2. Academic Validation
  3. Syntheses of benzothiazole amidoximes and arylimidamides and evaluation of their ADME and DNA binding properties and activity against Trypanosoma brucei

Syntheses of benzothiazole amidoximes and arylimidamides and evaluation of their ADME and DNA binding properties and activity against Trypanosoma brucei

  • Eur J Med Chem. 2025 Jun 7:296:117854. doi: 10.1016/j.ejmech.2025.117854.
Valentina Rep Kaulić 1,  Martina Piškor 1,  Sanja Koštrun 2,  Astrid Milić 2,  Marijana Radić Stojković 3,  Amanda Fortes Francisco 4,  Martin C Taylor 4,  John M Kelly 5,  Silvana Raić-Malić 6
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, University of Zagreb Faculty of Chemical Engineering and Technology, Marulićev trg 19, 10 000, Zagreb, Croatia.
  • 2 Selvita d.o.o., Prilaz baruna Filipovića 29, 10 000, Zagreb, Croatia.
  • 3 Ruđer Bošković Institute, Division of Organic Chemistry and Biochemistry, Bijenička cesta 54, 10 000, Zagreb, Croatia.
  • 4 Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.
  • 5 Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK. Electronic address: john.kelly@lshtm.ac.uk.
  • 6 Department of Organic Chemistry, University of Zagreb Faculty of Chemical Engineering and Technology, Marulićev trg 19, 10 000, Zagreb, Croatia. Electronic address: sraic@fkit.unizg.hr.
PMID: 40499247 DOI: 10.1016/j.ejmech.2025.117854
Abstract

Novel 6-amidoxime- and 6-arylimidamide-substituted benzothiazoles were synthesised to investigate their activity against Trypanosoma brucei, the causative agent of African trypanosomiasis. Benzothiazole amidoxime 12b, with diethylaminoethyl and fluorine substituents on a phenoxymethylene linker exhibited pronounced (IC50 = 0.92 μM) and selective (SI = 18) antitrypanosomal activity. ADME profiling showed that the majority of compounds synthesised are metabolically stable and that arylimidamides have low membrane permeability, while amidoximes, including 12b, have moderate to high permeability. Binding assays indicate that amidoxime 12b binds to DNA/RNA by intercalation, whereas arylimidamide 29b displays groove binding. 12b was found to be a substrate of the P-glycoprotein efflux pump, a factor that may have limited its activity in a murine model of Infection, despite the Other favourable properties. Structural diversification of aryl-substituted motif in amidoxime benzothiazole series will be explored to further optimize activity and ADME properties, and to overcome issues associated with low membrane permeability.

Keywords

ADME; Antitrypanosomal activity; Benzothiazole; DNA/RNA binding; amidoxime; arylimidamide.

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