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Identification of Novel Thiazolo[5,4-b]Pyridine Derivatives as Potent Phosphoinositide 3-Kinase Inhibitors

Authors :
Liang Xia
Yan Zhang
Jingbo Zhang
Songwen Lin
Kehui Zhang
Hua Tian
Yi Dong
Heng Xu
Source :
Molecules, Vol 25, Iss 20, p 4630 (2020)
Publication Year :
2020
Publisher :
MDPI AG, 2020.

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.

Details

Language :
English
ISSN :
14203049
Volume :
25
Issue :
20
Database :
Directory of Open Access Journals
Journal :
Molecules
Publication Type :
Academic Journal
Accession number :
edsdoj.5f27b64c29564b26915b9d893dd9dc89
Document Type :
article
Full Text :
https://doi.org/10.3390/molecules25204630