New and selective ryanodine receptor activators for insect control.

The past 30 years have witnessed a period of significant expansion in the use of halogenated compounds in the field of agrochemical research and development. The introduction of halogens into active ingredients has become an important concept in the quest for a modern agrochemical with optimal efficacy, environmental safety, user friendliness and economic viability. Outstanding progress has been made, especially in synthetic methods for particular halogen-substituted key intermediates that were previously prohibitively expensive. Interestingly, there has been a rise in the number of commercial products containing 'mixed' halogens, e.g. one or more fluorine, chlorine, bromine or iodine atoms in addition to one or more further halogen atoms. Extrapolation of the current trend indicates that a definite growth is to be expected in fluorine-substituted agrochemicals throughout the twenty-first century. A number of these recently developed agrochemical candidates containing halogen substituents represent novel classes of chemical compounds with new modes of action. However, the complex structure-activity relationships associated with biologically active molecules mean that the introduction of halogens can lead to either an increase or a decrease in the efficacy of a compound, depending on its changed mode of action, physicochemical properties, target interaction or metabolic susceptibility and transformation. In spite of modern design concepts, it is still difficult to predict the sites in a molecule at which halogen substitution will result in optimal desired effects. This review describes comprehensively the successful utilisation of halogens and their unique role in the design of modern agrochemicals, exemplified by various commercial products from Bayer CropScience coming from different agrochemical areas.

The unique role of halogen substituents in the design of modern agrochemicals.

Ryanodine receptors (RyRs) are a distinct class of ligand-gated calcium channels controlling the release of calcium from intracellular stores. They are located on the sarcoplasmic reticulum of muscle and the endoplasmic reticulum of neurons and many other cell types. Ryanodine, a plant alkaloid and an important ligand used to characterize and purify the receptor, has served as a natural botanical insecticide, but attempts to generate synthetic commercial analogues of ryanodine have proved unsuccessful. Recently two classes of synthetic chemicals have emerged resulting in commercial insecticides that target insect RyRs. The phthalic acid diamide class has yielded flubendiamide, the first synthetic ryanodine receptor insecticide to be commercialized. Shortly after the discovery of the phthalic diamides, the anthranilic diamides were discovered. This class has produced the insecticides Rynaxypyr and Cyazypyr. Here we review the structure and functions of insect RyRs and address the modes of action of phthalic acid diamides and anthranilic diamides on insect ryanodine receptors. Particularly intersting is the inherent selectivity both chemical classes exhibit for insect RyRs over their mammalian counterparts. The future prospects for RyRs as a commercially-validated target site for insect control chemicals are also considered.

Insect ryanodine receptors: molecular targets for novel pest control chemicals

The present invention relates to compositions, in particular within a fungicide composition, which comprises (A) a dithiino-tetracarboximide of formula (I) and a further fungicidally active compound (B). Moreover, the invention relates to a method for curatively or preventively controlling the phytopathogenic fungi of plants or crops, to the use of a combination according to the invention for the treatment of seed, to a method for protecting a seed and to the treated seed.

Active compound combinations

Resistance to diamide insecticides in diamondback moth, Plutella xylostella (Lepidoptera: Plutellidae) is associated with a mutation in the membrane-spanning domain of the ryanodine receptor.

Flubendiamide, N2-[1,1-dimethyl-2-(methylsulfonyl)ethyl]-3-iodo-N1-[2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-1,2-benzenedicarboxamide, is a novel class of insecticide having a unique chemical structure. The uniqueness of the structure results from three parts with novel substituents; a heptafluoroisopropyl group in the anilide moiety, a sulfonylalkyl group in the aliphatic amide moiety, and an iodine atom at the 3-position of the phthalic acid moiety. The compound shows extremely strong insecticidal activity especially against lepidopterous pests including resistant strains. Flubendiamide would have a novel mode of action, because the insecticidal symptoms accompanied by a discriminative contraction of the larval body are distinguished from those of commercial insecticides. It is also very safe for non-target organisms. Flubendiamide is expected to be a suitable agent for controlling lepidopterous insects as part of the insect resistance management and the integrated pest management programs. © Pesticide Science Society of Japan

Flubendiamide, a Novel Insecticide Highly Active against Lepidopterous Insect Pests

