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. 2023. Development of a 2,4-Diaminothiazole Series for the Treatment of Human African Trypanosomiasis Highlights the Importance of Static–Cidal Screening of Analogues. [Online]. ACS Publications. Available from: https://doi.org/10.1021/acs.jmedchem.3c00509.s002
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. Development of a 2,4-Diaminothiazole Series for the Treatment of Human African Trypanosomiasis Highlights the Importance of Static–Cidal Screening of Analogues [Internet]. ACS Publications; 2023. Available from: https://doi.org/10.1021/acs.jmedchem.3c00509.s002
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 (2023). Development of a 2,4-Diaminothiazole Series for the Treatment of Human African Trypanosomiasis Highlights the Importance of Static–Cidal Screening of Analogues. [Data Collection]. ACS Publications. https://doi.org/10.1021/acs.jmedchem.3c00509.s002
Description
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.
| Data capture method | Experiment |
|---|---|
| Date (Date published in a 3rd party system) | 21 June 2023 |
| Language(s) of written materials | English |
| Data Creators | 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 |
|---|---|
| LSHTM Faculty/Department | Faculty of Infectious and Tropical Diseases > Department of Infection Biology |
| Participating Institutions | London School of Hygiene & Tropical Medicine, London, United Kingdom |
| Date Deposited | 25 Sep 2023 09:02 |
|---|---|
| Last Modified | 25 Sep 2023 09:02 |
| Publisher | ACS Publications |
