Novel 5-substituted derivatives of 2'-deoxy-6-azauridine with antibacterial activity

The Journal of Antibiotics
Sergey D NegryaLiudmila A Alexandrova

Abstract

The emergence of new drug-resistant strains of bacteria necessitates the development of principally new antibacterial agents. One of the novel classes of antibacterial agents is nucleoside analogs. We have developed a fast and simple one-pot method for preparation of α- and β-anomers of 5-modified 6-aza- and 2-thio-6-aza-2'-deoxyuridine derivatives in high yields. 2-Thio derivatives demonstrated moderate activity against Mycobacterium smegmatis (MIC = 0.2-0.8 mM), Staphylococcus aureus (MIC = 0.03-0.9 mM) and some other Gram-positive bacteria. 2'-Deoxy-2-thio-5-phenyl-6-azauridine (2b) effectively suppressed the growth of Gram-negative bacteria Pseudomonas aeruginosa ATCC 27853 (MIC = 0.03 mM)-the one that causes diseases difficult to treat due to high resistance to antibiotics. 5'-Monophosphates of compounds 2a, b and 3a, b were docked into a binding site of Mycobacterium tuberculosis flavin-dependent thymidylate synthase (ThyX) enzyme. The molecular modeling demonstrates the possibility of binding of the 5-modified 2-thio-6-aza-2'-deoxyuridine 5'-monophosphates within the active site of the enzyme and thereby inhibiting the growth of the bacteria.

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Citations

Oct 12, 2019·International Journal of Molecular Sciences·Daniel Fernández-VillaLuis Rojo
Jan 15, 2020·The Journal of Antibiotics·Sergey D NegryaLiudmila A Alexandrova
Apr 28, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Cecilia PozziStefano Mangani
Feb 15, 2021·European Journal of Medicinal Chemistry·Liudmila A AlexandrovaAlexander A Zhgun

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Methods Mentioned

BETA
glycosylation
nuclear magnetic resonance
transglycosylation
column chromatography
NMR

Software Mentioned

MOE
MMFF94x
Molecular Operating Enviroment program ( MOE )
AMBER

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