Structure–Activity Relationships and Docking Studies of Hydroxychavicol and Its Analogs as Xanthine Oxidase Inhibitors

• Published in: Chemical & pharmaceutical bulletin Vol. 66; no. 7; pp. 741 - 747
• Main Authors: Nishiwaki, Keiji, Ohigashi, Kanae, Deguchi, Takahiro, Murata, Kazuya, Nakamura, Shinya, Matsuda, Hideaki, Nakanishi, Isao
• Format: Journal Article
• Language: English; Japanese
• Published: Japan The Pharmaceutical Society of Japan 01.07.2018; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Allopurinol; Analogs; Chemical bonds; Docking; docking study; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - pharmacology; Eugenol - analogs & derivatives; Eugenol - chemistry; Eugenol - isolation & purification; Eugenol - pharmacology; Humans; Hydrogen bonding; Hydrogen bonds; hydroxychavicol; Inhibitors; Molecular Docking Simulation; Molecular Structure; Piperaceae - chemistry; Plant Leaves - chemistry; Structure-Activity Relationship; Xanthine oxidase; Xanthine Oxidase - antagonists & inhibitors; Xanthine Oxidase - metabolism; xanthine oxidase inhibitor; structure–activity relationship; hydroxychavicol; xanthine oxidase inhibitor; docking study
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c18-00197

Hydroxychavicol (HC), which is obtained from the leaves of Piper betle LINN. (Piperaceae), inhibits xanthine oxidase (XO) with an IC50 value of 16.7 µM, making it more potent than the clinically used allopurinol (IC50=30.7 µM). Herein, a structure–activity relationship analysis of the polar part analogs of HC was conducted and an inhibitor was discovered with a potency 13 times that of HC. Kinetic studies have revealed that HC and its active analog inhibit XO in an uncompetitive manner. The binding structure prediction of these inhibitor molecules to the XO complex with xanthine suggested that both compounds (HC and its analog) could simultaneously form hydrogen bonds with xanthine and XO.