Exploration of the imidazo[1,2-b]pyridazine scaffold as a protein kinase inhibitor.

Abstract : 3,6-Disubstituted imidazo[1,2-b]pyridazine derivatives were synthesized to identify new inhibitors of various eukaryotic kinases, including mammalian and protozoan kinases. Among the imidazo[1,2-b]pyridazines tested as kinase inhibitors, several derivatives were selective for DYRKs and CLKs, with IC50 < 100 nM. The characterization of the kinome of several parasites, such as Plasmodium and Leishmania, has pointed out profound divergences between protein kinases of the parasites and those of the host. This led us to investigate the activities of the prepared compounds against 11 parasitic kinases. 3,6-Disubstituted imidazo[1,2-b]pyridazines showed potent inhibition of Plasmodium falciparum CLK1 (PfCLK1). Compound 20a was found to be the most selective product against CLK1 (IC50 = 82 nM), CLK4 (IC50 = 44 nM), DYRK1A (IC50 = 50 nM), and PfCLK1 (IC50 = 32 nM). The compounds were also tested against Leishmania amazonensis. Several compounds showed anti-leishmanial activity at rather high (10 μM) concentration, but were not toxic at 1 μM or 10 μM, as judged by viability assays carried out using a neuroblastoma cell line.
Type de document :
Article dans une revue
European Journal of Medicinal Chemistry, Elsevier, 2017, 125, pp.696-709. 〈10.1016/j.ejmech.2016.09.064〉
Liste complète des métadonnées

https://hal-pasteur.archives-ouvertes.fr/pasteur-01451099
Contributeur : Christel Ricard Andraos <>
Soumis le : mardi 31 janvier 2017 - 16:15:33
Dernière modification le : jeudi 11 janvier 2018 - 06:27:30

Identifiants

Collections

Citation

Lyamin Z Bendjeddou, Nadège Loaëc, Benoît Villiers, Eric Prina, Gerald F Späth, et al.. Exploration of the imidazo[1,2-b]pyridazine scaffold as a protein kinase inhibitor.. European Journal of Medicinal Chemistry, Elsevier, 2017, 125, pp.696-709. 〈10.1016/j.ejmech.2016.09.064〉. 〈pasteur-01451099〉

Partager

Métriques

Consultations de la notice

119