Classifications

• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
  • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
  • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N27/00—Biocides, pest repellants or attractants, or plant growth regulators containing hydrocarbons
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
  • A01N31/04—Oxygen or sulfur attached to an aliphatic side-chain of a carbocyclic ring system
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
  • A01N33/02—Amines; Quaternary ammonium compounds
  • A01N33/06—Nitrogen directly attached to an aromatic ring system
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
  • A01N33/02—Amines; Quaternary ammonium compounds
  • A01N33/08—Amines; Quaternary ammonium compounds containing oxygen or sulfur
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
  • A01N33/26—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds containing nitrogen-to-nitrogen bonds, e.g. azides, diazo-amino compounds, diazonium compounds, hydrazine derivatives
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N35/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical
  • A01N35/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical containing aliphatically bound aldehyde or keto groups, or thio analogues thereof; Derivatives thereof, e.g. acetals
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N35/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical
  • A01N35/06—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical containing keto or thioketo groups as part of a ring, e.g. cyclohexanone, quinone; Derivatives thereof, e.g. ketals
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
  • A01N37/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group —CO—N<, e.g. carboxylic acid amides or imides; Thio analogues thereof
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N41/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom
  • A01N41/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom containing a sulfur-to-oxygen double bond
  • A01N41/04—Sulfonic acids; Derivatives thereof
  • A01N41/08—Sulfonic acid halides; alpha-Hydroxy-sulfonic acids; Amino-sulfonic acids; Thiosulfonic acids; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N41/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom
  • A01N41/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom containing a sulfur-to-oxygen double bond
  • A01N41/10—Sulfones; Sulfoxides
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
  • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
  • A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
  • A01N43/08—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings with oxygen as the ring hetero atom
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
  • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
  • A01N43/14—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings
  • A01N43/16—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings with oxygen as the ring hetero atom
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
  • A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
  • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
  • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
  • A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
  • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
  • A01N43/647—Triazoles; Hydrogenated triazoles
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
  • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
  • A01N43/76—1,3-Oxazoles; Hydrogenated 1,3-oxazoles
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
  • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
  • A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
  • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
  • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
  • A01N47/20—N-Aryl derivatives thereof
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
  • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
  • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
  • A01N47/30—Derivatives containing the group >N—CO—N aryl or >N—CS—N—aryl
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
  • A01N57/10—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-oxygen bonds or phosphorus-to-sulfur bonds
  • A01N57/12—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-oxygen bonds or phosphorus-to-sulfur bonds containing acyclic or cycloaliphatic radicals

Definitions

• Nematodes (derived from the Greek word for thread) are active, flexible, elongate, organisms that live on moist surfaces or in liquid environments, including films of water within soil and moist tissues within other organisms. While only 20,000 species of nematode have been identified, it is estimated that 40,000 to 10 million actually exist. Some species of nematodes have evolved to be very successful parasites of both plants and animals and are responsible for significant economic losses in agriculture and livestock and for morbidity and mortality in humans (Whitehead (1998) Plant Nematode Control. CAB International, New York). Nematode parasites of plants can inhabit all parts of plants, including roots, developing flower buds, leaves, and stems.
• Plant parasites are classified on the basis of their feeding habits into the broad categories: migratory ectoparasites, migratory endoparasites, and sedentary endoparasites.
• Sedentary endoparasites which include the root knot nematodes (Meloidogyne) and cyst nematodes (Globodera and Heterodera) induce feeding sites and establish long-term infections within roots that are often very damaging to crops (Whitehead, supra). It is estimated that parasitic nematodes cost the horticulture and agriculture industries in excess of $78 billion worldwide a year, based on an estimated average 12% annual loss spread across all major crops.
• nematodes cause soybean losses of approximately $3.2 billion annually worldwide (Barker et al. (1994) Plant and Soil Nematodes: Societal Impact and Focus for the Future. The Committee on National Needs and Priorities in Nematology. Cooperative State Research Service, US Department of Agriculture and Society of Nematologists).
• Several factors make the need for safe and effective nematode controls urgent.
• famines, and environmental degradation have heightened concern for the sustainability of agriculture, and new government regulations may prevent or severely restrict the use of many available agricultural anthelmintic agents.
• the macrocyclic lactones e.g., avermectins and milbemycins
• delta-toxins from Bacillus thuringiensis Bt
• Bt Bacillus thuringiensis
• macrocyclic lactones e.g., avermectins and milbemycins
• Bt delta toxins must be ingested to affect their target organ, the brush border of midgut epithelial cells (Marroquin et al. (2000) Genetics. 155(4):1693-1699). Consequently they are not anticipated to be effective against the dispersal, non-feeding, juvenile stages of plant parasitic nematodes in the field. Because juvenile stages only commence feeding when a susceptible host has been infected, nematicides may need to penetrate the plant cuticle to be effective. Transarticular uptake of a 65-130 kDa protein - the size of typical Bt delta toxins - is unlikely. Furthermore, soil mobility is expected to be relatively poor.
• Fatty acids are a class of natural compounds that have been investigated as alternatives to the toxic, non-specific organophosphate, carbamate and fumigant pesticides (Stadler et al. (1994) Planta Medica 60(2):128-132; US Pat. Nos. 5,192,546; 5,346,698; 5,674,897; 5,698,592; 6,124,359). It has been suggested that fatty acids derive their pesticidal effects by adversely interfering with the nematode cuticle or hypodermis via a detergent (solubilization) effect, or through direct interaction of the fatty acids and the lipophilic regions of target plasma membranes (Davis et al.
• fatty acids are used in a variety of pesticidal applications including as herbicides (e.g., SCYTHE by Dow Agrosciences is the C9 saturated fatty acid pelargonic acid), bactericides and fungicides (US Pat. Nos. 4,771,571; 5,246,716) and insecticides (e.g., SAFER INSECTICIDAL SOAP by Safer, Inc.).
• herbicides e.g., SCYTHE by Dow Agrosciences is the C9 saturated fatty acid pelargonic acid
• bactericides and fungicides US Pat. Nos. 4,771,571; 5,246,716
• insecticides e.g., SAFER INSECTICIDAL SOAP by Safer, Inc.
• Ricinoleic acid the major component of castor oil, has been shown to have an inhibitory effect on water and electrolyte absorption using everted hamster jejunal and ileal segments (Gaginella et al. (1975) J Pharmacol Exp Ther 195(2):355-61) and to be cytotoxic to isolated intestinal epithelial cells (Gaginella et al. (1977) J Pharmacol Exp Ther 201(l):259-66). These features are likely the source of the laxative properties of castor oil which is given as a purgative in humans and livestock (e.g., castor oil is a component of some de- worming protocols because of its laxative properties). In contrast, the methyl ester of ricinoleic acid is ineffective at suppressing water absorption in the hamster model (Gaginella et al. (1975) J Pharmacol Exp Ther 195(2):355-61).
• Castor beans are plowed under as a green manure before a seed crop is set.
• a significant drawback of the castor plant is that the seed contains toxic compounds (such as ricin) that can kill humans, pets, and livestock and is also highly allergenic.
• toxic compounds such as ricin
• the active principle(s) for plant nematicidal activity has not been discovered and it remains difficult to derive commercially successful nematicidal products from these resistant plants or to transfer the resistance to crops of agronomical importance such as soybeans and cotton.
• nematodes Genetic resistance to certain nematodes is available in some commercial cultivars (e.g., soybeans), but these are restricted in number and the availability of cultivars with both desirable agronomic features and resistance is limited.
• the production of nematode resistant commercial varieties by conventional plant breeding based on genetic recombination through sexual crosses is a slow process and is often further hampered by a lack of appropriate germplasm.
• Nematode parasites of vertebrates include gut roundworms, hookworms, pinworms, whipworms, and filarial worms. They can be transmitted in a variety of ways, including by water contamination, skin penetration, biting insects, or by ingestion of contaminated food.
• hi domesticated animals, nematode control or "de-worming" is essential to the economic viability of livestock producers and is a necessary part of veterinary care of companion animals.
• Parasitic nematodes cause mortality in animals (e.g., heartworm in dogs and cats) and morbidity as a result of the parasites' inhibiting the ability of the infected animal to absorb nutrients.
• the parasite-induced nutrient deficiency leads to disease and stunted growth in livestock and companion animals. For instance, in cattle and dairy herds, a single untreated infection with the brown stomach worm can permanently restrict an animal's ability to convert feed into muscle mass or milk.
• Two factors contribute to the need for novel anthelmintics and vaccines to control animal parasitic nematodes.
• Some of the more prevalent species of parasitic nematodes of livestock are building resistance to the anthelmintic drugs available currently, meaning that these products will eventually lose their efficacy. These developments are not surprising because few effective anthelmintic drugs are available and most have been used continuously.
• Some parasitic species have developed resistance to most of the anthelmintics (Geents et al.
• hookworms examples include hookworms, filarial worms, and pinworms.
• Hookworms (1.3 billion infections) are the major cause of anemia in millions of children, resulting in growth retardation and impaired cognitive development.
• Filarial worms invade the lymphatics, resulting in permanently swollen and deformed limbs (elephantiasis), and the eyes, causing African river blindness.
• the large gut roundworm Ascaris lumbricoides infects more than one billion people worldwide and causes malnutrition and obstructive bowel disease.
• pinworms are common and often transmitted through children in daycare.
• nematodes can still deprive the host of valuable nutrients and increase the ability of other organisms to establish secondary infections. In some cases, infections can cause debilitating illnesses and can result in anemia, diarrhea, dehydration, loss of appetite, or death.
• C. elegans is a small free-living bacteriovorous nematode that for many years has served as an important model system for multicellular animals (Burglin (1998) Int. J. Parasitol. 28(3):395-411). The genome of C. elegans has been completely sequenced and the nematode shares many general developmental and basic cellular processes with vertebrates (Ruvkin et al. (1998) Science 282:2033-41). This, together with its short generation time and ease of culturing, has made it a model system of choice for higher eukaryotes (Aboobaker et al. (2000) Ann. Med. 32:23-30).
• C. elegans serves as a good model system for vertebrates, it is an even better model for study of parasitic nematodes, as C. elegans and other nematodes share unique biological processes not found in vertebrates.
• nematodes produce and use chitin, have gap junctions comprised of innexin rather than connexin and contain glutamate-gated chloride channels rather than glycine-gated chloride channels (Bargmann (1998) Science 282:2028-33).
• the latter property is of particular relevance given that the avermectin class of drugs is thought to act at glutamate-gated chloride receptors and is highly selective for invertebrates (Martin (1997) Vet. J. 154:11-34).
• a subset of the genes involved in nematode-specii ⁇ c processes will be conserved in nematodes and absent or significantly diverged from homologues in other phyla. In other words, it is expected that at least some of the genes associated with functions unique to nematodes will have restricted phylogenetic distributions.
• the completion of the C. elegans genome project and the growing database of expressed sequence tags (ESTs) from numerous nematodes facilitate identification of these "nematode-specific" genes.
• conserved genes involved in nematode- specific processes are expected to retain the same or very similar functions in different nematodes. This functional equivalence has been demonstrated in some cases by transforming C.
• RNA interference RNA interference
• Treatment of a nematode with double-stranded RNA of a selected gene can destroy expressed sequences corresponding to the selected gene thus reducing expression of the corresponding protein.
• By preventing the translation of specific proteins, their functional significance and contribution to the fitness of the nematode can be assessed. Determination of essential genes and their corresponding proteins using C. elegans as a model system will assist in the rational design of anti-parasitic nematode control products.
• the phylum apicomplexa contains several important pathogens including Plasmodium species (i.e. malaria), Eimeria species, Neospora, Babesia, Theileria, Cryptosporidium and Toxoplasma species.
• compositions and processes for controlling nematodes, apicomplexa and other pathogens are described herein.
• the subject invention comprises the use of certain compounds to control nematodes that infest plants or the situs of plants.
• Nematodes and apicomplexa that parasitize animals can also be controlled using the methods and compounds of this invention.
• Certain of the useful the compounds maybe inhibitors of nematode and/or apicomplexa phosphoethanolamine JV-methyltransferase and related enzymes (also referred to herein as nematode PEAMT enzymes).
• Useful compounds include N-substituted ethanolamine analogs such as 2- (diisopropylamino)ethanol, 2-(tert-butylam ⁇ io)ethanol and N-(2-hydroxyethyl)aniline and C-substituted ethanolamine analogs such as D-phenylalaninol.
• Useful compounds also include N- or C-substituted derivatives of phosphoethanolamine (phosphate analogs), derivatives of 2-aminoethylphosphonic acid and 3-aminopropylphosphonic acid (phosphonate analogs), and taurine derivatives (sulfonate analogs).
• ethanolamine analogs examples include 2-arnino-3-phenylpropyl phosphonic acid (phosphonate analog) and N-phenyltaurine (sulfonate analog).
• useful compounds include sulfonate esters, phosphonate diesters and phosphate diesters such as alkyl, phenyl or alkoxyalkyl esters which can be activated to the corresponding sulfonic acid, phosphate or phosphonate compound in vivo.
• Other useful analogs have non-ionizable groups in place of the phosphate moiety.
• Such compounds include alkyl compounds (e.g., N- ethylaniline, 4-(N-ethyl-N-methylamino)azobenzene, 4-(dimethylamino)azobenzene, 4- (N-methylamino)azobenzene), sulfonyl fluorides (e.g., 2-(4-phenylazo-phenylarnino)- ethanesulfonyl fluoride, 2-[4-(4-dimethylamino-phenylazo)-phenylamino]- ethanesulfonyl fluoride), sulfonamides (e.g., 2-(4-phenylazo-phenylamino)- ethanesulfonamide, 2-[4-(4-dimethylamino-phenylazo)-phenylammo]- ethanesulfonamide), trifluoromethyl sulfonamides (e.g.,
• Certain methylene (CH 2 ) carbons may or may not have their hydrogens substituted, e.g., with fluorine (e.g., fluorinated phosphonate).
• Certain embodiments exclude the natural substrates or products of ethanolamine methyltransferases and phosphoethanolamine JV-rnethyltransferases such as ethanolamine (EA) or phosphoethanolamine (pEA), monomethylethanolamine (MME) or phosphomonomethylethanolamine (pMME), dimethylethanolamine (DME) or phosphodimethylethanolamine (pDME), choline (Cho) or phosphocholine (pCho) and their corresponding phosphate esters.
