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.
Citation
Malapati, P., Krishna, V.S., Nallangi, R., Srilakshmi, R.R., Sriram, D. (2017) Identification and development of benzoxazole derivatives as novel bacterial glutamate racemase inhibitors. European Journal of Medicinal Chemistry. 145:23-34.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping