Synthesis and fungicidal activity of novel imidazole-based ketene dithioacetals.

Novel imidazole-based ketene dithioacetals show impressive in planta activity against the economically important plant pathogens Alternaria solani, Botryotinia fuckeliana, Erysiphe necator and Zymoseptoria tritici. Especially derivatives of the topical antifungal lanoconazole, which bear an alkynyloxy or a heteroaryl group in the para-position of the phenyl ring, exhibit excellent control of the mentioned phytopathogens. These compounds inhibit 14α -demethylase in the sterol biosynthesis pathway of the fungi. Synthesis routes starting from either benzaldehydes or acetophenones as well as structure-activity relationships are discussed in detail.

Investigating the Structure-Activity Relationship of the Insecticidal Natural Product Rocaglamide.

The natural product Rocaglamide (1), isolated from the tree Aglaia elliptifolia, is a compelling but also challenging lead structure for crop protection. In laboratory assays, the natural product shows highly interesting insecticidal activity against chewing pests and beetles, but also phytotoxicity on some crop plants. Multi-step syntheses with control of stereochemistry were required to probe the structure-activity relationship (SAR), and seek simplified analogues. After a significant research effort, just two areas of the molecule were identified which allow modification whilst maintaining activity, as will be highlighted in this paper.

Synthesis and fungicidal activity of N-thiazol-4-yl-salicylamides, a new family of anti-oomycete compounds.

A novel class of experimental fungicides has been discovered, which consists of special N-thiazol-4-yl-salicylamides. They originated from amide reversion of lead structures from the patent literature and are highly active against important phytopathogens, such as Phytophthora infestans (potato and tomato late blight), Plasmopara viticola (grapevine downy mildew) and Pythium ultimum (damping-off disease). Structure-activity relationship studies revealed the importance of a phenolic or enolic hydroxy function in the ß-position of a carboxamide. An efficient synthesis route has been worked out, which for the first time employs the carbonyldiimidazole-mediated Lossen rearrangement in the field of thiazole carboxylic acids.

Synthesis and fungicidal activity of quinolin-6-yloxyacetamides, a novel class of tubulin polymerization inhibitors.

A novel class of experimental fungicides has been discovered, which consists of special quinolin-6-yloxyacetamides. They are highly active against important phytopathogens, such as Phytophthora infestans (potato and tomato late blight), Mycosphaerella graminicola (wheat leaf blotch) and Uncinula necator (grape powdery mildew). Their fungicidal activity is due to their ability to inhibit fungal tubulin polymerization, leading to microtubule destabilization. An efficient synthesis route has been worked out, which allows the diverse substitution of four identified key positions across the molecular scaffold.

Spiroindolines identify the vesicular acetylcholine transporter as a novel target for insecticide action.

The efficacy of all major insecticide classes continues to be eroded by the development of resistance mediated, in part, by selection of alleles encoding insecticide insensitive target proteins. The discovery of new insecticide classes acting at novel protein binding sites is therefore important for the continued protection of the food supply from insect predators, and of human and animal health from insect borne disease. Here we describe a novel class of insecticides (Spiroindolines) encompassing molecules that combine excellent activity against major agricultural pest species with low mammalian toxicity. We confidently assign the vesicular acetylcholine transporter as the molecular target of Spiroindolines through the combination of molecular genetics in model organisms with a pharmacological approach in insect tissues. The vesicular acetylcholine transporter can now be added to the list of validated insecticide targets in the acetylcholine signalling pathway and we anticipate that this will lead to the discovery of novel molecules useful in sustaining agriculture. In addition to their potential as insecticides and nematocides, Spiroindolines represent the only other class of chemical ligands for the vesicular acetylcholine transporter since those based on the discovery of vesamicol over 40 years ago, and as such, have potential to provide more selective tools for PET imaging in the diagnosis of neurodegenerative disease. They also provide novel biochemical tools for studies of the function of this protein family.

Aryldiones incorporating a [1,4,5]oxadiazepane ring. Part 2: chemistry and biology of the cereal herbicide pinoxaden.

BACKGROUND: Pinoxaden is a new cereal herbicide that provides outstanding levels of post-emergence activity against a broad spectrum of grass weed species for worldwide selective use in both wheat and barley. RESULTS: Factors influencing activity and tolerance to pinoxaden were in part linked to distinct structural parts of the active ingredient. Three complementary contributions that decisively impact upon the herbicidal potency against grasses were identified: a preferred 2,6-diethyl-4-methyl aromatic substitution pattern, a dione area suitable for proherbicide formation and beneficial adjuvant effects. The uptake and translocation pattern of pinoxaden when coapplied with its tailored adjuvant were analysed by autoradiography, indicating extensive and rapid penetration, followed by effective distribution throughout the plant. Crop injury reduction on incorporation of the [1,4,5]oxadiazepane ring into the aryldione template was reinforced with safener technology. Comparative studies on the behaviour of pinoxaden applied either alone or in combination with the safener cloquintocet-mexyl demonstrated that addition of the safener resulted in significant enhancement of metabolic degradation in wheat and barley, providing excellent crop tolerance and a substantial selectivity margin without adverse effects on weed control. CONCLUSION: The biological potential of pinoxaden and its active principle pinoxaden dione in terms of grass weed control and tolerance in cereals was fully exploited by inclusion of the safener cloquintocet-mexyl in the formulation in combination with a specific and tailor-made tank-mix adjuvant based on methylated rape seed oil.

Aryldiones incorporating a [1,4,5]oxadiazepane ring. Part I: Discovery of the novel cereal herbicide pinoxaden.

Derivatives of the new class of 3-hydroxy-4-phenyl-5-oxo-pyrazolines were optimized towards both herbicidal activity on key annual grass weed species and selectivity in small grain cereal crops. The generic structure can be separated into three parts for the analysis of the structure-activity relationships, namely the aryl, the dione with its prodrug forms and the hydrazine moiety. Each area appears to play distinct and different roles in overall expression of biological performance which is further beneficially influenced by adjuvant response and safener action. Pinoxaden 6, a novel graminicide for use in wheat and barley incorporating a [1,4,5]oxadiazepane ring, eventually emerged as a development candidate from the discovery and optimization process.

Multicomponent reactions in fungicide research: the discovery of mandipropamid.

Isocyanide-based multicomponent reactions of the Ugi- and Passerini-type have been valuable tools for the rapid exploration of the novel fungicidal compound classes of phenylglycinamides and mandelamides. Mandipropamid (6), which was discovered during this derivatisation, displays excellent activity against the economically important phytopathogens Phytophthora infestans (potato and tomato late blight) and Plasmopara viticola (grape downy mildew).

Synthesis and fungicidal activity of N-2-(3-methoxy-4-propargyloxy)phenethyl amides. Part II: anti-oomycetic mandelamides.

Novel types of anti-oomycetic compounds have been designed and prepared. The synthetic approach to these mandelamides is outlined. Biological data demonstrate their high efficacy against important plant diseases such as tomato and potato late blight (Phytophthora infestans De Bary) and grape downy mildew (Plasmopara viticola Berliner & de Toni). Structure-activity relationship studies are discussed. The new development product mandipropamid is presented.