Development of a 2,4-Diaminothiazole Series for the Treatment of Human African Trypanosomiasis Highlights the Importance of Static-Cidal Screening of Analogues.

Cleghorn, Laura AT; Wall, Richard J; Albrecht, Sébastien; MacGowan, Stuart A; Norval, Suzanne; De Rycker, Manu; Woodland, Andrew; Spinks, Daniel; Thompson, Stephen; Patterson, Stephen; +12 more... Corpas Lopez, Victoriano; Dey, Gourav; Collie, Iain T; Hallyburton, Irene; Kime, Robert; Simeons, Frederick RC; Stojanovski, Laste; Frearson, Julie A; Wyatt, Paul G; Read, Kevin D; Gilbert, Ian H; Wyllie, Susan; (2023) Development of a 2,4-Diaminothiazole Series for the Treatment of Human African Trypanosomiasis Highlights the Importance of Static-Cidal Screening of Analogues. Journal of medicinal chemistry, 66 (13). pp. 8896-8916. ISSN 0022-2623 DOI: https://doi.org/10.1021/acs.jmedchem.3c00509

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.

Additional Information

Item Type	Article
Faculty and Department	Faculty of Infectious and Tropical Diseases > Department of Infection Biology
PubMed ID	37343180
Elements ID	206204
Official URL	http://dx.doi.org/10.1021/acs.jmedchem.3c00509