Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosis pathogen. The increasing prevalence of multi-drug resistant strains of M. tuberculosis, means there is an urgent need to develop new anti-TB drugs with novel modes of action.Aporphine alkaloid natural products, such as (S)-methoxynordomesticine, have demonstrated a specific anti-mycobacterial effect, as well as M. tuberculosis MurE inhibitory activity.1 These aporphines contain a common tetrahydroisoquinoline skeleton, providing a unique template for the development of new anti-TB drugs.Recently we have developed biomimetic reaction conditions for the Pictet-Spengler condensation of aldehydes and amines into tetahydroisoquinolines.2 The reaction is mediated by phosphate and proceeds under mild reaction conditions, suitable for a variety of less stable aldehyde and amine substrates. Several tetrahydroisoquinolines synthesised using this method have been found active against M. tuberculosis H37Rv.We have been investigating the scope of the biomimetic Pictet-Spengler reaction, to access novel alkaloid structures, and identify new leads for mycobacterial growth inhibitors. Studies into asymmetric versions of the reaction using chiral phosphates, and extending the reaction for construction of larger ring sizes are also on-going. A number of novel tetrahydroisoquinoline derivatives have been synthesised and initial biological evaluation has allowed us to design a series of compounds for SAR studies, focussing on modification of substituents on the aromatic ring, and at the C-1 position.1. Guzman, J. D. et al., J. Antimicrob. Chemother., 2010  , 65, 2101-21072. Pesnot, T.; Hailes, H. C. et al. Chem. Commun., 2011  , 47, 3242�3244

Design, synthesis, and biological evaluation of alkaloids as potential antituberculosis drugs

247th National Meeting (2014)

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