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

Autor: Negrya SD; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova St., 119991, Moscow, Russia., Jasko MV; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova St., 119991, Moscow, Russia., Solyev PN; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova St., 119991, Moscow, Russia., Karpenko IL; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova St., 119991, Moscow, Russia., Efremenkova OV; Gause Institute of New Antibiotics, 11 Bolshaya Pirogovskaya St., 119021, Moscow, Russia., Vasilyeva BF; Gause Institute of New Antibiotics, 11 Bolshaya Pirogovskaya St., 119021, Moscow, Russia., Sumarukova IG; Gause Institute of New Antibiotics, 11 Bolshaya Pirogovskaya St., 119021, Moscow, Russia., Kochetkov SN; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova St., 119991, Moscow, Russia., Alexandrova LA; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova St., 119991, Moscow, Russia. ala2004_07@mail.ru.
Jazyk: angličtina
Zdroj: The Journal of antibiotics [J Antibiot (Tokyo)] 2020 Apr; Vol. 73 (4), pp. 236-246. Date of Electronic Publication: 2020 Jan 14.
DOI: 10.1038/s41429-019-0273-x
Abstrakt: 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 -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 ).
Databáze: MEDLINE
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