Mitochondrial electron transport inhibitors

Simple stilbenes (Phe-CH=CH-Phe) include the Vitis vinifera (grape) (Vitaceae) cytotoxic resveratrol (4,3, 5 -trihydroxystilbene), the mitochondrial electron transport inhibitor oxyresveratrol (3,5,2, 4 -tetrahydroxystilbene) and the protein kinase inhibitor piceatannol (3,4,3, 5 -tetrahydroxystilbene), all these compounds having antifungal activity. The isoprenylated stilbene chlorophorin (4-geranyl-3,5,2, 4 -tetrahydroxystilbene) is an antioxidant free radical scavenger (AO/FRS). 

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. 

Synthetic analogs were evaluated for potency as mitochondrial electron transport inhibitors in a 96-well plate assay, based on oxidation of NADH by mitochondrial fragments and the associated reduction in absorbance at 340 nm. Table I shows that, based on I50 values, V is a potent mitochondrial inhibitor across a broad spectrum of fungal pathogens, including the important cereal... 

In mitochondria, the allelochemlcals acted primarily as electron transport inhibitors. Malate oxidation was more sensitive than either succinate or NADH oxidation. No evidence for interaction with a specific membrane complex was obtained. Instead, Inhibition of substrate oxidation seems to result from alterations and perturbations produced in the inner membrane as reflected in interference with the behavior of transport processes. The compounds did not act as uncouplers or directly inhibit ATP synthesis. However, naringenin, some of the flavones, and the cinnamic acids dj inhibit the hydrolysis of ATP catalyzed by mitochondrial Mg -ATPase. 

Table 4.1 Comparative in vitro activity of mitochondrial electron transport (NADH to 2) by complex III inhibitors.

Hollingworth, R.M., Ahammadsahib, K.I., Gadelhak, G., and McLaughlin, J.L. Inhibitors of complex I in the mitochondrial electron transport chain with activities as pesticides. Biochem. Soc. Trans., 22, 230, 1994. 

The development of toxic symptoms on plants treated with pure electron transport inhibitors, such as simazine, diuron, and the uracils, can be prevented if the plants are supplied exogenously with a respirable carbohydrate (2). This observation suggests that the glycolytic or the mitochondrial system can provide sufficient energy to prevent the appearance of phyto-... 

TOXICANT-INDUCED MITOCHONDRIAL APOPTOSIS/NECROSIS 17.4.1 Electron Transport Inhibitors... 

Mitochondrial electron transport system Sulfuramid, chlorfenapyr Azocyclotin, cyhexatin, Fenbutatin-oxide, propargite, Tetradifon, diafenthiuron Uncouplers of oxidative phosphorylation Inhibitors of ATP synthase... 

The basis for this combination is two distinct and unrelated mechanisms of action against the parasite. Atovaquone is a selective inhibitor of the Plasnuidiiim s mitochondrial electron transport system, and cycloguanil is a dihydrofolatc reductase inhibitor. Atovaquone s chemistry is based on it... 

Several Inhibitors of the Mitochondrial Electron Transport Chain. 

Rotenone is an alkaloid botanical pesticide isolated from plants (Denis sp. or Lonchocarpus sp.). It blocks mitochondrial electron transport. It is associated with dermatitis and mucous membrane irritation in humans and is very potent in fish. In humans, intoxication is rare but when present is directed toward the respiratory system. Rotenone is used as a topical ectoparasiticide. As mentioned in the text, it has been implicated as possibly having a role in Parkinson s disease. The newest and by far safest class of insecticides available today are the insect growth inhibitors, such as methoprene (PreCor ), and chitin synthesis inhibitors, such as lufenuron (Program ). 

The electron transport inhibitors do not directly affect photophosphorylation or interfere with mitochondrial electron transport and phosphorylation ( 1), However, the inhibitory uncouplers, in addition to interfering with electron transport in thylakoids, uncouple photophosphorylation and oxidative phosphorylation, and inhibit mitochondrial electron transport. 

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