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

• Published in: Journal of antibiotics Vol. 73; no. 4; pp. 236 - 246
• Main Authors: Negrya, Sergey D, Jasko, Maxim V, Solyev, Pavel N, Karpenko, Inna L, Efremenkova, Olga V, Vasilyeva, Byazilya F, Sumarukova, Irina G, Kochetkov, Sergey N, Alexandrova, Liudmila A
• Format: Journal Article
• Language: English
• Published: Japan Nature Publishing Group 01.04.2020
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Cell Line; Deoxyuridine - chemical synthesis; Deoxyuridine - chemistry; Deoxyuridine - pharmacology; Gram-positive bacteria; Gram-Positive Bacteria - drug effects; Humans; Hydrophobic and Hydrophilic Interactions; Microbial Sensitivity Tests; Prodrugs; Solubility; Structure-Activity Relationship; Water - chemistry
• ISSN: 0021-8820; 1881-1469
• DOI: 10.1038/s41429-019-0273-x

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 2'-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 ) against some Gram-positive bacteria including resistant strains of Staphylococcus aureus and Mycobacterium smegmatis and were low cytotoxic for human cell lines (CD  >> 100 µg·ml ).