PUBLICATION

Identification and development of benzoxazole derivatives as novel bacterial glutamate racemase inhibitors

Authors
Malapati, P., Krishna, V.S., Nallangi, R., Srilakshmi, R.R., Sriram, D.
ID
ZDB-PUB-180109-7
Date
2017
Source
European Journal of Medicinal Chemistry   145: 23-34 (Journal)
Registered Authors
Keywords
Benzoxazole, Racemization, Thermal shift assay screening, Tuberculosis, glutamate racemase
MeSH Terms
  • Amino Acid Isomerases/antagonists & inhibitors*
  • Amino Acid Isomerases/metabolism
  • Animals
  • Anti-Bacterial Agents/chemical synthesis
  • Anti-Bacterial Agents/chemistry
  • Anti-Bacterial Agents/pharmacology*
  • Benzoxazoles/chemical synthesis
  • Benzoxazoles/chemistry
  • Benzoxazoles/pharmacology*
  • Biofilms/drug effects
  • Cell Survival/drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors/chemical synthesis
  • Enzyme Inhibitors/chemistry
  • Enzyme Inhibitors/pharmacology*
  • Kinetics
  • Mice
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation
  • Molecular Structure
  • Mycobacterium/drug effects*
  • Mycobacterium/enzymology
  • RAW 264.7 Cells
  • Structure-Activity Relationship
  • Zebrafish
PubMed
29310027 Full text @ Eur. J. Med. Chem.
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 (IC50 20.07 ± 0.29 μM). Among all the compounds; compound 22 (IC50 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.
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Human Disease / Model
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