Abstract
A series of novel 2-pyridyl, 4-morpholinyl substituted thiazolo[5,4-b]pyridine analogues have been designed and synthesized in this paper. These thiazolo[5,4-b]pyridines were efficiently prepared in seven steps from commercially available substances in moderate to good yields. All of these N-heterocyclic compounds were characterized by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) analysis and tested for phosphoinositide 3-kinase (PI3K) enzymatic assay. The results indicated that these N-heterocyclic compounds showed potent PI3K inhibitory activity, and the IC50 of a representative compound (19a) could reach to 3.6 nm. The structure−activity relationships (SAR) study showed that sulfonamide functionality was important for PI3Kα inhibitory activity, and 2-chloro-4-florophenyl sulfonamide (19b), or 5-chlorothiophene-2-sulfonamide (19c) showed potent inhibitory activity with a nanomolar IC50 value. The pyridyl attached to thiazolo[5,4-b]pyridine was another key structural unit for PI3Kα inhibitory potency, and replacement by phenyl lead to a significant decrease in activity. Enzymatic Inhibition results showed that compound 19a inhibited PI3Kα, PI3Kγ, or PI3Kδ with a nanomolar IC50 value, but its inhibitory activity on PI3Kβ was approximately 10-fold reduced. Further docking analysis revealed that the N-heterocyclic core of compound 19a was directly involved in the binding to the kinase through the key hydrogen bonds interaction.
Highlights
Heterocycles are important organic chemical structures commonly found in a large number of agrochemicals, materials, and pharmaceutical molecules [1,2,3]
The nitro with Fe powder in acetic acid at 60 ◦ C; the subsequent intramolecular cyclization occurred in one-pot group was reduced by treatment with Fe powder in acetic acid at 60 °C; the subsequent to construct the thiazolo[5,4-b]pyridine skeleton, and the corresponding amino thiazolo[5,4-b]pyridine intramolecular cyclization occurred in one-pot to construct the thiazolo[5,4-b]pyridine skeleton, and derivative (14) was obtained in moderate yield
We evaluated the inhibitory selectivity of compound 19a against four isoforms of class I phosphoinositide 3-kinase (PI3K) (Table 2)
Summary
Heterocycles are important organic chemical structures commonly found in a large number of agrochemicals, materials, and pharmaceutical molecules [1,2,3]. It is estimated that about 70% of pharmaceutical products contain heterocyclic substructures, which clearly shows that heterocycles play an extremely important role in drug development and discovery [7,8]. Over the past few decades, many biological compounds containing bicyclic heterocycles have been found with potent pharmacological activities; some of them have been successfully developed into drugs approved for marketing [9,10]. Over the past few decades, many biological compounds containing bicyclic heterocycles have been found with Molecules. 4630 potent pharmacological activities; some of them have 2been of 10 successfully developed into drugs approved for marketing [9,10]. Thiazolo[5,4-b]pyridine analogues have been found to skeletona [11]
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