Synthesis of water-soluble prodrugs of 5-modified 2ʹ-deoxyuridines and their antibacterial activity
| Autor: | Inna L. Karpenko, L. A. Alexandrova, Maxim V. Jasko, Pavel N. Solyev, Olga V. Efremenkova, I. G. Sumarukova, Sergey N. Kochetkov, Sergey D Negrya, Byazilya F. Vasilyeva |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pharmacology Pyrimidine biology 010405 organic chemistry Stereochemistry Mycobacterium smegmatis 030106 microbiology Substituent Prodrug biology.organism_classification 01 natural sciences 0104 chemical sciences 03 medical and health sciences chemistry.chemical_compound chemistry Drug Discovery Nucleic acid Structure–activity relationship Antibacterial activity Nucleoside |
| Zdroj: | The Journal of Antibiotics. 73:236-246 |
| ISSN: | 1881-1469 0021-8820 |
| DOI: | 10.1038/s41429-019-0273-x |
| Popis: | 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 (CD50 >> 100 µg·ml−1). |
| Databáze: | OpenAIRE |
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