Synthesis and evaluation of C-5 modified 2'-deoxyuridine monophosphates as inhibitors of M. tuberculosis thymidylate synthase.
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.
Engelhardt Institute of Molecular Biology RAS, Vavilova 32, Moscow 119991, Russia. Electronic address: ala2004_07@mail.ru.
Liudmila A
LA
Alexandrova
Engelhardt Institute of Molecular Biology RAS, Vavilova 32, Moscow 119991, Russia; Moscow Institute of Physics and Technology, Dolgoprudny 141700, Moscow Region, Russia.
Vladimir O
VO
Chekhov
Engelhardt Institute of Molecular Biology RAS, Vavilova 32, Moscow 119991, Russia.
Eduard R
ER
Shmalenyuk
Engelhardt Institute of Molecular Biology RAS, Vavilova 32, Moscow 119991, Russia.
Sergey N
SN
Kochetkov
Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
Rania Abu
RA
El-Asrar
Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
Piet
P
Herdewijn
D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D013940:Thymidylate Synthase; D003857:Deoxyuridine
2′-Deoxyuridine analogs; Inhibition; Mycobacterium tuberculosis; Nucleoside 5′-monophosphates; Thymidylate synthase