• Ethanolamine analogs e.g., alcohols, phosphates, phosphonates, flurophosphonates sulfonates, sulfonyl fluorides, sulfonamides, trifluoromethyl sulfonamides, trifluoromethyl sulfones, phosphate diesters, phosphonate diesters and sulfonate esters
• Ethanolamine analogs e.g., alcohols, phosphates, phosphonates, flurophosphonates sulfonates, sulfonyl fluorides, sulfonamides, trifluoromethyl sulfonamides, trifluoromethyl sulfones, phosphate diesters, phosphonate diesters and sulfonate esters
• a specific inhibitor of a PEAMT are those analogs that inhibit the activity of a nematode phosphoethanolamine N- methyltransferas
• the substrate e.g., pEA
• the product e.g., pMME
• uncharged precursors to the phosphorylated chemicals such as EA and MME capable of in vivo conversion to the corresponding phosphobases (e.g., pEA or pMME) can also be used.
• a phosphoethanolamine N-methyltransferase also referred to herein as a PEAMT
• the inhibitor, the substrate (or uncharged substrate precursor) and product (or uncharged product precursor) of the PEAMT are present in equal concentrations.
• Useful compounds include those that inhibit the expression of a PEAMT at the level of transcription or translation. Other useful compounds impair the modification of a PEAMT resulting in a change in the activity or localization of the methyltransferase.
• Some compounds are relatively selective inhibitors of one or more nematode or apicomplexa PEAMT polypeptides relative to one or more plant PEAMT-like polypeptides or plant or animal phosphatidylethanolamine N-methyltransferase polypeptides.
• the compounds can have a Kj for a nematode PEAMT that is 10-fold, 100-fold, 1, 000-fold or more lower than for plant or animal methyltransferase-like polypeptides, e.g., a host plant or host animal of the parasite.
• Other compounds are relatively non-selective inhibitors or completely non-selective inhibitors.
• a method of treating a disorder e.g., an infection
• a nematode e.g., M. incognita, H. glycines, H. contortus, A. suum
• the invention features a method of treating a disorder (e.g., an infection) caused by an apicomplexan, (e.g., a Plasmodium species, Eimeria species, Neospora, Babesia, Theileria, Cryptosporidium or Toxoplasma species) in a subject, e.g., a host animal, or person.
• an apicomplexan e.g., a Plasmodium species, Eimeria species, Neospora, Babesia, Theileria, Cryptosporidium or Toxoplasma species
• the method includes administering to the subject an effective amount of a compound having Formula I, II, Ha, lib, He, lid, HI, IVa, IVb or IVc .
• the compound may be delivered by several means including pre-planting, post-planting and as a feed additive, drench, external application, pill or by injection.
• methods of inhibiting a nematode e.g., M. incognita, H. glycines, H. contortus, A. suum
• an apicomplexan e.g., P. falciparum
• Such methods can include the steps of: (a) providing a nematode or an apicomplexan or other parasite; (b) contacting the nematode, apicomplexan or other parasite with a compound, e.g., a compound having Formula I, II, Ha, lib, He, ⁇ d, HI, rVa, rVb or rVc is provided.
• a compound e.g., a compound having Formula I, II, Ha, lib, He, ⁇ d, HI, rVa, rVb or rVc is provided.
• a pesticidal compound e.g., a compound having Formula I, ⁇ , Ha, lib, Hc, ⁇ d, III, IVa, IVb or IVc is provided.
• Such methods comprise the steps of (a) providing a nematode or apicomplexan or other parasite; (b) contacting the nematode or apicomplexan or other parasite with specific a compound, e.g., a compound having Formula I, ⁇ , Ha, lib, Hc, Hd, III, IVa, IVb or IVc; (c) reducing the viability or fecundity of the nematode or apicomplexan or other parasite.
• a compound e.g., a compound having Formula I, ⁇ , Ha, lib, Hc, Hd, III, IVa, IVb or IVc
• Also described is a method for reducing the viability, growth, or fecundity of a nematode or an apicomplexan or other parasite comprising exposing the nematode or an apicomplexan or other parasite to a compound having Formula I, II, Ila, lib, Hc, Ed, III, IVa, rVb or rVc and a method of protecting a plant from a nematode infection, the method comprising applying to the plant, to the soil, or to seeds of the plant an compound a compound having Formula Formula I, II, Ha, lib, Hc, Hd, in, IVa, rVb or rVc.
• a method for protecting a vertebrate e.g., a bird or a mammal
• a vertebrate e.g., a bird or a mammal
• the method comprising administering to the vertebrate a compound having Formula I, II, Ha, Hb, Hc, ⁇ d, HI, rVa, IVb or IVc.
• the bird can be a domesticated fowl (e.g., a chicken, turkey, duck, or goose).
• the mammal can be a domesticated animal, e.g., a companion animal (e.g., a cat, dog, horse or rabbit) or livestock (e.g., a cow, sheep, pig, goat, alpaca or llama) or can be a human.
• livestock e.g., a cow, sheep, pig, goat, alpaca or llama
• the methods described hereon are particularly valuable for the control nematodes attacking the roots of desired crop plants, ornamental plants, and turf grasses.
• the desired crop plants can be, for example, soybeans, cotton, corn, tobacco, wheat, strawberries, tomatoes, banana, sugar cane, sugar beet, potatoes, or citrus.
• a composition e.g., a pesticidal composition, comprising: an effective amount of a compound or a mixture of compounds having any of the formula described herein, for example the compounds shown below.
• Useful compounds include those having Formula (I) or a salt thereof,
• R 1 and R 2 are independently selected from H, unsubstituted or substituted alkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 alkyl), oxo, -COR 7 , cyclyl, cyclylalkyl, heterocyclyl, heterocylylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; or R and R 2 , taken together with the nitrogen to which they are attached, form a heterocyclic ring;
• R 3 and R 4 are independently selected from H, substituted or unsubstituted alkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 alkyl) , aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
• X is H, -OH, -OPO 3 (R 5 ) 2 , -PO 3 (R 5 ) 2 , -CH 2 PO 3 H 2 , -SO 3 R 5 , -SO 2 F, -SO 2 NH 2 , - SO 2 R 5 ; -CO 2 H, -CO 2 R 5 , -OC(O)NR 6 , or -OCO 2 R 5 ;
• R 5 and R 6 are independently selected from H, substituted or unsubstituted alkyl; (e.g., C 1 to C 1O or C 1 to C 5 or C 1 to C 3 alkyl), or haloalkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 haloalkyl); and each R 7 is independently H, substituted or unsubstituted alkyl (e.g., C 1 to C 10 or Ci to C 5 or Ci to C 3 alkyl), hydroxy, or alkoxy.
• the compound of Formula (I) includes one or more of the following features.
• Each of R 1 and R 2 can be independently H, alkyl, aryl, or arylalkyl.
• each of R and R 2 can be independently H, methyl, isopropyl, phenyl, or benzyl.
• Each of R 3 and R 4 can be independently H, alkyl, or arylalkyl.
• Each of R 3 and R 4 can be independently H.
