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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 A T; Wall, Richard J; Albrecht, Sébastien; MacGowan, Stuart A; Norval, Suzanne; De Rycker, Manu; Woodland, Andrew; Spinks, Daniel; Thompson, Stephen; Patterson, Stephen; Corpas Lopez, Victoriano; Dey, Gourav; Collie, Iain T; Hallyburton, Irene; Kime, Robert; Simeons, Frederick R C; Stojanovski, Laste; Frearson, Julie A; Wyatt, Paul G; Read, Kevin D; Gilbert, Ian H; Wyllie, Susan.
Affiliation
  • Cleghorn LAT; Drug Discovery Unit, Wellcome Centre for Anti-infectives Research, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Wall RJ; Wellcome Centre for Anti-infectives Research, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Albrecht S; Drug Discovery Unit, Wellcome Centre for Anti-infectives Research, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • MacGowan SA; Division of Computational Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Norval S; Drug Discovery Unit, Wellcome Centre for Anti-infectives Research, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • De Rycker M; Drug Discovery Unit, Wellcome Centre for Anti-infectives Research, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Woodland A; Drug Discovery Unit, Wellcome Centre for Anti-infectives Research, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Spinks D; Drug Discovery Unit, Wellcome Centre for Anti-infectives Research, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Thompson S; Drug Discovery Unit, Wellcome Centre for Anti-infectives Research, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Patterson S; Wellcome Centre for Anti-infectives Research, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Corpas Lopez V; Wellcome Centre for Anti-infectives Research, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Dey G; Wellcome Centre for Anti-infectives Research, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Collie IT; Drug Discovery Unit, Wellcome Centre for Anti-infectives Research, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Hallyburton I; Drug Discovery Unit, Wellcome Centre for Anti-infectives Research, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Kime R; Drug Discovery Unit, Wellcome Centre for Anti-infectives Research, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Simeons FRC; Drug Discovery Unit, Wellcome Centre for Anti-infectives Research, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Stojanovski L; Drug Discovery Unit, Wellcome Centre for Anti-infectives Research, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Frearson JA; Drug Discovery Unit, Wellcome Centre for Anti-infectives Research, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Wyatt PG; Drug Discovery Unit, Wellcome Centre for Anti-infectives Research, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Read KD; Drug Discovery Unit, Wellcome Centre for Anti-infectives Research, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Gilbert IH; Drug Discovery Unit, Wellcome Centre for Anti-infectives Research, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
  • Wyllie S; Wellcome Centre for Anti-infectives Research, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
J Med Chem ; 66(13): 8896-8916, 2023 07 13.
Article in En | MEDLINE | ID: mdl-37343180
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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Trypanocidal Agents / Trypanosoma brucei brucei / Trypanosomiasis, African / Cytostatic Agents Type of study: Diagnostic_studies / Screening_studies Limits: Animals / Humans Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2023 Document type: Article Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Trypanocidal Agents / Trypanosoma brucei brucei / Trypanosomiasis, African / Cytostatic Agents Type of study: Diagnostic_studies / Screening_studies Limits: Animals / Humans Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2023 Document type: Article Country of publication: United States