Synthesis of water-soluble prodrugs of 5-modified 2ʹ-deoxyuridines and their antibacterial activity

Recently we have synthesized a set of pyrimidine nucleoside derivatives bearing extended alkyltriazolylmethyl substituents at position 5 of the nucleic base, and showed their significant activity against Mycobacterium tuberculosis virulent laboratory strain H37Rv as well as drug-resistant MS-115 strain. The presence of a lengthy hydrophobic substituent leads to the reduction of nucleoside water solubility making their antibacterial activity troublesome to study. A series of water-soluble forms of 5-modified 2ʹ-deoxyuridines 4a–c and 8a–c were synthesized. They appeared at least two orders more soluble compared with the parent compounds 1a and 1b . Their half-hydrolysis time was 5–12 h, which can be considered optimal for prodrugs used in clinics. Obtained compounds showed moderate activity (MIC 48–95 µg·ml −1 ) against some Gram-positive bacteria including resistant strains of Staphylococcus aureus and Mycobacterium smegmatis and were low cytotoxic for human cell lines (CD 50  >> 100 µg·ml −1 ).