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Issue 11, 2017
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The synthesis, biological evaluation and structure–activity relationship of 2-phenylaminomethylene-cyclohexane-1,3-diones as specific anti-tuberculosis agents

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Abstract

The present study utilised whole cell based phenotypic screening of thousands of diverse small molecules against Mycobacterium tuberculosis H37Rv (M. tuberculosis) and identified the cyclohexane-1,3-dione-based structures 5 and 6 as hits. The selected hit molecules were used for further synthesis and a library of 37 compounds under four families was synthesized for lead generation. Evaluation of the library against M. tuberculosis lead to the identification of three lead antituberculosis agents (37, 39 and 41). The most potential compound, 2-(((2-hydroxyphenyl)amino)methylene)-5,5-dimethylcyclohexane-1,3-dione (39) showed an MIC of 2.5 μg mL−1, which falls in the range of MICs values found for the known antituberculosis drugs ethambutol, streptomycin and levofloxacin. Additionally, this compound proved to be non-toxic (<20% inhibition at 50 μM concentration) against four human cell lines. Like first line antituberculosis drugs (isoniazid, rifampicin and pyrazinamide) this compound lacks activity against general Gram positive and Gram negative bacteria and even against M. smegmatis; thereby reflecting its highly specific antituberculosis activity.

Graphical abstract: The synthesis, biological evaluation and structure–activity relationship of 2-phenylaminomethylene-cyclohexane-1,3-diones as specific anti-tuberculosis agents

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Article information


Submitted
12 Jul 2017
Accepted
10 Oct 2017
First published
13 Oct 2017

Med. Chem. Commun., 2017,8, 2133-2141
Article type
Research Article

The synthesis, biological evaluation and structure–activity relationship of 2-phenylaminomethylene-cyclohexane-1,3-diones as specific anti-tuberculosis agents

M. A. Rather, A. M. Lone, B. Teli, Z. S. Bhat, P. Singh, M. Maqbool, B. A. Shairgojray, M. J. Dar, S. Amin, S. K. Yousuf, B. A. Bhat and Z. Ahmad, Med. Chem. Commun., 2017, 8, 2133
DOI: 10.1039/C7MD00350A

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