Flubendiamide, developed by Nihon Nohyaku Co., Ltd. (Tokyo, Japan), is a novel activator of ryanodine-sensitive calcium release channels (ryanodine receptors; RyRs), and is known to stabilize insect RyRs in an open state in a species-specific manner and to desensitize the calcium dependence of channel activity. In this study, using flubendiamide as an experimental tool, we examined an impact of functional modulation of RyR on Ca 2+ pump. Strikingly, flubendiamide induced a 4-fold stimulation of the Ca 2+ pump activity (EC 50 = 11 nM) of an insect that resequesters Ca 2+ to intracellular stores, a greater increase than with the classical RyR modulators ryanodine and caffeine. This prominent stimulation, which implies tight functional coupling of Ca 2+ release with Ca 2+ pump, resulted in a marginal net increase in the extravesicular calcium concentration despite robust Ca 2+ release from the intracellular stores by flubendiamide. Further analysis suggested that luminal Ca 2+ is an important mediator for the functional coordination of RyRs and Ca 2+ pumps. However, kinetic factors for Ca 2+ pumps, including ATP and cytoplasmic Ca 2+ , failed to affect the Ca 2+ pump stimulation by flubendiamide. We therefore conclude that the stimulation of Ca 2+ pump by flubendiamide is mediated by the decrease in luminal calcium, which may induce calcium dissociation from the luminal Ca 2+ binding site on the Ca 2+ pump. This mechanism should play an essential role in precise control of intracellular Ca 2+ homeostasis.

https://molpharm.aspetjournals.org/content/molpharm/early/2006/02/15/mol.105.020339.full.pdf

Flubendiamide, a novel Ca2+ channel modulator, reveals evidence for functional cooperation between Ca2+ pumps and Ca2+ release.

A method for using a compound represented by the general formula: ##STR1## (wherein R1 and R2 are the substituents, respectively, defined in the specification) for agricultural and horticultural disease control, and a composition used in said method.

Agricultural and horticultural disease controller and a method for controlling the diseases

Tiadinil is a novel systemic fungicide for rice diseases discovered and developed by Nihon Nohyaku Co., Ltd. The compound is characterized by a unique heterocyclic moiety, 1,2,3-thiadiazole, and a unique mode of action of inducing the plant defense mechanism against a pathogen. The lead compound was found in the synthesis research of 1,2,3-thiadiazole chemistry with the appropriate screening system. Both application methods, nursery box and into-water applications, can be used in rice cultivation. It shows excellent activity against rice blast and also exhibits activity against some rice bacterial diseases. Tiadinil has a favorable toxicological, eco-toxicological and kinetic profile. © Pesticide Science Sociey of Japan

Development of a novel plant activator for rice diseases, tiadinil

Compound of the general formula (I), which is useful as an agricultural and horticultural fungicide, an agricultural and horticultural fungicidal composition containing the com-pound, use of the composition for controlling plant disease, and process for the production of the compound: (I) wherein: R1 and R2 each independently represent a C1-C6 alkyl group; one of R3 and R4 represents a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 alkoxy-C1-C6 alkyl group, a phenyl group or d benzyloxy group, and the other is a nitrogen atom-containing hetero ring which is selected from the group consisting of pyrrolidino, piperidine, morpholine, thiomorpholine, piperazine, hexa-methyleneimine, tetrahydroquinoline, tetrahydroisoquinoline, 2,3-dihydro-1,4-benzoxazine and octahydro-1,4-benzoxazine and which is attached at its nitrogen atom to the rest of the derivative, the nitrogen atom-containing hetero ring being unsubstituted or substituted by at least one substituent selected from the group consisting of halogen, C1-C3 alkyl, phenyl [which may further be substituted by 1 to 5 halogen atoms], C1-C6 alkoxy-carbonyl, benzyl, pyridiyl, pyrimidyl, 1,3-dioxolane and halogenated 1,3-dioxolane.

Kenji Tsubata

Papers

Flubendiamide, a Novel Insecticide Highly Active against Lepidopterous Insect Pests

Flubendiamide, a novel Ca2+ channel modulator, reveals evidence for functional cooperation between Ca2+ pumps and Ca2+ release.

Agricultural and horticultural disease controller and a method for controlling the diseases

Development of a novel plant activator for rice diseases, tiadinil

N-(substituted benzyloxy)imine derivatives, process for the production thereof, use thereof, and method of use thereof