅₀ 39.6 μg/mL), 3'-(4-(2<i>H</i>-5-ethoxycarbonyltetrazol-2-ylmethyl)-1<i>H</i>-1,2,3-triazol-1-yl)thymidine <b>11c</b> (IC₅₀ 31.6 μg/mL), and 3'-(4-(2<i>H</i>-5-(4-nitrophenyl)-tetrazol-2-ylmethyl)-1<i>H</i>-1,2,3-triazol-1-yl)thymidine <b>11g</b> (IC₅₀ 46.4 μg/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.