• R 3 can be benzyl and R 4 can be H.
• X can be H, - OH, -OPO 3 H 2 , -PO 3 H 2 , -CH 2 PO 3 H 2 , -SO 3 H, or SO 2 F.
• each of R 1 and R 2 can be independently H, alkyl, aryl, or arylalkyl; each R 3 and R 4 can be independently H, alkyl, or arylalkyl; and X is H, -OH, -OPO 3 H 2 , -PO 3 H 2 , -CH 2 PO 3 H 2 , -SO 3 H, or SO 2 F.
• each of R 1 and R 2 can be independently H, alkyl, aryl, or arylalkyl.
• Each of R 1 and R 2 can be independently H, methyl, isopropyl, phenyl, or benzyl.
• Each of R 3 and R 4 can be independently H.
• R 3 can be benzyl and R 4 can be H.
• the compound of Formula (I) is one of 2-Amino-ethanol, 2-
• the compound of Formula (I) has a molecular weight of less than 500 Daltons.
• the compound of Formula (I) includes at least one I or Br.
• Useful compounds also include a compound of Formula (Ha) or a salt thereof,
• R 11 and R 12 are independently selected from H, hydroxy, oxo, substituted or unsubstituted alkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 alkyl), sulfonyl, aminosulfonylalkyl, halosulfonylalkyl, haloalkyl (e.g., C 1 to Ci 0 or Ci to C 5 or C 1 to C 3 haloalkyl) or C(O)R 17 ; or R 11 and R 12 , together with the nitrogen to which they are attached, form a heterocyclyl or heteroaryl ring; or one of R 11 or R 12 , together with R 13 and the nitrogen to which is it attached, form a heterocyclyl or heteroaryl ring; each R and R 12 can optionally be independently be substituted by one or more R 15 ; each R 13 is independently halo, C(O)R 17 , hydroxy, alkoxy,
• Cx is phenyl, pyridyl, pyrimidyl, furanyl, pyranyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazinyl, isooxazolyl or pyrazolyl;
• Cy is phenyl, pyridyl, pyrimidyl, furanyl, pyranyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazinyl, isooxazolyl or pyrazolyl;
• the compound of formula (Ha) can include one or more of the following features.
• Cx or Cy can be pyridyl.
• Cx or Cy can be phenyl.
• Cx can be phenyl and Cy can be phenyl or pyridyl.
• Cx is phenyl and NR R is positioned para to Y.
• R 11 is H, alkyl, or oxo; or when taken together with R 12 and the nitrogen to which it is attached, forms a heterocyclyl or heteroaryl ring; or when taken together with R 13 and the nitrogen to which is it attached, form a heterocyclyl or heteroaryl ring; and R 12 is H, alkyl, hydroxy, halosulfonylalkyl, -C(O)R 17 , or when taken together with R 12 and the nitrogen to which it is attached, forms a heterocyclyl or heteroaryl ring; or when taken together with R and the nitrogen to which is it attached, form a heterocyclyl or heteroaryl ring.
• R 11 can be H and R 12 can be fluorosulfonylalkyl.
• R 12 can be flourosulfonylethyl.
• R 12 can be -C(O)CH 3 .
• R 11 taken together with R 12 and the nitrogen to which they are attached can form a heterocyclyl.
• R 11 taken together with R 13 and the nitrogen to which it is attached can form a heterocyclyl.
• R 11 and R 1 together with the nitrogen to which they are attached can be nitro.
• Each R and R can independently be H or alkyl or haloalkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 haloalkyl).
• R 11 can be H and R 12 can be methyl or ethyl or trifluoromethyl.
• R 11 and R 12 can both be alkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 alkyl) or haloalkyl, (e.g., C 1 to Ci 0 or C 1 to C 5 or C 1 to C 3 haloalkyl) for example, R 11 can be methyl or ethyl or trifluoromethyl and R 12 can be methyl or ethyl or trifluoromethyl.
• m is 0.
• n is 0. hi some instances, n is 1 ; and R 14 is halo, alkyl, hydroxy, alkoxy, amino, or nitro.
• R 13 include: COOH, SO 3 H, CF 3 , COCF 3 , CCl 3 , CBr 3 , CI 3 , N(CF 3 ) 2 , SO 2 CF 3 , SO 2 CH 3 , SO 2 CHF 2 , SO 2 CN, SO 2 N(CH3) 2 , SO 2 NHCH 3 , SO 2 NH 2 , and SO 2 C 6 H 5 .
• R 14 include COOH, SO 3 H, CF 3 , COCF 3 , CCl 3 , CBr 3 , CI 3 , N(CF 3 ) 2 , SO 2 CF 3 , SO 2 CH 3 , SO 2 CHF 2 , SO 2 CN, SO 2 N(OB) 2 , SO 2 NHCH 3 , SO 2 NH 2 , and SO 2 C 6 H 5
• R 11 is H, alkyl, or fluoroalkyl (e.g., C 1 to C 10 or C 1 to C 5 or Ci to C 3 fluoroalkyl);
• R 12 is H, alkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 alkyl), or fluoroalkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 fluoroalkyl),
• R 13 is alkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 alkyl), hydroxy, fluoroalkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 fluoroalkyl), aminofluoroalkyl, sulfonyl, or halo;
• R 14 is halo, alkyl, fluoroalkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to
• R 11 and R 12 are independently selected from H, hydroxy, oxo, substituted or unsubstituted alkyl (e.g., Ci to C 10 or C 1 to C 5 or Ci to C 3 alkyl), sulfonyl, aminosulfonylalkyl, halosulfonylalkyl, haloalkyl (e.g., Ci to C 10 or C 1 to C 5 or C 1 to C 3 haloalkyl), or C(O)R 17 ; or R 11 and R 12 , together with the nitrogen to which they are attached, form a heterocyclyl or heteroaryl ring; or one of R 11 or R 12 , together with R and the nitrogen to which is it attached, form a heterocyclyl or heteroaryl ring; each R and R 12 can independently be substituted by one or more R 15 (e.g., 1-4 R 15 ); each R 13 is independently halo, C(O)R 17 , hydroxy, alkoxy, substituted or un
• Cy is phenyl or pyridyl.
• R 11 and R 12 are CF 3 .
• Specific examples of R 13 include COOH, SO 3 H, CF 3 , COCF 3 , CCl 3 , CBr 3 , CI 3 , N(CF 3 ) 2 , SO 2 CF 3 , SO 2 CH 3 , SO 2 CHF 2 , SO 2 CN, SO 2 N(OB) 2 , SO 2 NHCH 3 , SO 2 NH 2 , SO 2 C 6 H 5 .
• R 14 include COOH, SO 3 H, CF 3 , COCF 3 , CCl 3 , CBr 3 , CI 3 , N(CF 3 ) 2 , SO 2 CF 3 , SO 2 CH 3 , SO 2 CHF 2 , SO 2 CN, SO 2 N(OB) 2 , SO 2 NHCH 3 , SO 2 NH 2 , SO 2 C 6 H 5 .
• compounds of Formula (He) or a salt thereof are also useful.
