Human African Trypanosomiasis (HAT), a neglected disease endemic in Sub- Saharan Africa, is usually fatal if left untreated. It is caused by the parasite Trypanosoma brucei, and is spread by the tsetse fly. The drugs currently available to treat HAT are few, and limited in efficacy. Furthermore, resistance towards these drugs is beginning to grow. In the last 25 years, only one advance has been made into HAT treatment and consequently, there is an increasing need for new drugs to be sought that are able to effectively treat this disease. This review provides a brief overview of drug discovery research for HAT, focusing on research published in the last four years, identifying new molecules with the potential to be developed into anti-HAT agents. The methods of drug discovery have been grouped into three key areas; new molecules inspired by known antitrypanosomal agents, target-based screening, and phenotypic screening.

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.

Condensation of phenylephrine with different aldehydes, under Pictet‐Spengler cyclisation conditions, afforded a series of tetrahydroisoquinoline derivatives as mixtures of cis/trans isomers. Single crystal X‐ray analysis of the dibenzoate derivative of one of the 4‐nitrophenyl isomers confirmed it to be the trans isomer. The conformation of the cis isomer was determined through computational experiments and comparison of the predicted and observed 1H NMR spectra, particularly the magnitude of the coupling constants. Fourteen tetrahydroisoquinoline derivatives were then evaluated for their activity towards T. b. rhodesiense, two strains of P. falciparum, and mammalian cells. The most promising derivative, the undecyl derivative, showed good activity towards T. b. rhodesiense with an IC50 value in the sub‐micromolar range and good selectivity over mammalian cells. The same derivative also showed activity against both strains of P. falciparum with IC50 values in the low micromolar range.

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