Design, synthesis, and molecular docking studies of N‐(9,10‐anthraquinone‐2‐carbonyl)amino acid derivatives as xanthine oxidase inhibitors

Design, synthesis, and molecular docking studies of... A series of N‐(9,10‐anthraquinone‐2‐carbonyl)amino acid derivatives (1a–j) was designed and synthesized as novel xanthine oxidase inhibitors. Among them, the L/D‐phenylalanine derivatives (1d and 1i) and the L/D‐tryptophan derivatives (1e and 1j) were effective with micromolar level potency. In particular, the L‐phenylalanine derivative 1d (IC50 = 3.0 μm) and the D‐phenylalanine derivative 1i (IC50 = 2.9 μm) presented the highest potency and were both more potent than the positive control allopurinol (IC50 = 8.1 μm). Preliminary SAR analysis pointed that an aromatic amino acid fragment, for example, phenylalanine or tryptophan, was essential for the inhibition; the D‐amino acid derivative presented equal or greater potency compared to its L‐enantiomer; and the 9,10‐anthraquinone moiety was welcome for the inhibition. Molecular simulations provided rational binding models for compounds 1d and 1i in the xanthine oxidase active pocket. As a result, compounds 1d and 1i could be promising lead compounds for further investigation. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Chemical Biology & Drug Design Wiley

Design, synthesis, and molecular docking studies of N‐(9,10‐anthraquinone‐2‐carbonyl)amino acid derivatives as xanthine oxidase inhibitors

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Publisher
Wiley Subscription Services, Inc., A Wiley Company
Copyright
Copyright © 2018 John Wiley & Sons A/S
ISSN
1747-0277
eISSN
1747-0285
D.O.I.
10.1111/cbdd.13156
Publisher site
See Article on Publisher Site

Abstract

A series of N‐(9,10‐anthraquinone‐2‐carbonyl)amino acid derivatives (1a–j) was designed and synthesized as novel xanthine oxidase inhibitors. Among them, the L/D‐phenylalanine derivatives (1d and 1i) and the L/D‐tryptophan derivatives (1e and 1j) were effective with micromolar level potency. In particular, the L‐phenylalanine derivative 1d (IC50 = 3.0 μm) and the D‐phenylalanine derivative 1i (IC50 = 2.9 μm) presented the highest potency and were both more potent than the positive control allopurinol (IC50 = 8.1 μm). Preliminary SAR analysis pointed that an aromatic amino acid fragment, for example, phenylalanine or tryptophan, was essential for the inhibition; the D‐amino acid derivative presented equal or greater potency compared to its L‐enantiomer; and the 9,10‐anthraquinone moiety was welcome for the inhibition. Molecular simulations provided rational binding models for compounds 1d and 1i in the xanthine oxidase active pocket. As a result, compounds 1d and 1i could be promising lead compounds for further investigation.

Journal

Chemical Biology & Drug DesignWiley

Published: Jan 1, 2018

Keywords: ; ; ;

References

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