Development
of a 2,4-Diaminothiazole Series for the
Treatment of Human African Trypanosomiasis Highlights the Importance
of Static–Cidal Screening of Analogues
Posted on 2023-06-21 - 19:36
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.
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Cleghorn, Laura
A. T.; Wall, Richard J.; Albrecht, Sébastien; MacGowan, Stuart A.; Norval, Suzanne; De Rycker, Manu; et al. (2023). Development
of a 2,4-Diaminothiazole Series for the
Treatment of Human African Trypanosomiasis Highlights the Importance
of Static–Cidal Screening of Analogues. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.3c00509
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AUTHORS (22)
LC
Laura
A. T. Cleghorn
RW
Richard J. Wall
SA
Sébastien Albrecht
SM
Stuart A. MacGowan
SN
Suzanne Norval
MD
Manu De Rycker
AW
Andrew Woodland
DS
Daniel Spinks
ST
Stephen Thompson
SP
Stephen Patterson
VC
Victoriano Corpas Lopez
GD
Gourav Dey
IC
Iain T. Collie
IH
Irene Hallyburton
RK
Robert Kime
FS
Frederick R. C. Simeons
LS
Laste Stojanovski
JF
Julie A. Frearson
PW
Paul G. Wyatt
KR
Kevin D. Read
KEYWORDS
using phenotypic screeningnonessential kinase involvedinositol biosynthesis pathwayhuman african trypanosomiasisdemonstrate significant potencysubsequent studies identifiedstudies highlightvivo efficacytrypanosoma bruceirealistic possibilitypotent drugpharmacokinetic propertiespart duenew drugsmolecular targetmeningoencephalitic stagelike inhibitorsimproved significantlyhemolymphatic stagediaminothiazole seriescytostatic mechanismcausative agentanimal model