| Summary: | A series of novel 2-pyridyl, 4-morpholinyl substituted thiazolo[5,4-<i>b</i>]pyridine analogues have been designed and synthesized in this paper. These thiazolo[5,4-<i>b</i>]pyridines were efficiently prepared in seven steps from commercially available substances in moderate to good yields. All of these <i>N</i>-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 <i>N</i>-heterocyclic compounds showed potent PI3K inhibitory activity, and the IC<sub>50</sub> of a representative compound (<b>19a</b>) 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 (<b>19b</b>), or 5-chlorothiophene-2-sulfonamide (<b>19c</b>) showed potent inhibitory activity with a nanomolar IC<sub>50</sub> value. The pyridyl attached to thiazolo[5,4-<i>b</i>]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 <b>19a</b> inhibited PI3Kα, PI3Kγ, or PI3Kδ with a nanomolar IC<sub>50</sub> value, but its inhibitory activity on PI3Kβ was approximately 10-fold reduced. Further docking analysis revealed that the <i>N</i>-heterocyclic core of compound <b>19a</b> was directly involved in the binding to the kinase through the key hydrogen bonds interaction.
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