Inhibition of chitin synthases and antifungal activities by 2′-benzoyloxycinnamaldehyde from Pleuropterus ciliinervis and its derivatives

In the course of search for potent chitin synthase inhibitors from natural resources, a novel chitin synthases inhibitor, 2′-benzoyloxycinnamaldehyde (2′-BCA) (I), was isolated from the aerial parts of Pleuropterus ciliinervis NAKAI. 2′-BCA inhibited chitin synthase 1 and 2 of Saccharomyces cerevisiae with the IC₅₀s of 54.9 and 70.8 μg/ml, respectively, whereas it exhibited no inhibitory activity for chitin synthase 3 up to 280 μg/ml. Its derivatives, 2′-chloro- (V) and 2(-bromo-cinnamaldehyde (VI), each showed 1.9 and 2.7-fold stronger inhibitory activities than 2′-BCA, with the IC₅₀s of 37.2 and 26.6 μg/ml, respectively. Especially, the IC₅₀ of compound VI against chitin synthase 2 represented 1.7-fold more potent inhibitory activity than polyoxin D, a well-known chitin synthase inhibitor. Furthermore, compounds V and VI showed potent antifungal activities against various fungi including human pathogenic fungi, with a particularly strong inhibitory activity against Cryptococcus neoformans (MIC=16 μg/ml). Although the chemical synthesis of this compound has been reported, the present study is the first report to describe the isolation of 2′-BCA from natural resources and chitin synthases inhibitory activities of its derivatives. These results suggested that 2′-BCA and its derivatives can potentially serve as useful lead compounds for development of antifungal agents.