Synthesis and evaluation of C-5 modified 2'-deoxyuridine monophosphates as inhibitors of M. tuberculosis thymidylate synthase

Liudmila A Alexandrova; Vladimir O Chekhov; Eduard R Shmalenyuk; Sergey N Kochetkov; Rania Abu El-Asrar; Piet Herdewijn

doi:10.1016/j.bmc.2015.09.053

Synthesis and evaluation of C-5 modified 2'-deoxyuridine monophosphates as inhibitors of M. tuberculosis thymidylate synthase

Bioorg Med Chem. 2015 Nov 15;23(22):7131-7. doi: 10.1016/j.bmc.2015.09.053. Epub 2015 Oct 9.

Authors

Liudmila A Alexandrova¹, Vladimir O Chekhov², Eduard R Shmalenyuk³, Sergey N Kochetkov³, Rania Abu El-Asrar⁴, Piet Herdewijn⁴

Affiliations

¹ Engelhardt Institute of Molecular Biology RAS, Vavilova 32, Moscow 119991, Russia. Electronic address: ala2004_07@mail.ru.
² Engelhardt Institute of Molecular Biology RAS, Vavilova 32, Moscow 119991, Russia; Moscow Institute of Physics and Technology, Dolgoprudny 141700, Moscow Region, Russia.
³ Engelhardt Institute of Molecular Biology RAS, Vavilova 32, Moscow 119991, Russia.
⁴ Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.

PMID: 26482569
DOI: 10.1016/j.bmc.2015.09.053

Abstract

A series of 5'-monophosphates of 5-substituted 2'-deoxyuridine analogs, which recently demonstrated in vitro substantial suppression of two strains of Mycobacterium tuberculosis growth (virulent laboratory H37Rv and multiple resistant MS-115), has been synthesized and evaluated as potential inhibitors of M. tuberculosis thymidylate synthases: classical (ThyA) and flavin dependent thymidylate synthase (ThyX). A systematic SAR study and docking revealed 5-undecyloxymethyl-2'-deoxyuridine 5'-monophosphate 3b, displaying an IC50 value against ThyX of 8.32 μM. All derivatives lack activity against the ThyA. It can be assumed that the mechanism of action of 3b may be partially associated with the inhibition of the ThyX.

Keywords: 2′-Deoxyuridine analogs; Inhibition; Mycobacterium tuberculosis; Nucleoside 5′-monophosphates; Thymidylate synthase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antitubercular Agents / chemical synthesis
Antitubercular Agents / chemistry
Antitubercular Agents / pharmacology
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / metabolism
Binding Sites
Deoxyuridine / analogs & derivatives*
Deoxyuridine / chemical synthesis
Deoxyuridine / pharmacology
Enzyme Activation / drug effects
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Molecular Docking Simulation
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / enzymology*
Protein Structure, Tertiary
Structure-Activity Relationship
Thymidylate Synthase / antagonists & inhibitors*
Thymidylate Synthase / metabolism

Substances

Antitubercular Agents
Bacterial Proteins
Enzyme Inhibitors
Thymidylate Synthase
Deoxyuridine