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Design, synthesis, and molecular docking studies of N ‐(9,10‐anthraquinone‐2‐carbonyl)amino acid derivatives as xanthine oxidase inhibitors
Author(s) -
Zhang TingJian,
Li SongYe,
Yuan WeiYan,
Zhang Yi,
Meng FanHao
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13156
Subject(s) - chemistry , moiety , xanthine oxidase , phenylalanine , stereochemistry , docking (animal) , tryptophan , xanthine oxidase inhibitor , phenylpyruvic acid , enantiomer , amino acid , anthraquinone , potency , biochemistry , enzyme , organic chemistry , in vitro , medicine , nursing
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 (IC 50 = 3.0 μ m ) and the D ‐phenylalanine derivative 1i (IC 50 = 2.9 μ m ) presented the highest potency and were both more potent than the positive control allopurinol (IC 50 = 8.1 μ m ). 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.