• R 11 and R 12 are independently selected from H, hydroxy, oxo, substituted or unsubstituted alkyl (e.g., C 1 to C 10, or C 1 to C 5 or C 1 to C 3 alkyl or methyl), sulfonyl, aminosulfonylalkyl, halosulfonylalkyl, haloalkyl (e.g., C 1 to C 10 or Ci to C 5 or C 1 to C 3 haloalkyl), or -C(O)R 17 ; or R 11 and R 12 , together with the nitrogen to which they are attached, form a heterocyclyl or heteroaryl ring; or one of R 11 or R 12 , together with R and the nitrogen to which is it attached, form a heterocyclyl or heteroaryl ring; each R and R 12 can independently be substituted by one or more R 15 ; each R 13 is independently halo, C(O)R 17 , hydroxy, alkoxy (e.g., C 1
• Cy is phenyl or pyridyl, for example Cy is phenyl.
• R 11 and R 12 are CF 3 .
• Specific examples of R 13 include COOH, SO 3 H, CF 3 , COCF 3 , CCl 3 , CBr 3 , CI 3 ,
• R 14 include COOH, SO 3 H, CF 3 , COCF 3 , CCl 3 , CBr 3 , CI 3 , N(CF 3 ) 2 , SO 2 CF 3 , SO 2 CH 3 , SO 2 CHF 2 , SO 2 CN, SO 2 N(OB) 2 , SO 2 NHCH 3 , SO 2 NH 2 , SO 2 C 6 H 5 .
• Useful compound also include a compound of Formula (Hd) or a salt thereof,
• R 11 and R 12 are independently selected from H, hydroxy, oxo, substituted or unsubstituted alkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 alkyl), sulfonyl, aminosulfonylalkyl, halosulfonylalkyl, haloalkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 haloalkyl), C(O)R 17 or R 11 and R 12 , together with the nitrogen to which they are attached, form a heterocyclyl or heteroaryl ring; or one of R 11 or R 12 , together with R and the nitrogen to which is it attached, form a heterocycleyl or heteroaryl ring; each R 11 and R 12 can independently be substituted by one or more R 15 ; each R 13 is independently halo, C(O)R 17 , hydroxy, alkoxy, substituted or unsubstituted alkyl (
• R 11 and R 12 are CF 3 .
• the invention includes one of the following compounds: Ethyl- methyl-(4-phenylazo-phenyl)-amine, 2-[4-(4-Dimethylamino-phenylazo)- phenylamino]-ethanesulfonyl fluoride, 2-(4-Phenylazo-phenylamino)-ethanesulfonic acid amide, 2-(4-Phenylazo-phenylamino)-ethanesulfonyl fluoride, Dimethyl-(4- phenylazo-phenyl)-amine, Dimethyl-(3 -methyl-4-phenylazo-phenyl)-amine, [4-(4- Bromo-phenylazo)-phenyl]-ethyl-amme, Ethyl-(4-p-tolylazo-phenyl)-amine, Dimethyl- (4-p-tolylazo-phenyl)-amine
• R 21 and R 22 are independently selected from H, substituted or unsubstituted alkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 alkyl), haloalkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 haloalkyl), C(O)R 26 , S(O) 2 R 27 , PO 3 H 2 , aryl, or arylalkyl; each of which is optionally substituted with 1-4 R 24 ; or R 21 and R 22 , together with the nitrogen to which they are attached, form a heterocyclyl, which is optionally substituted with 1-4 R 24 ; each R 23 is independently nitro, nitroso, amino, halo, substituted or unsubstituted alkyl (e.g., C 1 to C 10 or C 1 to C 5 or Ci to C 3 alkyl), haloalkyl (e.g., C 1 to Ci
• each R 21 and R 22 can be independently H or alkyl, for example, R can be H and R 22 can be alkyl; R 21 can be H and R 22 can be ethyl; or R 22 can be methyl or ethyl. In some instances, p is 1 or 2.
• Each R 23 can be independently halo, alkyl, hydroxy, alkoxy, nitro, nitroso, or amino. In some aspects, each R 21 and R 22 is H or alkyl; each R 23 is independently halo, alkyl, hydroxy, alkoxy, nitro, nitroso, or amino; and p is 0-2.
• each R 21 and R 22 is H, methyl, or ethyl.
• the compound of Formula (III) has a molecular weight of less than 500 Daltons. hi some instances, the compound of Formula (III) includes at least one I or Br.
• the compound of Formula (III) is one of the following compounds: 2-Phenylamino-ethanesulfonyl fluoride, N-ethylaniline, Methyl-phenyl- amine, Dimethyl-phenyl-amine, N,N,N',N'-Tetramethyl-benzene-l,4-diamine, Methyl- (4-nitro-phenyl)-amine, Ethyl-(4-nitro-phenyl)-amine, Methyl-(2-nitro-phenyl)-amine, Dimethyl-(4-nitro-phenyl)-amine, (2-Chloro-4-nitro-phenyl)-dimethyl-amine, (2-
• Chloro-phenyl)-dimethyl-amine Ethyl-(2-methyl-5-nitro-phenyl)-amine, Nl-Methyl-4- nitro-benzene-l,2-diamine, Nl-Ethyl-4-nitro-benzene-l,2-diamine, (2,4-Dinitro- phenyi)-methyl-amine, (2,4-Dinitro-phenyl)-ethyl-amine, Methyl-(4-nitroso-phenyl)- amine, N,N-Dimethyl-benzene-l,4-diamine, (4-Methoxy-phenyl)-methyl-amine, N- Methyl-benzene- 1,2-diamine, (2-Bromo-4-methyl-phenyl)-ethyl-amine, Methyl-o- tolyl-amine, Dimethyl-o-tolyl-amine, Dimethyl-m-tolyl-amine, Dimethyl-p-tolyl-amine
• each R 30 is independently hydrogen, C(O)R 33 , halo, hydroxy, alkoxy, amino, aminohaloalkyl, haloalkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 haloalkyl), sulfonyl, substituted or unsubstituted alkyl (e.g., Ci to Ci 0 or Ci to C 5 or C 1 to C 3 alkyl), nitro, aryl, heteroaryl or cyclyl; each of which is optionally substituted with 1-4 R ; specific examples of R 30 include COOH, SO 3 H, CF 3 , COCF 3 , CCl 3 , CBr 3 , CI 3 , N(CF 3 ) 2 , SO 2 CF 3 , SO 2 CH 3 , SO 2 CHF 2 , SO 2 CN, SO 2 N(CH3) 2 , SO 2 NHCH 3 , SO 2 NH 2 , SO 2 NH 2 , SO 2
• Cx is phenyl, pyridyl, pyrimidyl, furanyl, pyranyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazinyl, isooxazolyl or pyrazolyl;
• Cy is phenyl, pyridyl, pyrimidyl, furanyl, pyranyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazinyl, isooxazolyl or pyrazolyl
• the compound of Formula (IVa) can include one or more of the following features.
• Cx or Cy can be pyridyl.
• Cx or Cy can be phenyl.
• Cx can be phenyl and Cy can be phenyl or pyridyl. Both Cx and Cy are phenyl.
• Cx is phenyl, n is 1, and C 30 is positioned para to Y.
• both Cx and Cy are phenyl, both n and m are 1, and both C30 and C 31 are positioned para to Y.
• n O.
