Inhibitors of succinic dehydrogenase

Other phenylamides with the same mode of action are fenfuram, flutalonil, furametpyr, mepronil, and oxycarboxin. 

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Barbiturates such as amobarbital inhibit NAD-hnked dehydrogenases by blocking the transfer from FeS to Q. At sufficient dosage, they are fatal in vivo. Antin cin A and dimercaprol inhibit the respiratory chain between cytochrome b and cytochrome c. The classic poisons H2S, carbon monoxide, and cyanide inhibit cytochrome oxidase and can therefore totally arrest respiration. Malonate is a competitive inhibitor of succinate dehydrogenase. 

Flutolanil is an inhibitor of succinate dehydrogenase complex (Complex II), in the mitochondrial respiratory electron transport chain. ... 

Complex II. The succinate dehydrogenase complex, or complex IF, contains a non-haem iron-sulfur component and utilises the electron acceptor FAD to effect the transfer of electrons from FADH2 to coenzyme Q. Inhibitors of succinate dehydrogenase are specific basidio-mycete fungicides, with uses against smuts, bunts, and Rhizoctonia spp. (Figure 4.21). 

During the terminal stages of electron transfer in complex II, cytochrome bysg is involved however, its specific function is not understood. Oxaloacetate and malonate are competitive inhibitors of succinate dehydrogenase and compete with the substrate for binding at the active site (Chapters 6 and 13). Carboxin and thenoyltrifluoroacetone (Figure 14-7) inhibit electron transfer from FADH2 to CoQ. 

Malonate anion is a potent competitive inhibitor of succinate dehydrogenase, which catalyzes the conversion of succinate to malate. 

We have successfully applied LOGANA and LOGON in a number of cases [122-126, 171] and use both methods routinely. As a simple example we shall present here results [122] obtained for a series of fungicidal carboxamides as inhibitors of succinate dehydrogenase (experimental data from [172]). The series comprises 89 compounds of the general stractuie presented in Fig. 5. Stmctuial variations are so extensive that QSAR methods of the Hansch or Free-Wilson type do not lead to meaningful results. Tables 6 and 7 summarize the topological descriptors used in the analysis. 

Compound (LVII) is very rapidly excreted into the kidney. It is metabolised to 5-(3 -hydroxy-4 -aminophenyl)cytosine and its O-glucuronide, as well as derivatives acetylated on both amino groups [343]. It is a competitive inhibitor of succinate dehydrogenase (K = 9-2 x 10 m K,- = 5 0 X IO m), and it has been considered that this is its mode of action [343]. One role of this enzyme involves aspartate synthesis, via fumarate. This pyrimidine enhances the incorporation of orotic acid into nucleic acid but is not itself incorporated. 

Scheme 35.4. From carboxin (63) to halogenated inhibitors of succinate dehydrogenase complex II (64-67, see Table 35.9).

Table 35.9 Halogenated inhibitors of succinate dehydrogenase (SD) -complex II (64-67) (see Scheme 35.4 for the basic structure).

Malonic add HOOC-CH2-COOH, a dicarboxyl-ic acid, m.p. 135.6 °C, which has been found in the free form in plants, but is of only sporadic occurrence. At the pH of the cell M.a. is present as its anion (mal-onate), which is a known competitive inhibitor of succinate dehydrogenase in the tricarboxylic acid cycle. A metabolically important derivative of M.a. is malo-nyl-CoA, an intermediate of Fatty acid biosynthesis (see). 

The finding that malonic acid is a product of p3ndmidine metabohsm throws doubt upon the common impression that malonic acid is invariably an unnatural metabolic poison. Current findings have revealed that malonic acid, in addition to its well-known role as an inhibitor of succinic dehydrogenase, can be metabolized by rnice, rats, and microorganisms.Also, pig heart preparations form this acid from oxalacetic acid. ... 

Szent-GySrgyi having also observed the depressant effect of malonate (an inhibitor of succinic dehydrogenase) on the respiration of the muscle mince, he saw that the malonate must hinder the restoration by the succinate of the respiratory system which had become completely oxidized. He therefore proposed the following scheme to explain respiration ... 

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