Phthalic acid diamides

Flubendiamide is an example of a new chemical class of insecticides that have been termed phthalic acid diamides (Nauen 2006, Copping and Duke 2007). They are related to the alkaloid ryanodine, which is extracted from Ryania species. Ryanodine affects muscles by binding to calcium channels of the sarcoplasmic reticulum. Ca + ions act as intracellular messengers, and their flux is modulated by calcium channels of this type. The toxic action of ryanodine and synthetic insecticides related to it is due to the disturbance of calcium flux. 

The baking process has remained much the same until the present day at a stoichiometric ratio of 1 4, phthalic anhydride or phthalic acid reacts with an ammonia releasing compound. The reaction may also start from other suitable materials, such as phthalic acid derivatives, including phthalic acid esters, phthalic acid diamide, or phthalimide. Appropriate ammonia releasing agents include urea and its derivatives, such as biuret, guanidine, and dicyanodiamide. The fact that a certain amount of urea decomposes to form side products makes it necessary to use excess urea. Approximately 0.2 to 0.5, preferably 0.25 equivalents of copper salt should be added for each mole of phthalic anhydride. 0.1 to 0.4 moles of molybdenum salt per mole of phthalic anhydride is sufficient. The reaction temperature is between 200 and 300°C. 

Ebbinghaus-Kintscher, U., Luemmen, P, Lobitz, N., Schsulte, T., Funke, C., Fischer, R., Masaki, T., Yasokawa, N., and Tohnishi, M., Phthalic acid diamides activate ryanodine-sensitive Ca2+ release channels in insects, Cell Calcium, 39, 21, 2006. 

Flubendiamide is a promising new insecticide which is particularly active against lepidopteran pest species and is currently being co-developed by Nihon Nohyaku and Bayer CropScience. It is the first member ofa new chemical class of insecticides named phthalic acid diamides (Figure 5) to be developed. It has been shown to be extremely potent against lepidopterous pests including those resistant... 

Figure 5. Structures of the phthalic acid diamides used in the MoA study.

Phthalic acid diamides Mode of action and target selectivity (U. Ebbinghaus-Kintscher, Bayer CropScience, Germany)... 

This ranking of halogen atoms can be exemplified by the recently described SAR of halogenated phthalic acid diamides (F < Cl < Br < I) in the development product fiubendiamide (54 ISO-proposed, Hal = I Nihon Nohyaku Co., Ltd./ Bayer Crop Science) [24], which activates selective ryanodine-sensitive intracellular Ca + release channels in insects as novel mode of action [25]. Introduction of a bulky and moderate lipophilic halogen such as iodine into 3-position of the phthalic acid aryl moiety increased the insecticidal activity considerably (Fig. 35.4) (for more details see Chapter 34). 

Fig. 35.4. SAR of halogen-containing phthalic acid diamides, flubendiamide (54 Hal = I).

Phthalic Acid Diamides Activate Insect Ryanodine... 

In this communication, we present evidence that the phthalic acid diamides, a novel chemical class of highly potent insecticides discovered by Nihon Nohyaku Co., Ltd. (14), act on ryanodine-sensitive calcium release channels in insects by a mechanism distinct from that of ryanodine. 

The phthalic acid diamides flubendiamide and the corresponding sulfoxide were synthesized by Nihon Nohyaku Co., Ltd., and Bayer CropScience AG. Ryanodine, Fura-2 acetoxymethyl ester (Fura-2 AM) and Fura-2 were obtained from Sigma and stored frozen as aliquots (stock solution ImM in DMSO). 

Phthalic Acid Diamides Elicited Intracellular Calcium Transients in Heliothis Neurons... 

Figure I. Structures of the Phthalic Acid Diamides Employed in the Current Study (I, flubendiamide II, flubendiamide-sulfoxide)...

In sununary, phthalic acid diamides increased the ryanodine affinity of the Heliothis ryanodine receptor. At low [Ca ] the compounds offset the cooperativity between the ryanodine sites. 

Phthalic Acid Diamides Elicited Calcium Release Mediated by Ryanodine Receptors... 

The current study shows that phthalic acid diamide insecticides, represented by flubendiamide and its sulfoxide analogue, activated ryanodine receptors present in isolated Heliothis neurons, as concluded from the following results. Firstly, calcium transients evoked by phthalic acid diamides were independent of the extracellular [Ca ], in contrast to the signals elicited by acetylcholine. This was interpreted as calcium release from intracellular stores of the endo(sarco)plasmic reticulum, which could in principle be mediated by two different release channels, namely the ryanodine receptor and the IP3 receptor. 

Secondly, the calcium transients were sensitive to inhibition by ryanodine, but they were not affected by the IP3R blocker xestospongine (18 19). Consequently, it was concluded that the ryanodine receptor was the target site of phthalic acid diamides. 

Phthalic Acid Diamides Increased the Ryanodine Affinity of Ryanodine Receptors... 

Equilibrium binding of [ H]ryanodine to Heliothis flight muscle microsomes clearly revealed cooperativity between the binding sites at 100 pM [Ca ]. Based on the assumption that RyRs are arranged in arrays of calcium release units in insect as well as in mammalian sarcpplasmic reticulum membranes (22), a plausible explanation would be that ryanodine receptors opened by calcium may have activated adjacent RyR channels by intermolecular interactions. Phthalic acid diamides completely converted the receptors to the high-affinity conformation as revealed by the hyperbolic binding iso erm. 

Interestingly, even at 800 pM [Ca ], when the Heliothis RyRs were in the ryanodine-binding state, phthalic acid diamides hirther increased the affinity to [ HJryanodine slightly but significantly. From these results, it can be concluded that the compounds induced and/or stabilized the activated, calcium-conducting channel state. 

Besides their importance as potent insecticides, phthalic acid diamides, a new class of allosteric ryanodine receptor effectors, may be used as novel pharmacological tools in the functional and structural characterization of this fascinating ion channel. 

Synonyms 1,2-Benzenedicarboxamide o-Carbamoylbenzamide P-D Phthaldiamide o-Phthalic acid diamide... 

Phthalic acid, diallyl ester o-Phthalic acid, diallyl ester. See Diallyl phthalate o-Phthalic acid diamide. See Phthalamide Phthalic acid, dicyclohexyl ester. See Dicyclohexyl phthalate Phthalic acid, didecyl ester. See Didecyl phthalate... 

---