• n is 1; and R 30 is halo, haloalkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 haloalkyl), alkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 alkyl), aminohaloalkyl, sulfonyl, hydroxy, alkoxy, amino, or nitro.
• haloalkyl e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 haloalkyl
• alkyl e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 alkyl
• aminohaloalkyl e.g., aminohaloalkyl, sulfonyl, hydroxy, alkoxy, amino, or nitro.
• Useful compounds include those having Formula (IVb) and salts thereof.
• each R >3*0 ⁇ . is independently hydrogen, C(O)R 33 , halo, hydroxy, alkoxy, amino, aminohaloalkyl, haloalkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 haloalkyl), sulfonyl, substituted or unsubstituted alkyl (e.g., C 1 to C 10 or Ci to C 5 or Ci to C 3 alkyl), nitro, aryl, heteroaryl, cyclyl; each of which is optionally substituted with 1-4 R 32 ; specific examples of R 30 include COOH, SO 3 H, CF 3 , COCF 3 , CCl 3 , CBr 3 , CI 3 , N(CF 3 ) 2 , SO 2 CF 3 , SO 2 CH 3 , SO 2 CHF 2 , SO 2 CN, SO 2 N(CH3) 2 , SO 2 NHCH 3 , SO 2
• Cy is phenyl, pyridyl, pyrimidyl, furanyl, pyranyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazinyl, isooxazolyl or pyrazolyl;
• the compound of Formula (IVb) can include one or more of the following features.
• Cy can be phenyl or pyridyl. Cy can phenyl, hi some instances, n is 1 , and C 30 is positioned para to Y. In some instances Cy is phenyl, both n and m are 1 , and both C 30 and C 31 are positioned para to Y. hi some instances, m is 1 ; and R is alkyl, haloalkyl, aminohaloalkyl, sulfonyl, hydroxy, halo, for example, R 31 is methyl, trifluoromethyl, N(CF 3 ) 2 , sulfonamide, hydroxy, or chloro. In some instances, n is 0.
• n 1 ; and R 30 is halo, haloalkyl, alkyl, aminohaloalkyl, sulfonyl, hydroxy, alkoxy, amino, or nitro.
• Useful compounds include those having Formula (IVc) and salts thereof.
• each R 30 is independently hydrogen, C(O)R 33 , halo, hydroxy, alkoxy, amino, aminohaloalkyl, haloalkyl (e.g., Ci to C 10 or C 1 to C 5 or C 1 to C 3 haloalkyl), sulfonyl, substituted or unsubstituted alkyl (e.g., C 1 to C 10 or C 1 to C 5 or C 1 to C 3 alkyl), nitro, aryl, heteroaryl, cyclyl; each of which is optionally independently substituted with 1-4 R 32 ; specific examples of R 30 include COOH 5 SO 3 H, CF 3 , COCF 3 , CCl 3 , CBr 3 , CI 3 , N(CF 3 ) 2 , SO 2 CF 3 , SO 2 CH 3 , SO 2 CHF 2 , SO 2 CN, SO 2 N(CH3) 2 , SO 2 NHCH 3 , SO 2 NH 2 , SO 2 C 6 H
• Cy is phenyl, pyridyl, pyrimidyl, furanyl, pyranyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazinyl, isooxazolyl or pyrazolyl;
• the compound of Formula (IVc) can include one or more of the following features.
• n is i, and C 30 is positioned para to Y.
• both n and m are 1
• both C 30 and C 31 are positioned para to Y.
• m is 1; and R is substituted or unsubstituted alkyl, haloalkyl, aminohaloalkyl, sulfonyl, hydroxy, halo, for example, R 31 is methyl, trifluoromethyl, N(CH 3 ) 2 , sulfonamide, hydroxy, or chloro.
• n is O.
• n 1 ; and R 30 is halo, haloalkyl, alkyl, aminohaloalkyl, sulfonyl, hydroxy, alkoxy, amino, or nitro.
• R 30 and R 31 are not Cl, Br, Fl, -OH, -CH 3 or • OCH 3 .
• Y For Formulas Ha, lib, IVa, IVb and IVc, specific examples of Y include:
• a pesticidal composition including an effective amount of any of the formulae described herein is described, for example one of the following formulas:
• the pesticidal composition further includes an aqueous surfactant. In some apsects, the pesticidal composition further includes a permeation enhancer. In some aspects, the pesticidal composition further includes a co-solvent.
• the pesticidal composition further includes a pesticide (e.g., insecticide or fungicide) such as avermectins (e.g., ivermectin), milbemycin, aldicarb, oxamyl, fenamiphos, fosthiazate, metam sodium, etridiazole, penta-chloro-nitrobenzene (PCNB), flutolanil, metalaxyl, mefonoxam, and fosetyl-al.
• a pesticide e.g., insecticide or fungicide
• avermectins e.g., ivermectin
• milbemycin aldicarb
• oxamyl fenamiphos
• fosthiazate fosthiazate
• metam sodium etridiazole
• PCNB penta-chloro-nitrobenzene
• Useful fungicides include, but are not limited to, myclobutanil, azoxystrobin, chlorothalonil, propiconazole, tebuconazole and pyraclostrobin
• a method for control of unwanted nematodes or apicomplexan parasites including administering to vertebrates, plants, seeds or soil a pesticidal composition including a compound of any of the formulae described herein in any of the pesticidal compositions described herein.
• the method features one or more of the following features.
• the nematode infects plants and the pesticidal composition is applied to the soil or to plants.
• the pesticidal composition is applied to soil before planting.
• the pesticidal composition is applied to soil after planting.
• the pesticidal composition is applied to soil using a drip system.
• the pesticidal composition is applied to soil using a drench system.
• the pesticidal composition is applied to plant roots or plant foliage (e.g., leaves, stems).
• the pesticidal composition is applied to seeds.
• the nematode or apicomplexan parasite infects a vertebrate.
• the pesticidal composition is administered to non-human vertebrate.
• the pesticidal composition is administered to a human.
• the pesticidal composition is formulated as a drench to be administered to a non-human animal.
• the pesticidal composition is formulated as an orally administered drug.
• the pesticidal composition is formulated as an injectable drug.
• a pesticidal feed for a non-human vertebrate including:
• a pesticidal composition including a pesticidal composition described herein.
• the feed has been treated to reduce choline content.
• the feed is selected from the group consisting of: soy, wheat, corn, sorghum, millet, alfalfa, clover, and rye.
• halo or halogen refers to any radical of fluorine, chlorine, bromine or iodine.
• alkyl refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms.
• C 1 -Ci 2 alkyl indicates that the group may have from 1 to 12 (inclusive) carbon atoms in it, e.g., 1 to 3, 1 to 4, 1 to 5, 1 to 6, 2 to 3, 2 to 4, 2 to 3, and 2 to 6, etc.
• alkyl include but are not limited to methyl, ethyl, propyl, isoproyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptly, etc.
• haloalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a halogen, and includes alkyl moieties in which all hydrogens have been replaced by a halogen (e.g., perfluoroalkyl).
• arylalkyl or aralkyl refer to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group (e.g, a C 6 aryl group).
• Aralkyl includes groups in which more than one hydrogen atom has been replaced by an aryl group.
• arylalkyl or “aralkyl” include benzyl, 9-fluorenyl, benzhydryl, and trityl groups.
