Synthesis and evaluation of tetrahydroisoquinoline derivatives against Trypanosoma brucei rhodesiense

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 mu M) 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. (C) 2021 Published by Elsevier Masson SAS.

Automated summary

This study reports the synthesis and antitrypanosomal activity of 80 compounds based on a core tetrahydroisoquinoline scaffold, revealing five derivatives with inhibition of T. b. rhodesiense growth in the sub-micromolar range. Four of these derivatives show good selectivity over mammalian cells and are predicted to have good absorption and metabolic stability, with the ability to permeate the blood brain barrier, making them promising candidates for antitrypanosomal drugs.