Abstract
There is an urgent need for new, brain penetrant small molecules that target the central nervous system second stage of human African trypanosomiasis (HAT). We report that a series of novel indoline-2-carboxamides have been identified as inhibitors of Trypanosoma brucei from screening of a focused protease library against Trypanosoma brucei brucei in culture. We describe the optimization and characterization of this series. Potent antiproliferative activity was observed. The series demonstrated excellent pharmacokinetic properties, full cures in a stage 1 mouse model of HAT, and a partial cure in a stage 2 mouse model of HAT. Lack of tolerability prevented delivery of a fully curative regimen in the stage 2 mouse model and thus further progress of this series.
Highlights
Human African trypanosomiasis (HAT) or sleeping sickness occurs in sub-Saharan Africa and is caused by two subspecies of the protozoan parasite Trypanosoma brucei; Trypanosoma brucei gambiense in West and Central Africa and Trypanosoma brucei rhodesiense in East Africa
Pentamidine (T. b. gambiense) and suramin (T. b. rhodesiense) are currently used to treat infection at stage 1, while there are three treatments for stage 2: (i) melarsoprol, an arsenical, can be used to treat both strains but has severe side effects[5] and is given by intravenous injection over an extended time period; (ii) eflornithine is less toxic than melarsoprol but only effective against T. b. gambiense strain and is not suitable for a rural African setting given the requirement for an extended period of intravenous dosage;[6,7] and (iii) in 2009, a combination treatment of nifurtimox and eflornithine (NECT) was introduced, this is not effective against T. b. rhodesiense.[8−10]
An initial hit expansion was carried out with 10 indoline-2-carboxamides contained within our protease set and a further small number of analogues that were commercially available
Summary
Human African trypanosomiasis (HAT) or sleeping sickness occurs in sub-Saharan Africa and is caused by two subspecies of the protozoan parasite Trypanosoma brucei; Trypanosoma brucei gambiense in West and Central Africa and Trypanosoma brucei rhodesiense in East Africa. Compound 1 contained several desirable features for a potential therapeutic agent for stage 2 HAT: low molecular weight (344), clogP (2.4) compatible with oral and CNS bioavailability, and low PSA (59 Å2). These properties are all consistent with CNS penetration, and 1 was predicted to cross the blood−brain barrier using StarDrop (www.optibrium.com). Upon reaction with an aldehyde, this formed vinylazide 5.20 A rhodium-catalyzed reaction was utilized to cyclize vinylazide 5 to indole 6.21 Reduction using magnesium turnings afforded the desired methyl indolinecarboxylate 722 that was subsequently reacted with methylamine and the appropriate acid chloride to yield aromatically substituted diamide indolines 8. Details of other synthetic routes used to synthesize individual compounds are described in the Supporting Information
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