• haloalkyl refers to an alkyl chain where some of the hydrogens have been replaced by a halogen (e.g, F or Cl).
• cyclyl refers to a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons.
• Examples of cyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
• alkenyl refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms (e.g., 2 to 3, 2 to 4, 2 to 5, 2 to 6, 3 to 4, 3 to 5, 3 to 6 or 2 to 8 carbon ataoms) and having one or more double bonds.
• alkenyl groups include, but are not limited to, allyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups.
• One of the double bond carbons may optionally be the point of attachment of the alkenyl substituent.
• alkynyl refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms (e.g., 2 to 3, 2 to 4, 2 to 5, 2 to 6, 3 to 4, 3 to 5, 3 to 6 or 2 to 8 carbon ataoms and characterized in having one or more triple bonds.
• alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl.
• One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.
• alkoxy refers to an -O-alkyl radical.
• the alkyl radical can include from 1 to 12 (inclusive) carbon atoms in it, e.g., 1 to 3, 1 to 4, 1 to 5, 1 to 6, 2 to 3, 2 to 4, 2 to 3, and 2 to 6, etc.
• alkoxy radical inlcude e.g., methoxy, ethoxy, butoxy, etc.
• aryl refers to an aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system, having, for example, from 6 to 10 ring carbon atoms, and having at least one aromatic ring, wherein any ring atom capable of substitution can be substituted by a substituent.
• aryl moieties include, but are not limited to, phenyl, naphthyl, and anthracenyl.
• heteroaryl refers to a monocyclic, bi- or tricyclic aromatic ring system (only one ring need to be aromatic) having from 5 to 14, preferably 5 to 10 ring atoms such as 5, 6, 7, 8, 9 or 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, sulfur, oxygen and selenium as part of the ring system.
• heteroaryloxy refers to a heteroaryl group bonded to an oxygen atom.
• heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline (i e 2,3-dihydroindole), isoindoline (i.e.
• 1,3- dihydroisoindole 1,3- dihydroisoindole), benzothiophene, benzofuran, isobenzofuran, benzoxazole, 2,1,3- benzoxadiazole, benzopyrazole; benzothiazole, 2,1,3-benzothiazole, 2,1,3- benzoselenadiazole, benzimidazole, indazole, benzodioxane, indane, 1,2,3,4- tetrahydroquinoline, 3,4-dihydro-2H-l,4-benzoxazine, 1,5-naphthyridine, 1,8- naphthyridine, pyrido[3,2-b]thiophene, tetralin, methylenedioxyindole, 2,3- dihydrobensofuran, 2,3-dihydrobensotiofen, 1,3-benzoxathiole, acridine, fenazine
• heterocyclyl refers to a monocyclic, bi- or tricyclic non-aromatic (saturated or non-saturated) ring system having from 3 to 14, preferably 5 to 10 ring atoms such as 5, 6, 7, 8, 9 or 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, sulfur, oxygen and selenium as part of the ring system.
• substituted refers to a group “substituted” on an alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, aryl, or heteroaryl group at any atom of that group. Any atom can be substituted.
• Suitable substituents include, without limitation, alkyl, cycloalkyl, haloalkyl (e.g., perfluoroalkyl), aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl, alkoxy, haloalkoxy (perfluoroalkoxy), halo, hydroxy, carboxy, carboxylate, cyano, nitro, amino, alkyl aminosulfonate, sulfonate, sulfate, phosphate, methylenedioxy, ethylenedioxy, oxo, thioxo, imino (alkyl, aryl, aralkyl), S(O) n alkyl (where n is 0-2), S(O) n aryl (where n is 0-2), S(O) n heteroaryl (where n is
• compositions can also include one or more nematicides such as an avermectin (e.g., ivermectin), milbemycin, aldicarb, oxamyl, fenamiphos, fosthiazate or metam sodium.
• avermectin e.g., ivermectin
• milbemycin e.g., ivermectin
• aldicarb oxamyl
• fenamiphos fosthiazate or metam sodium
• the composition may also include insecticides (e.g., cinnamaldehyde, sucrose octaonate esters, spinosad), herbicides (e.g., trifloxysulfuron, glyphosate, halosulfuron) and other chemicals for disease control (e.g., chitosan).
• insecticides e.g., cinnamaldehyde
• the nematicidal compositions can also include co-solvents, permeation enhancers and aqueous surfactants.
• a permeation enhancer is generally an agent that facilitates the active compounds of the invention, e.g., the ethanolamine analogs of the invention, to pass through cellular membranes.
• a co-solvent i.e., a latent solvent or indirect solvent
• a latent solvent or indirect solvent is an agent that becomes an effective solvent in the presence of an active solvent and can improve the properties of the primary (active) solvent.
• the composition can be produced in concentrated form that includes little or no water.
• the composition can be diluted with water or some other solvent prior to use to treat plants, seeds, soil or vertebrates.
• a nematicidal composition comprising: ethanolamine analogs or mixture of analogs selected from the group consisting of alkyl compounds N- ethylaniline and 4-(N-ethyl-N-methylamino)azobenzene, 4-
• esters include methyl esters, ethyl esters, phenyl esters, alkoxyalkyl (e.g., pivaloyloxymethyl) esters and alkoxyphenyl (e.g., phenoxyethyl) esters.
• the composition further comprises an aqueous surfactant or surfactant mixture selected from the group consisting of: ethyl lactate, Span 20, Span 40, Span 80, Span 85, Tween 20, Tween 40, Tween 80, Tween 85, Triton X 100, Makon 10, Igepal CO 630, Brij 35, Brij 97, Tergitol TMN 6, Dowfax 3B2, Physan and Toximul TA 15 ; the composition further comprises a permeation enhancer (e.g., cyclodextrin); the composition further comprises a co-solvent (e.g., isopropanol, acetone, 1,2-propanediol, a petroleum based-oil (e.g., aromatic 200) or a mineral oil (e.g., paraffin oil)); the composition further comprises a nematicide selected from the group consisting of: avermectins (e.g., iverme
• composition may also comprise insecticides (e.g., cinnamaldehyde, sucrose octaonate esters, spinosad), herbicides (e.g., trifloxysulfuron, glyphosate, halosulfuron) and other chemicals for disease control (e.g., chitosan).
• insecticides e.g., cinnamaldehyde, sucrose octaonate esters, spinosad
• herbicides e.g., trifloxysulfuron, glyphosate, halosulfuron
• other chemicals for disease control e.g., chitosan
• Described herein are methods for controlling nematodes or apicomplexan parasites by administering a compound described herein.
• the methods include administering to vertebrates, plants, seeds or soil a nematicidal composition comprising:
• compositions can also include one or more nematicides such as an avermectin (e.g., ivermectin), milbemycin, aldicarb, oxamyl, fenamiphos, fosthiazate or metam sodium.
• the composition may also include insecticides (e.g., cinnamaldehyde, sucrose octaonate esters, spinosad), herbicides (e.g., trifloxysulfuron, glyphosate, halosulfuron) and other chemicals for disease control (e.g., chitosan).
• the nematicidal compositions can also comprise co-solvents, permeation enchancers and aqueous surfactants.
