Scoping Studies into the Structure‐Activity Relationship (SAR) of Phenylephrine‐Derived Analogues as Inhibitors of Trypanosoma brucei rhodesiense

Human African Trypanosomiasis (HAT) is a disease caused by the parasite Trypanosoma brucei and is classified as a neglected tropical disease of concern in sub‐Saharan Africa. A scoping study has been undertaken to develop a preliminary structure activity relationship of a tetrahydroisoquinoline scaffold. Fourteen compounds based around this core scaffold were synthesised and evaluated for their activity against Trypanosoma brucei rhodesiense in vitro. Initial results are promising with a number of analogues showing low micromolar inhibition of T.b.rhodesiense with acceptable selectivity over mammalian cells. The most promising is a secondary amine analogue showing the most potent inhibition of T.b.rhodesiense, with an IC50 value of 0.25 ± 0.02 μM, while also showing low cytotoxicity to mammalian cells. Derivatives of 4,6‐dihydroxy‐N‐methyl‐1,2,3,4‐tetrahydroisoquinoline were synthesised and found to show in vitro activity against the parasite Trypanosoma brucei rhodesiense, the causative agent of Human African Trypanosomiasis. The most promising derivatives showed inhibition in the low micromolar range with acceptable selectivity over mammalian cells. The same derivatives were also found to inhibit Plasmodium falciparum, the causative agent of malaria.