期刊
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
卷 70, 期 6, 页码 1691-1703出版社
OXFORD UNIV PRESS
DOI: 10.1093/jac/dkv010
关键词
tuberculosis; TB; Mycobacterium tuberculosis; drug resistance; cell wall peptidoglycan; aporphine alkaloids; SPOTi
资金
- Medical Research Council, UK (MRC) [G0801956]
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/G014426/1]
- GlaxoSmithKline
- Engineering and Physical Sciences Research Council (EPSRC)
- Bloomsbury Colleges, University of London
- BBSRC [BB/G014426/1] Funding Source: UKRI
- MRC [G0801956] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/G014426/1] Funding Source: researchfish
- Medical Research Council [G0801956] Funding Source: researchfish
Objectives: (S)-Leucoxine, isolated from the Colombian Lauraceae tree Rhodostemonodaphne crenaticupula Madrinan, was found to inhibit the growth of Mycobacterium tuberculosis H(37)Rv. 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 H(37)Rv 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.
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