Obovatols, new chitin synthase 2 inhibitors of Saccharomyces cerevisiae from Magnolia obovata

• Published in: Journal of antimicrobial chemotherapy 2002-01, Vol.49 (1), p.95-101
• Main Authors: Hwang, Eui-Il, Kwon, Byoung-Mog, Lee, Seoung-Ho, Kim, Na-Rae, Kang, Tae-Hoon, Kim, Young-Tae, Park, Byoung-Keun, Kim, Sung-Uk
• Format: Article
• Language: English
• Subjects: Anti-Infective Agents - chemistry; Anti-Infective Agents - isolation & purification; Anti-Infective Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal agents; Antifungal Agents - chemistry; Antifungal Agents - isolation & purification; Antifungal Agents - pharmacology; Biological and medical sciences; Biphenyl Compounds - chemistry; Biphenyl Compounds - isolation & purification; Biphenyl Compounds - pharmacology; Candida albicans - drug effects; Candida albicans - enzymology; Chitin Synthase - antagonists & inhibitors; Chitin Synthase - biosynthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - pharmacology; Isoenzymes - antagonists & inhibitors; Magnoliaceae - chemistry; Medical sciences; Pharmacology. Drug treatments; Phenyl Ethers - chemistry; Phenyl Ethers - isolation & purification; Phenyl Ethers - pharmacology; Phytotherapy - methods; Plant Extracts - chemistry; Plant Extracts - isolation & purification; Plant Extracts - pharmacology; Plant Leaves - chemistry; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - enzymology
• ISSN: 0305-7453; 1460-2091; 1460-2091
• DOI: 10.1093/jac/49.1.95

In the course of the search for inhibitors of ScCHS2 from natural sources, we have isolated a new type of chitin synthase 2 inhibitor, obovatol, which has a biphenol skeleton, from Magnolia obovata. Obovatol inhibited chitin synthase 2 activity of Saccharomyces cerevisiae with an IC50 of 38 μM. Its derivative, tetrahydroobovatol, inhibited chitin synthase 2 activity under the same conditions with an IC50 of 59 μM. These compounds exhibited no inhibitory activity for ScCHS3, and showed less inhibitory activity for chitin synthase 1 than for chitin synthase 2 (IC50 > 1 mM). These results indicated that obovatol and tetrahydroobovatol are specific inhibitors of ScCHS2. They also inhibited CaCHS1, which is structurally and functionally analogous to ScCHS2, with similar IC50s to ScCHS2 (IC50 28 and 51 μM, respectively). The compounds exhibited mixed competitive inhibition with respect to UDP-N-acetyl-d-glucosamine as substrate [inhibition constant (Ki) 21.8 μM for obovatol and 23.1 μM for tetrahydroobovatol]. Furthermore, they showed antifungal activities against various pathogenic fungi, with a particularly strong inhibitory activity against Cryptococcus neoformans (MIC 7.8 mg/L). The results indicate that obovatol and tetrahydroobovatol can potentially serve as antifungal agents.