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Synthesis and Structure–Activity Relationship Studies of Benzo[ b ][1,4]oxazin‐3(4 H )‐one Analogues as Inhibitors of Mycobacterial Thymidylate Synthase X
Author(s) -
Modranka Jakub,
Li Jiahong,
Parchina Anastasia,
Vanmeert Michiel,
Dumbre Shrinivas,
Salman Mayla,
Myllykallio Hannu,
Becker Hubert F.,
Vanhoutte Roeland,
Margamuljana Lia,
Nguyen Hoai,
Abu ElAsrar Rania,
Rozenski Jef,
Herdewijn Piet,
De Jonghe Steven,
Lescrinier Eveline
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800739
Subject(s) - thymidylate synthase , mycobacterium tuberculosis , enzyme , stereochemistry , cofactor , biosynthesis , chemistry , flavin group , structure–activity relationship , biochemistry , tuberculosis , biology , in vitro , genetics , medicine , fluorouracil , chemotherapy , pathology
Since the discovery of a flavin‐dependent thymidylate synthase (ThyX or FDTS) that is absent in humans but crucial for DNA biosynthesis in a diverse group of pathogens, the enzyme has been pursued for the development of new antibacterial agents against Mycobacterium tuberculosis , the causative agent of the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti‐TB drugs, we have built upon our previous screening efforts and report herein an optimization campaign of a novel series of inhibitors with a unique inhibition profile. The inhibitors display competitive inhibition toward the methylene tetrahydrofolate cofactor of ThyX, enabling us to generate a model of the compounds bound to their target, thus offering insight into their structure–activity relationships.