1. Lead identification and optimization of bacterial glutamate racemase inhibitors.
- Author
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Malapati P, Siva Krishna V, Nallangi R, Meda N, Reshma Srilakshmi R, and Sriram D
- 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
- 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
50 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 IC50 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)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2018
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