1. Development of a 2,4-Diaminothiazole Series for the Treatment of Human African Trypanosomiasis Highlights the Importance of Static-Cidal Screening of Analogues.
- Author
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Cleghorn LAT, Wall RJ, Albrecht S, MacGowan SA, Norval S, De Rycker M, Woodland A, Spinks D, Thompson S, Patterson S, Corpas Lopez V, Dey G, Collie IT, Hallyburton I, Kime R, Simeons FRC, Stojanovski L, Frearson JA, Wyatt PG, Read KD, Gilbert IH, and Wyllie S
- Subjects
- Animals, Humans, Blood-Brain Barrier, Trypanosomiasis, African drug therapy, Trypanocidal Agents therapeutic use, Trypanocidal Agents pharmacokinetics, Cytostatic Agents therapeutic use, Trypanosoma brucei brucei
- Abstract
While treatment options for human African trypanosomiasis (HAT) have improved significantly, there is still a need for new drugs with eradication now a realistic possibility. Here, we report the development of 2,4-diaminothiazoles that demonstrate significant potency against Trypanosoma brucei , the causative agent of HAT. Using phenotypic screening to guide structure-activity relationships, potent drug-like inhibitors were developed. Proof of concept was established in an animal model of the hemolymphatic stage of HAT. To treat the meningoencephalitic stage of infection, compounds were optimized for pharmacokinetic properties, including blood-brain barrier penetration. However, in vivo efficacy was not achieved, in part due to compounds evolving from a cytocidal to a cytostatic mechanism of action. Subsequent studies identified a nonessential kinase involved in the inositol biosynthesis pathway as the molecular target of these cytostatic compounds. These studies highlight the need for cytocidal drugs for the treatment of HAT and the importance of static-cidal screening of analogues.
- Published
- 2023
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