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Issue 1, 2014
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Design, synthesis and characterization of novel inhibitors against mycobacterial β-ketoacyl CoA reductase FabG4

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Abstract

We report the design and synthesis of triazole-polyphenol hybrid compounds 1 and 2 as inhibitors of the FabG4 (Rv0242c) enzyme of Mycobacterium tuberculosis for the first time. A major advance in this field occurred only a couple of years ago with the X-ray crystal structure of FabG4, which has helped us to design these inhibitors by the computational fragment-based drug design (FBDD) approach. Compound 1 has shown competitive inhibition with an inhibition constant (Ki) value of 3.97 ± 0.02 μM. On the other hand, compound 2 has been found to be a mixed type inhibitor with a Ki value of 0.88 ± 0.01 μM. Thermodynamic analysis using isothermal titration calorimetry (ITC) reveals that both inhibitors bind at the NADH co-factor binding domain. Their MIC values, as determined by resazurin assay against M. smegmatis, indicated their good anti-mycobacterial properties. A preliminary structure–activity relationship (SAR) study supports the design of these inhibitors. These compounds may be possible candidates as lead compounds for alternate anti-tubercular drugs. All of the reductase enzymes of the Mycobacterium family have a similar ketoacyl reductase (KAR) domain. Hence, this work may be extrapolated to find structure-based inhibitors of other reductase enzymes.

Graphical abstract: Design, synthesis and characterization of novel inhibitors against mycobacterial β-ketoacyl CoA reductase FabG4

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Publication details

The article was received on 15 Aug 2013, accepted on 19 Sep 2013 and first published on 19 Sep 2013


Article type: Paper
DOI: 10.1039/C3OB41676C
Citation: Org. Biomol. Chem., 2014,12, 73-85
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    Design, synthesis and characterization of novel inhibitors against mycobacterial β-ketoacyl CoA reductase FabG4

    D. R. Banerjee, D. Dutta, B. Saha, S. Bhattacharyya, K. Senapati, A. K. Das and A. Basak, Org. Biomol. Chem., 2014, 12, 73
    DOI: 10.1039/C3OB41676C

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