Golankiewicz B, Januszczyk P, Ikeda S, Balzarini J, De Clercq E
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan.
J Med Chem. 1995 Sep 1;38(18):3558-65. doi: 10.1021/jm00018a015.
A variety of imidazo[1,5-a]-1,3,5-triazine derivatives carrying C-, O-, and S-benzyl and/or 4-methylbenzyl groups were synthesized and examined for their inhibitory effects on the replication of ortho- and paramyxoviruses. The key compounds 8-R-2-thioxo-2,3-dihydroimidazo [1,5-a]-1,3,5-triazin-4(1H)-ones 3a,b,d were synthesized by chlorotrimethylsilane/HMDS-effected cyclization--rearrangement of the corresponding 6-amino-5-(formylamino)-5-R-2-mercaptopyrimidin-4(5H)-ones 2a,b,d (R = benzyl, 4-methylbenzyl and 5-(benzyloxy)pentyl). Compounds 3a,b were further transformed into 4-thiones 5a,b and 4-dimethylamino derivatives 7a,b. Preparation of S-methyl, S-benzyl, and S-(4-methylbenzyl) derivatives 12-19 was carried out by the treatment of thioxo compounds 3b,d, 5b, and 8b in an alcohol/potassium carbonate system with methyl iodide or the appropriate aralkyl bromide. Simultaneous presence of the benzyl and thio structural units was found to be indispensable for any selective biological activity. Some 2-thio substituted compounds were specifically inhibitory to some viruses, e.g., 8-(4-methylbenzyl)-2-[(4-methylbenzyl) thio]imidazo[1,5-a]-1,3,5-triazin-4-one (13) and 8-[5-(benzyloxy)pentyl]-2-[(4-methylbenzyl)thio]imidazo [1,5-a]-1,3,5-triazin-4-one (15) inhibited influenza A virus at a concentration of 4.1 and 5.3 microM, and 2-(benzylthio)-6, 8-dimethylimidazo[1,5-a]-1,3,5-triazin-4-one (16) and 6, 8-dimethyl-2-[(4-methylbenzyl)thio]imidazo[1,5-a]1,3, 5-triazin-4-one (17) inhibited respiratory syncytial virus at a concentration of 21.9 and 15.7 microM, respectively, that is, at concentrations that were 20-50-fold lower than the cytotoxic concentrations. Compound 13 was inhibitory to respiratory syncytial virus at a concentration of 1.4 microM, that is, at a concentration that was 180-fold lower than the cytotoxic concentration to MDCK or Vero cells but only 7-fold lower than the cytotoxic concentration to HeLa cells. The 4-thiones 5a,b were nonselectively inhibitory to ortho-and paramyxoviruses at concentrations that coincided with their cytotoxic concentrations.
合成了多种带有C-、O-和S-苄基及/或4-甲基苄基的咪唑并[1,5-a]-1,3,5-三嗪衍生物，并检测了它们对正粘病毒和副粘病毒复制的抑制作用。关键化合物8-R-2-硫代-2,3-二氢咪唑并[1,5-a]-1,3,5-三嗪-4(1H)-酮3a、b、d是通过氯代三甲基硅烷/六甲基二硅氮烷促进的相应6-氨基-5-(甲酰氨基)-5-R-2-巯基嘧啶-4(5H)-酮2a、b、d（R = 苄基、4-甲基苄基和5-(苄氧基)戊基）的环化-重排反应合成的。化合物3a、b进一步转化为4-硫酮5a、b和4-二甲基氨基衍生物7a、b。通过在醇/碳酸钾体系中用碘甲烷或适当的芳基溴处理硫代化合物3b、d、5b和8b来制备S-甲基、S-苄基和S-(4-甲基苄基)衍生物12 - 19。发现苄基和硫结构单元的同时存在对于任何选择性生物活性都是必不可少的。一些2-硫代取代化合物对某些病毒具有特异性抑制作用，例如，8-(4-甲基苄基)-2-[(4-甲基苄基)硫代]咪唑并[1,5-a]-1,3,5-三嗪-4-酮（13）和8-[5-(苄氧基)戊基]-2-[(4-甲基苄基)硫代]咪唑并[1,5-a]-1,3,5-三嗪-4-酮（15）在浓度为4.1和5.3 microM时抑制甲型流感病毒，2-(苄基硫代)-6,8-二甲基咪唑并[1,5-a]-1,3,5-三嗪-4-酮（16）和6,8-二甲基-2-[(4-甲基苄基)硫代]咪唑并[1,5-a]1,3,5-三嗪-4-酮（17）在浓度为21.9和15.7 microM时分别抑制呼吸道合胞病毒，即，这些浓度比细胞毒性浓度低20 - 50倍。化合物13在浓度为1.4 microM时抑制呼吸道合胞病毒，即，该浓度比MDCK或Vero细胞的细胞毒性浓度低180倍，但仅比HeLa细胞的细胞毒性浓度低7倍。4-硫酮5a、b在与其细胞毒性浓度一致的浓度下对正粘病毒和副粘病毒具有非选择性抑制作用。
