Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase. (4th February 2015)

• Record Type: Journal Article
• Authors: Guzman, Juan D.; Pesnot, Thomas; Barrera, Diana A.; Davies, Heledd M.; McMahon, Eleanor; Evangelopoulos, Dimitrios; Mortazavi, Parisa N.; Munshi, Tulika; Maitra, Arundhati; Lamming, Eleanor D.; Angell, Richard; Gershater, Markus C.; Redmond, Joanna M.; Needham, Deborah; Ward, John M.; Cuca, Luis E.; Hailes, Helen C.; Bhakta, Sanjib
• Is Part Of: Journal of antimicrobial chemotherapy. Volume 70:Number 6(2015:Jun.)
• Page Start: 1691
• Page End: 1703
• Publication Date: 2015-02-04
• Subjects: tuberculosis -- TB -- Mycobacterium tuberculosis -- drug resistance -- cell wall peptidoglycan -- aporphine alkaloids -- SPOTi; Anti-infective agents -- Periodicals; Chemotherapy -- Periodicals; 615.58
• DOI: 10.1093/jac/dkv010
• Languages: English
• ISSNs: 0305-7453

Abstract

Abstract: Objectives: ( S )-Leucoxine, isolated from the Colombian Lauraceae tree Rhodostemonodaphne crenaticupula Madriñan, was found to inhibit the growth of Mycobacterium tuberculosis H37 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 H37 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 .