Chitin synthase inhibitors

Triflumuron (Alsystin , Baycidal ) [91,92], an /V-benzoyl-W-phenyl urea chitin synthase inhibitor commercialized by Bayer CropScience, is a broad spectrum insecticide that is active against chewing insects, as well as fleas and cockroaches. 

Chitin synthase inhibitors are used commercially as insecticides because they preventthe formation of a new exoskeleton and the shedding of the old one. The insect becomes trapped in an old exoskeleton that cannot grow. These inhibitors are highly toxic to insects and crustaceans, but relatively nontoxic to mammals. The most common chitin synthase inhibitors are substituted benzoyl-ureas such as diflubenzuron, which was first registered as an insecticide in 1976. 

Chitin synthase inhibitors are used commercially to kill termite colonies. These compounds prevent the formation of a new exoskeleton, trapping the termites in an old exoskeleton that cannot grow with them. 

Figure 2. Bona Fide Chitin Synthase Inhibitors...

C20H25N 5010 495.445 Nucleoside antibiotic. Isol. from Strepto-myces tendae and Streptomyces cacaoi. Chitin synthase inhibitor. Active against insects and fungi. Powder. 

Both compounds (Figure 4.7) are non-competitive inhibitors of chitin synthase and also interfere with the Bremner-Greenberg methylation pathway.6 Their activity is dependent upon the oxidation of the phosphorous - sulfur linkage, a feature that is the basis of resistance development, which is common sensitive strains of P. oryzae metabolise the compounds more rapidly than resistant strains. 

Another group of fungicides interferes with cell wall formation. Two examples of this group include 1) the polyoxines, which prevent chitin formation by competitively inhibiting chitin-synthase, the final enzyme involved in chitin biosynthesis, and 2) melanine biosynthesis inhibitors, especially in Pyricularia oryzae. Examples of... 

Nikkomycins are nucleoside amide antibiotics produced by Streptomyces tendae Tii 901 and are known to show antifungal, anti-insecticidal, and acaricidal activities. They are competitive inhibitors of chitin synthase. Nikkomycins are produced as a complex mixture, with nikkomycin Z (13) and nikkomycin X (14) representing the major components. ... 

Inhibitors of acetolactate synthase Inhibitors of chitin synthesis... 

Gaughran JP, Lai MH, Kirsch DR, Silverman SJ. Nikkomycin Z is a specific inhibitor of Saccharomyces cerevisiae chitin synthase isozyme Chs3 in vitro and in vivo. J. Bacterial. 1994, 176, 5857-5860. 

Compound 130, made by oxidative cleavage of the GlcNAc allyl C-glycoside followed by Wittig extension, has been used to make the nucleoside derivative 131 for studies of potential inhibitors of chitin synthases. ... 

Inhibition of chitin synthase (CS, EC 2.4.1.16) is widely recognized as a largely untapped, intrinsically manunalian-safe, arthropodicidal mechanism of action. Certain classes of cyanine dyes were observed as hits in a high-throughput Lepidopteran (tobacco budworm, Heliothis virescem) chitin synthase assay. Optimization produced in v/vo-active analogs however, ultimately these were shown to be off-target, active instead as mitochondrial electron transport inhibitors (METl) at Complex 1. An overview of the chitin synthase project and chemistry is presented. 

Xanthofulvin (1004) was first isolated by Masubuchi and co-workers from a Eupenicillium strain and found to be a chitin synthase II inhibitor (/C50 = 2.2 pM). Kimura and co-workers reported the isolation of SM-216289 or xanthofulvin (1004, Fig. 13.22) in addition to the known tautomer, vinaxanthone (991, (Fig. 13.21), from cultures of Penicillium sp. SPF-3059 (660). The authors demonstrated that xanthofulvin (1004) (Fig. 13.22) is also a semaphorin inhibitor (see vinaxanthmie, above) Sema3A was inhibited at a low concentration level (JCso = 0.16 pM). 

UDP-7V-acetylglucosamine (uridine diphosphate), nikkomycins act as potent competitive inhibitors of chitin synthase and exhibit potent fungicidal, insecticidal, and acaricidal activities [320]. Nikkomycin X and Z, isolated as major components, contain the hydroxypyridylhomothreonine (HPHT) moiety, the aminohexuronic acid, and a nucleoside moiety N-glycosidically linked to 4-formyl-imidazolin-2-one or a uracil base, respectively [321, 322]. 

Nucleoside antibiotic. Isol. from Streptomyces tendae. Inhibitor of chitin synthase and fungi. 

The maximum specific activity of the chitin synthase in Mortierella vinacea is associated with cessation of exponential growth. Mg + ions stimulated the enzymic activity, whereas soluble chitodextrins are inhibitors, in contrast to their effect on the corresponding enzyme from A. flavus. Chitin synthase has been detected in yeast forms of preparations of Mucor rouxii, chiefly in a latent state that is activated by proteases. It is initially present as an active form in mycelial preparations, but is rapidly degraded by endogenous proteases. The different behaviours of chitin synthase in crude extracts of mycelium and yeast cells is consistent with, and perhaps responsible for, differences in the structures of the cell walls. The activating factor for the chitin synthase of S. cerevisiae has been purified and shown to be identical with an enzyme previously designated as protease B (E.C. 3.4.22.9). ... 

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