Kaulić Valentina Rep, Piškor Martina, Koštrun Sanja, Milić Astrid, Stojković Marijana Radić, Francisco Amanda Fortes, Taylor Martin C, Kelly John M, Raić-Malić Silvana
Department of Organic Chemistry, University of Zagreb Faculty of Chemical Engineering and Technology, Marulićev trg 19, 10 000, Zagreb, Croatia.
Selvita d.o.o., Prilaz baruna Filipovića 29, 10 000, Zagreb, Croatia.
Eur J Med Chem. 2025 Oct 15;296:117854. doi: 10.1016/j.ejmech.2025.117854. Epub 2025 Jun 7.
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 (IC = 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.
合成了新型的6-脒基肟和6-芳基咪唑酰胺取代的苯并噻唑，以研究它们对非洲锥虫病病原体布氏锥虫的活性。苯并噻唑脒基肟12b在苯氧基亚甲基连接基上带有二乙氨基乙基和氟取代基，表现出显著的（IC = 0.92 μM）和选择性的（SI = 18）抗锥虫活性。药物代谢动力学性质分析表明，合成的大多数化合物在代谢上是稳定的，芳基咪唑酰胺具有低膜通透性，而包括12b在内的脒基肟具有中度至高通透性。结合试验表明，脒基肟12b通过插入与DNA/RNA结合，而芳基咪唑酰胺29b表现出沟槽结合。尽管12b具有其他有利性质，但发现它是P-糖蛋白外排泵的底物，这一因素可能限制了其在小鼠感染模型中的活性。将探索脒基肟苯并噻唑系列中芳基取代基序的结构多样化，以进一步优化活性和药物代谢动力学性质，并克服与低膜通透性相关的问题。
