Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase.

Autor:	Guzman JD; Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK., Pesnot T; Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK., Barrera DA; Departamento de Química, Facultad de Ciencias, Universidad Nacional de Colombia, Carrera 30 No. 45-03, Bogotá, Colombia., Davies HM; Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK., McMahon E; Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK., Evangelopoulos D; Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK., Mortazavi PN; Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK., Munshi T; Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK., Maitra A; Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK., Lamming ED; Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK., Angell R; Drug Discovery Group, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK., Gershater MC; The Advanced Centre for Biochemical Engineering, University College London, Gordon Street, London WC1H 0AH, UK., Redmond JM; Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK., Needham D; Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK., Ward JM; Drug Discovery Group, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK., Cuca LE; Departamento de Química, Facultad de Ciencias, Universidad Nacional de Colombia, Carrera 30 No. 45-03, Bogotá, Colombia., Hailes HC; Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK., Bhakta S; Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK s.bhakta@bbk.ac.uk sanjib.bhakta@ucl.ac.uk.
Jazyk:	angličtina
Zdroj:	The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2015; Vol. 70 (6), pp. 1691-703. Date of Electronic Publication: 2015 Feb 04.
DOI:	10.1093/jac/dkv010
Abstrakt:	Objectives: (S)-Leucoxine, isolated from the Colombian Lauraceae tree Rhodostemonodaphne crenaticupula Madriñan, was found to inhibit the growth of Mycobacterium tuberculosis H37Rv. A biomimetic approach for the chemical synthesis of a wide array of 1-substituted tetrahydroisoquinolines was undertaken with the aim of elucidating a common pharmacophore for these compounds with novel mode(s) of anti-TB action. Methods: Biomimetic Pictet-Spengler or Bischler-Napieralski synthetic routes were employed followed by an evaluation of the biological activity of the synthesized compounds. Results: In this work, the synthesized tetrahydroisoquinolines were found to inhibit the growth of M. tuberculosis H37Rv and affect its whole-cell phenotype as well as the activity of the ATP-dependent MurE ligase, a key enzyme involved in the early stage of cell wall peptidoglycan biosynthesis. Conclusions: As the correlation between the MIC and the half-inhibitory enzymatic concentration was not particularly strong, there is a credible possibility that these compounds have pleiotropic mechanism(s) of action in M. tuberculosis. (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)
Databáze:	MEDLINE
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