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 IC < 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 (IC = 82 nM), CLK4 (IC = 44 nM), DYRK1A (IC = 50 nM), and PfCLK1 (IC = 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.

Design of new disubstituted imidazo[1,2-b]pyridazine derivatives as selective Haspin inhibitors. Synthesis, binding mode and anticancer biological evaluation

“…This linear synthetic pathway prompted us to develop a versatile skeleton to explore molecular diversity in C-3 and C-6 positions. We focussed our attention on a bis-halogenated platform 6, which can be regio-selectively functionalised in C-3 and C-6 positions ( Scheme 1 ) by chlorine and bromine discrimination 38 . However, the method suffered in our hands from long reaction times under thermal conditions, leading to purification difficulties and low yields.…”

5-Methoxybenzothiophene-2-Carboxamides as Inhibitors of Clk1/4: Optimization of Selectivity and Cellular Potency

“…The best chemical inhibitors described thus far inhibit Clk1, 2 and 4 with about the same potency; Nassima et al succeeded in developing two highly potent imidazo [1 ,2b]pyridazines (A, B in Figure 1) with IC50 values of 28 and 23 nM, respectively; both displayed equal potency against Clk2 and Clk4 kinases [14]. Moreover, Sunitinib (C, Figure 1), which is clinically approved for the treatment of imatinib-resistant gastrointestinal stromal tumor (GIST), renal carcinoma, and pancreatic neuroendocrine tumors [15], was reported by Murar et al to be a highly potent Clk1 inhibitor with an IC50 of 22 nM, also showing high activity against Clk2 and Clk4, with IC50 values of 20 and 29 nM, respectively [16].…”

Towards discovery of new leishmanicidal scaffolds able to inhibitLeishmaniaGSK-3

“…Protein kinases are involved in processes such as the inter-stage differentiation during the life cycle of the parasite 15–17 , macrophage invasion 18 , response to stress 19 , intracellular survival in the host 20 , 21 , or drug resistance 22 , among others. Several groups have provided a consistent proof of concept on the druggability of Leishmania kinome as a new chemotherapy venue 23 , 24 . In fact, protein phosphorylation site descriptors for Leishmania proteins have been reported 25 , and PK inhibition was carried out for a number of enzymes, such as Akt-like 26 , CK1.2 27 , PKA 28 , PKC 29 , 30 , Aurora kinase 31 , as well as GSK-3 32–34 .…”