Synthesis and Structure-Activity Relationship Studies of Benzo[b][1,4]oxazin-3(4H)-one Analogues as Inhibitors of Mycobacterial Thymidylate Synthase X.
Jakub ModrankaJiahong LiAnastasia ParchinaMichiel VanmeertShrinivas G DumbreMayla SalmanHannu MyllykallioHubert F BeckerRoeland VanhoutteLia MargamuljanaHoai NguyenRania Abu El-AsrarJef RozenskiPiet HerdwijnSteven De JongheEveline LescrinierPublished in: ChemMedChem (2019)
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.
Keyphrases
- mycobacterium tuberculosis
- structure activity relationship
- pulmonary tuberculosis
- infectious diseases
- small molecule
- circulating tumor
- emergency department
- molecular docking
- single molecule
- hepatitis c virus
- multidrug resistant
- silver nanoparticles
- single cell
- hiv aids
- human immunodeficiency virus
- hiv infected
- case control
- electronic health record