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

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.

[Search for natural substances with therapeutic activity: George R. Pettit]. / Recherche de substances naturelles à activité thérapeutique (2) - George R. Pettit.

This series of brief reviews covers the "life and work" of famous and iconic researchers who discovered major therapeutics from natural products: their life history, the circumstances of their discoveries, the molecules and their molecular, cellular and physiological mechanisms of action, and their biomedical applications. Dedicated to George R. Pettit, the second article reviews the life of the famous researcher, his worldwide exploration of natural products, especially of marine origin, in search of promising anticancer leads, his discovery and structural elucidation of very potent drug candidates, their synthesis and the launch of some of them on the pharmaceutical market. An extraordinary scientific career which lead George R. Pettit from exploration of Nature to state-of-the-art analytical and synthetic chemistry and from clinical trials to therapeutic successes.