Lead identification and optimization of bacterial Glutamate racemase inhibitors

Publication date: Available online 21 November 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Prasanthi Malapati, Vagolu Siva Krishna, Radhika Nallangi, Nikhila Meda, Rudraraju Reshma Srilakshmi, Dharmarajan Sriram
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).

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