Design and biological evaluation of novel imidazolyl flavonoids as potent and selective protein tyrosine phosphatase inhibitors

(E-pub Abstract Ahead of Print)

Author(s): Rong Ye Han, Yu Ge, Ling Zhang*, Qing Ming Wang.

Journal Name: Medicinal Chemistry

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Background: Protein tyrosine phosphatases 1B is considered to be one desirable validated target for therapeutic development of type II diabetes and obesity.

Method: A new series of imidazolyl flavonoids as potential protein tyrosine phosphatase inhibitors were synthesized and evaluated.

Result: Bioactive results indicated that some synthesized compounds exhibited potent protein phosphatase 1B (PTP1B) inhibitory activities at the micromolar range. Especially, compound 8b showed the best inhibitory activity (IC50 = 1.0 μM) with 15-fold selectivity for PTP1B over the closely related T-cell protein tyrosine phosphatase (TCPTP). Cell viability assays indicated 8b is cell permeable with lower cytotoxicity. Molecular modeling and dynamics studies revealed the reason of selectivity for PTP1B over TCPTP. Quantum chemical studies were carried out on these compounds to understand the structural features essential for activity.

Conclusion: Compound 8b should be a potential selective PTP1B inhibitor.

Keywords: Flavonoid, Imidazole, Protein tyrosine phosphatase, Selectivity, Cell viability, Molecular modeling

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(E-pub Abstract Ahead of Print)
DOI: 10.2174/1573406415666190430125547
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