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Identification and development of benzoxazole derivatives as novel bacterial glutamate racemase inhibitors.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2018 Feb 10; Vol. 145, pp. 23-34. Date of Electronic Publication: 2017 Dec 30. - Publication Year :
- 2018
-
Abstract
- In the present study, we attempted to develop novel class of Mycobacterium tuberculosis (Mtb) inhibitors by exploring the pharmaceutically underexploited enzyme targets which are majorly involved in cell wall biosynthesis of mycobacteria. For this purpose glutamate racemase was selected which racemizes d-glutamate from l-glutamate, a key step in peptidoglycan synthesis. Furthermore, enzyme is neither expressed nor its product, d-glutamate is produced in mammals, and hence inhibiting this enzyme will have no vulnerable effect in host organism. A library of our in-house compounds were screened against glutamate racemase using a biophysical technique; thermal shift assay and further by enzyme inhibition assay to identify Lead 1 molecule. Lead 1 optimization and expansion resulted in twenty four compounds. Among the synthesized compounds twelve compounds shown good enzyme inhibition than Lead 1 (IC <subscript>50</subscript> 20.07 ± 0.29 μM). Among all the compounds; compound 22 (IC <subscript>50</subscript> 1.1 ± 0.52 μM) showed potent non-competitive mode of inhibition in enzyme assay. Further showed good susceptibility (in replicating bacteria) of MIC 8.72 μM and bactericidal time dependant kill on dormant culture. It also exhibited significant activity in Mtb nutrient starvation model (2.5) and Mtb biofilm model (2.4) and in vivo M. marinum infected Zebra fish model studies (3.6) reduction at logarithmic scale.<br /> (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Amino Acid Isomerases metabolism
Animals
Anti-Bacterial Agents chemical synthesis
Anti-Bacterial Agents chemistry
Benzoxazoles chemical synthesis
Benzoxazoles chemistry
Biofilms drug effects
Cell Survival drug effects
Dose-Response Relationship, Drug
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Kinetics
Mice
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Structure
Mycobacterium enzymology
RAW 264.7 Cells
Structure-Activity Relationship
Zebrafish
Amino Acid Isomerases antagonists & inhibitors
Anti-Bacterial Agents pharmacology
Benzoxazoles pharmacology
Enzyme Inhibitors pharmacology
Mycobacterium drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 145
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29310027
- Full Text :
- https://doi.org/10.1016/j.ejmech.2017.12.088