Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors

Institute of Chemical Biology and Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 06/2008; 18(10):3029-3033. DOI: 10.1016/j.bmcl.2008.04.038


Previous structure-based design studies resulted in the discovery of alkyl substituted diphenyl ether inhibitors of InhA, the enoyl reductase from Mycobacterium tuberculosis. Compounds such as 5-hexyl-2-phenoxyphenol 19 are nM inhibitors of InhA and inhibit the growth of both sensitive and isoniazid-resistant strains of Mycobacterium tuberculosis with MIC(90) values of 1-2 microg/mL. However, despite their promising in vitro activity, these compounds have ClogP values of over 5. In efforts to reduce the lipophilicity of the compounds, and potentially enhance compound bioavailability, a series of B ring analogues of 19 were synthesized that contained either heterocylic nitrogen rings or phenyl rings having amino, nitro, amide, or piperazine functionalities. Compounds 3c, 3e, and 14a show comparable MIC(90) values to that of 19, but have improved ClogP values.

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    ABSTRACT: The enoyl ACP reductase enzyme (InhA) involved in the type II fatty acid biosynthesis pathway of Mycobacterium tuberculosis is an attractive target enzyme for antitubercular drug development. Arylamide derivatives are a novel class of InhA inhibitors used to overcome the drug-resistance problem of isoniazid, the frontline drug for tuberculosis treatment. Their remarkable property of inhibiting the InhA enzyme directly without requiring any coenzyme, makes them especially appropriate for the design of new antibacterials. In order to find a sound binding conformation for the different arylamide analogs, molecular docking experiments were performed with subsequent QSAR investigations. The X-ray conformation of one arylamide within its cocrystallized complex with InhA was used as a starting conformation for the docking experiments. The results thus obtained are perfectly consistent (rmsd = 0.73 Å) with the results from X-ray analysis. A thorough investigation of the arylamide binding modes with InhA provided ample information about structural requirements for appropriate inhibitor–enzyme interactions. Three different QSAR models were established using two three-dimensional (CoMFA and CoMSIA) and one two-dimensional (HQSAR) techniques. With statistically ensured models, the QSAR results obtained had high correlation coefficients between molecular structure properties of 28 arylamide derivatives and their biological activity. Molecular fragment contributions to the biological activity of arylamides could be obtained from the HQSAR model. Finally, a graphic interpretation designed in different contour maps provided coincident information about the ligand–receptor interaction thus offering guidelines for syntheses of novel analogs with enhanced biological activity. Graphical abstract
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    ABSTRACT: Many series of direct InhA inhibitors, arylamide, pyrrolidine carboxamide, diphenyl ether and triclosan derivatives, have been developed as antituberculosis agents to combat the drug-resistance of isoniazid (INH). However, an effort to design novel antituberculosis drugs in the class of direct InhA inhibitors is confronted with a poor in vitro antibacterial activity of the available compounds. To evaluate the key structural features relating to the antibacterial activity of direct InhA inhibitors against M. tuberculosis, 2D and 3D QSAR approaches, HQSAR, CoMFA and CoMSIA are convenient tools to establish correlations between biological activities and various molecular properties. The results obtained from the graphic interpretation designed in different QSAR models indicate the structure requirement to improve the antibacterial activity of direct InhA inhibitors. Moreover, our results are the first findings which provide the quantitative relationship between the structural property and antibacterial activity of direct InhA inhibitors. Consequently, the obtained results suggest a structural guideline for design and synthesis of a new generation of direct InhA inhibitors which will display a better potency against M. tuberculosis.
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