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Lead identification and optimization of bacterial glutamate racemase inhibitors.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2018 Jan 01; Vol. 26 (1), pp. 177-190. Date of Electronic Publication: 2017 Nov 21. - Publication Year :
- 2018
-
Abstract
- Mycobacterium tuberculosis glutamate racemase is an essential enzyme involved in peptidoglycan synthesis and conserved in most bacteria. Small molecule inhibitors were reported on other bacterial species whereas in M. tuberculosis it wasn't explored much. In this study we have screened in house compound library using fluorescence thermal shift assay and enzyme inhibition assay, form this (1-(3-(benzo[d]thiazol-2-yl)phenyl)-3-(p-tolyl)thiourea) was identified as lead compound with IC <subscript>50</subscript> 19.47 ± 0.81 μM. Further lead optimization by synthesis resulted in twenty-three compounds, of which Compound 25 has shown more efficacy compared to lead 1 showing non-competitive mode of inhibition with IC <subscript>50</subscript> 1.32 ± 0.43 μM. It also showed significant activity (represented in log reduction) in nutrient starved dormant M. tuberculosis model (2.1), M. tuberculosis biofilm assay (2.0) and in vivo M. marinum infected zebrafish model (3.5).<br /> (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Subjects :
- Amino Acid Isomerases metabolism
Animals
Antitubercular Agents chemical synthesis
Antitubercular Agents chemistry
Cell Survival drug effects
Dose-Response Relationship, Drug
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Mice
Microbial Sensitivity Tests
Molecular Structure
Mycobacterium tuberculosis enzymology
Mycobacterium tuberculosis growth & development
RAW 264.7 Cells
Structure-Activity Relationship
Amino Acid Isomerases antagonists & inhibitors
Antitubercular Agents pharmacology
Enzyme Inhibitors pharmacology
Mycobacterium tuberculosis drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 26
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29239770
- Full Text :
- https://doi.org/10.1016/j.bmc.2017.11.031