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Lead identification and optimization of bacterial glutamate racemase inhibitors.

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 IC50 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).

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Malapati P,Siva Krishna V,Nallangi R,Meda N,Reshma Srilakshmi R,Sriram D

doi

10.1016/j.bmc.2017.11.031

subject

Has Abstract

pub_date

2018-01-01 00:00:00

pages

177-190

issue

1

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(17)31962-4

journal_volume

26

pub_type

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