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

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 IC 50 of 38 μM. Its derivative, tetrahydroobovatol, inhibited chitin synthase 2 activity under the same conditions with an IC 50 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 (IC 50 > 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 IC 50 s to ScCHS2 (IC 50 28 and 51 μM, respectively). The compounds exhibited mixed competitive inhibition with respect to UDP-N-acetyl-D-glucosamine as substrate [inhibition constant (K i ) 21.8 μM for obovatol and 23.1 pM for tetrahydroobovatol]. Furthermore, they showed antifungal activities against various pathogenic fungi, with a particularly strong inhibitory activity against Cryptococcus neoformans (MIC 7.8 mglL). The results indicate that obovatol and tetrahydroobovatol can potentially serve as antifungal agents.