Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 26, Issue 1, Pages 177-190Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2017.11.031
Keywords
Tuberculosis; Glutamate racemase; Fluorescence thermal shift assay; Dormant tuberculosis; Biofilm; Zebra fish
Funding
- Department of Science and Technology, Government of India
- Department of Biotechnology, Government of India [BT/HRD/35/01/04/2015]
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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 IC50 19.47 +/- 0.81 mu M. 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 mu M. 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). (C) 2017 Elsevier Ltd. All rights reserved.
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