Succinate dehydrogenase inhibitors

Already in 1977 a general structure (Fig. 13.3.1) had been published for carboxylic amides as succinate dehydrogenase inhibitors, a structure that still forms the basis of most modern molecules [1]. 

At that time about ten compounds of this structural class were developmental candidates or had been introduced into the market. Of these carboxin (1) and oxy-carboxin (2) (Table 13.3.1 below) are well known examples that are still used today [2], 

Similar to some of the early examples like fenfuram, the amide group is attached to a five-membered heterocycle in furametpyr (7) (Sumitomo Chemical 

10] and thifluzamide (8) (Dow AgroSciences) [11, 12], which were introduced in the 1990s. The biology again focuses on the pathogens characteristic for this class of compounds, especially Rhizoctonia spp. 

A structurally very similar molecule, tiadinil (11, Fig. 13.3.2), has been shown to have another mode of action as it is an activator of systemic acquired resistance and induces defense gene expression [13]. This illustrates that succinate dehydrogenase inhibitors cannot be recognized based on their structure alone. 

---

Greene JG, Greenamyre JT (1995) Characterization of the excitotoxic potential of the reversible succinate dehydrogenase inhibitor malonate. J Neurochem 64 430-436 Gunne LM, Andren PE (1993) An animal model for coexisting tardive dyskinesia and tardive parkinsonism—a glutamate hypothesis for tardive dyskinesia. Clin Neuropharmacol 16 90-95... 

Excitotoxic lesions generated in primates using NMDA receptor agonists such as quinolinic acid cause neuronal loss similar to that found in HD, emphasizing, the potential role of excitotoxicity in HD. Intrastriatal injections of the reversible succinate dehydrogenase inhibitor, malonate, into rats caused a decrease in ATP levels and increased lactate and excitotoxic lesions, which could be prevented by NMDA antagonists. 

Some bioactive flavones include aldose reductase inhibitors (apigenin 4 -methyl ether (acacetin), apigenin 7-0-apioside (apiin), 5,7-dihydroxyflavone (chrysin) and luteolin) antiinflammatory 5-LOX inhibitors (5,6,7-trihydroxyflavone (baicalein), 5,6,3, 4 -tetrahydroxy 7-methoxyflavone (pedalitin), 5,3, 4 -trihydroxy 6,7-dimethoxyflavone (cirsiliol, 6-0-methylpedalitin) and flavone) a COX inhibitor (flavone) iodothyronine deiodinase inhibitors (acacetin, chrysin and luteolin) a NADH and succinate dehydrogenase inhibitor (luteolin) millet-derived, goitrogenic inhibitors of thyroid peroxidase (flavone C-glycosides orientin and vitexin) and protein kinase inhibitors (acacetin, apigenin, baicalein, flavone, luteolin, 5,7,3, 4, 5 -pentahydroxyflavone (tricetin) and tricetin 3, 4, 5 -trimethyl ether). 

Some bioactive flavonols include aldose reductase inhibitors (axillarin (5,7,3, 4 -tetrahy-droxy-6-methoxyflavone), 2,3-dihydroquercetin (taxifolin), 6-hydroxykaempferol (galetin), hyperin (quercetin 3-0-galactoside), isoquercetrin, morin (3,5,7,2, 4 -pentahydroxy-flavone), quercetin, quercitrin and rutin) anti-inflammatory 5-LOX inhibitors (fisetin (3,7,3, 4 -tetrahydroxyflavone), kaempferol, morin, myricetin, quercetin and rutin) a GOX inhibitor (galangin (3,5,7-trihydroxyflavone)) iodothyronine deiodinase inhibitors (fisetin, kaempferol and morin) NADH and succinate dehydrogenase inhibitors (fisetin and myricetin) and protein kinase inhibitors (fisetin, galangin, isorhamnetin, kaempferide... 

Fig. 13.3.1. General structure for carboxylic amides as succinate dehydrogenase inhibitors.

Several studies on structure-activity relationships of succinate dehydrogenase inhibitors have been published [22-28]. Each of the analyses has focused on specific carboxylic acid moieties of the molecule. The influence of substituents of the carboxylic acid and of the aniline has then been studied based on enzyme inhibition and biological data. Some empirical relationships have been established within each structural subclass. The importance of electron-withdrawing groups on the carboxylic acid and of lipophilic effects on the aniline has been observed. The orientation of the amide bond has also been discussed, suggesting that the cis configuration of the amide bond may be important in molecules with bulky ortho substituents [28]. 

One class of seed treatment fungicides is the carboxanilides they are amides of aniline. Carboxin, mepronil, and flutolanil are all commercial members of this class [66], They are in group C2 and are succinate dehydrogenase inhibitors. 

Succinate-dehydrogenase inhibitors SDHI Carboxamide Isopyrazam... 

---