2. Academic Validation
  3. Synthesis and evaluation of tetrahydroisoquinoline derivatives against Trypanosoma brucei rhodesiense

Synthesis and evaluation of tetrahydroisoquinoline derivatives against Trypanosoma brucei rhodesiense

  • Eur J Med Chem. 2021 Dec 15:226:113861. doi: 10.1016/j.ejmech.2021.113861.
Danica R Cullen 1,  Ashlee Gallagher 2,  Caitlin L Duncan 1,  Jutharat Pengon 3,  Roonglawan Rattanajak 3,  Jason Chaplin 4,  Hendra Gunosewoyo 5,  Sumalee Kamchonwongpaisan 3,  Alan Payne 1,  Mauro Mocerino 6
Affiliations

Affiliations

  • 1 School of Molecular and Life Sciences - Curtin University, GPO Box U1987, Perth, WA, 6845, Australia.
  • 2 School of Molecular and Life Sciences - Curtin University, GPO Box U1987, Perth, WA, 6845, Australia. Electronic address: ashlee.gallagher@postgrad.curtin.edu.au.
  • 3 BIOTEC Medical Molecular Biotechnology Research Group - National Science and Technology Development Agency, 113 Thailand Science Park, Phahonyothin Road, Khlong Luang, Pathum Thani, 12120, Thailand.
  • 4 Epichem Pty Ltd. Suite 5, 3 Brodie-Hall Drive Bentley, WA, 6102, Australia.
  • 5 Curtin Medical School - Curtin University, GPO Box U1987, Perth, WA, 6845, Australia.
  • 6 School of Molecular and Life Sciences - Curtin University, GPO Box U1987, Perth, WA, 6845, Australia. Electronic address: m.mocerino@curtin.edu.au.
PMID: 34624822 DOI: 10.1016/j.ejmech.2021.113861
Abstract

Human African Trypanosomiasis (HAT) is a neglected tropical disease caused by the parasitic protozoan Trypanosoma brucei (T. b.), and affects communities in sub-Saharan Africa. Previously, analogues of a tetrahydroisoquinoline scaffold were reported as having in vitro activity (IC50 = 0.25-70.5 μM) against T. b. rhodesiense. In this study the synthesis and antitrypanosomal activity of 80 compounds based around a core tetrahydroisoquinoline scaffold are reported. A detailed structure activity relationship was revealed, and five derivatives (two of which have been previously reported) with inhibition of T. b. rhodesiense growth in the sub-micromolar range were identified. Four of these (3c, 12b, 17b and 26a) were also found to have good selectivity over mammalian cells (SI > 50). Calculated logD values and preliminary ADME studies predict that these compounds are likely to have good absorption and metabolic stability, with the ability to passively permeate the blood brain barrier. This makes them excellent leads for a blood-brain barrier permeable antitrypanosomal scaffold.

Keywords

Antitrypanosomal; BBB permeable; Human African trypanosomiasis (HAT); Structure activity relationship (SAR); Tetrahydroisoquinoline; Trypanosoma brucei rhodesiense; VERO cells.

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