• Also features is a method for control of unwanted nematodes or apicomplexa comprising administering to vertebrates, plants, seeds or soil a nematicidal composition comprising an effective amount of: (a) a compound selected from the group consisting of alkyl compounds N-ethylaniline and 4-(N-ethyl-N-methylamino)azobenzene, 4- (dimethylamino)azobenzene, 4-(N-methylamino)azobenzene, sulfonyl fluorides 2-(4- phenylazo-phenylamino)-ethanesulfonyl fluoride and 2-[4-(4-dimethylamino- phenylazo)-phenylamino]-ethanesulfonyl fluoride, sulfonamides 2-(4-phenylazo- phenylamino)-ethanesulfonamide and 2-[4-(4-dimethylamino
• esters include methyl esters, ethyl esters, phenyl esters, alkoxyalkyl (e.g., pivaloyloxymethyl) esters and alkoxyphenyl (e.g., phenoxyethyl) esters.
• the composition further comprises an aqueous surfactant or surfactant mixture selected from the group consisting of: ethyl lactate, Span 20, Span 40, Span 80, Span 85, Tween 20, Tween 40, Tween 80, Tween 85, Triton X 100, Makon 10, Igepal CO 630, Brij 35, Brij 97, Tergitol TMN 6, Dowfax 3B2, Physan and Toximul TA 15 ;
• the composition may comprise a permeation enhancer (e.g., a cyclodextrin);
• the composition may comprise a co-solvent (e.g., isopropanol, acetone, 1,2-propanediol, a petroleum based-oil (e.g., aromatic 200) or a mineral oil (e.g., paraffin oil));
• the method includes administering (before, after or in conjunction with the ethanolamine analog) a nematicide selected from the group consisting of
• the invention features a pesticidal feed for a non-human vertebrate comprising: (a) an animal feed; (b) an effective amount of a nematicidal compound or mixtures of compounds having any of the formulae described herein, for example having one of the formula below, formulas:
• the feed can be treated to reduce choline content.
• the feed can be selected from the group consisting of: soy, wheat, corn, sorghum, millet, alfalfa, clover, and rye.
• an agent with "anthelmintic or anthelminthic or antihelminthic activity” is an agent, which when tested, has measurable nematode-killing activity or results in reduced fertility or sterility in the nematodes such that fewer viable or no offspring result, or compromises the ability of the nematode to infect or reproduce in its host, or interferes with the growth or development of a nematode.
• the agent may also display nematode repellant properties, hi the assay, the agent is combined with nematodes, e.g., in a well of microtiter dish, in liquid or solid media or in the soil containing the agent. Staged nematodes are placed on the media.
• An agent with "anthelmintic or anthelminthic or antihelmthic activity" can, for example, reduce the survival time of adult nematodes relative to unexposed similarly staged adults, e.g., by about 20%, 40%, 60%, 80%, or more.
• an agent with "anthelmintic or anthelminthic or antihelminthic activity” may also cause the nematodes to cease replicating, regenerating, and/or producing viable progeny, e.g., by about 20%, 40%, 60%, 80%, or more. The effect may be apparent immediately or in successive generations.
• altering an activity refers to a change in level, either an increase or a decrease in the activity, (e.g., an increase or decrease in the ability of the polypeptide to bind or regulate other polypeptides or molecules) particularly a PEAMT-like activity (e.g., the ability to methylate pEA, pMME or pDME).
• the change can be detected in a qualitative or quantitative observation. If a quantitative observation is made, and if a comprehensive analysis is performed over a plurality of observations, one skilled in the art can apply routine statistical analysis to identify modulations where a level is changed and where the statistical parameter, the p value, is, for example, less than 0.05.
• FIG. 1 is a set of drawings depicting the structures of ethanolamine and its methylated analogs monomethylethanolamine (MME), dimethylethanolamine (DME) and choline chloride (Cho Cl). Also shown are phosphoethanolamine (pEA) a substrate of PEAMTs, two phosphonic analogs of pEA (2-aminoethylphosphonic acid and 3- aminopropylphosphonic acid) and a sulfonic analog of pEA (taurine).
• MME monomethylethanolamine
• DME dimethylethanolamine
• Cho Cl choline chloride
• FIG. 2 depicts drawings of four pesticidal ethanolamine (alcohol) analogs: 2- (diisopropylamino)ethanol, 2-(tert-butlylamino)ethanol, D-phenylalaninol and N-(2- hydroxyethyl)aniline.
• FIG. 3 shows ethanolamine and a sulfonic acid analog taurine and the nematicidal N-(2-hydroxyethyl)aniline analog and its corresponding sulfonic acid analog N-phenyltaurine.
• FIG. 4 shows a test of 2-(4-phenylazo-phenylamino)-ethanesulfonyl fluoride
• Choline (Cho) plays a number of important roles in biological systems. In bacteria, fungi, plants and animals, phosphatidylcholine is a major component of membrane phospholipids and the free base is a precursor to the neurotransmitter acetylcholine in animals. Choline is also an intermediate in glycine betaine (a compound that increases tolerance to osmotic stresses) synthesis in plants (McNeil et al. (2001) Proc Natl Acad Sci USA 98:10001-5). Choline is an essential nutrient in humans and other animals, and also plays a critical role in brain development in humans (Sheard et al. (1986) Am J Clin Nutr. 1986 43:219-24; Tayek et al.
• choline precursors such as ethanolamine (EA), monomethylethanolamine (MME) and dimethylethanolamine (DME) can also be incorporated into phospholipids via the CPD-choline or Kennedy pathway.
• Rhizobacteria have an additional Kennedy-independent pathway that also allows the incorporation of choline excreted from plant roots directly into phospholipids (Rudder et al. (1999) J Biol Chem. 274:20011-6; Lopez-Lara & Geiger (2001) J Biotechnol 91:211-21).
• Mammalian nerve cells are reported to have additional phopho-base methylation activity and three distinct enzymes appear to be involved (Andriamampandry et al. (1992) Biochem J. 288 (l):267-72; Mukherjee et al. (1995) Neurochem Res. 20(10):1233-7).
• Plant methyltransferases from spinach and Arabidopsis have been cloned by complementation of choline biosynthetic mutants in fission and budding yeast, respectively (Bolognese & McGraw (2000) Plant Physiol. 124(4):1800-13; Nuccio et al. (2000) J Biol Chem. 275(19):14095-101).
• yeast methyltransferases which act on the phosphatidylethanolamine
• these plant enzymes have been shown to act on phosphoethanolamine.
• a similar gene has recently been cloned from chilled wheat tissues (Charron et al. (2002). Plant Physiol. 129(l):363-73).
• the plant enzymes are predicted to encode soluble proteins of approximately 55kDa that have two domains containing separate SAM binding sites. Each domain contains motifs - termed I, post-I, II, and III - that are conserved among SAM-dependent methyltransferases.
• cDNA clones encompassing partial sequence from both SAM binding sites have been isolated from numerous plants, including Oryza sativa, Brassica napus, Gossypium hirsutum, and Hordeum vulgare.
• the plant methyltransferase structure is thought to have arisen from a gene duplication event, since prokaryotic and animal methyltransferases are approximately half the size of the plant enzymes and have only one methyltransferase domain.
• Some basic kinetic characteristics of the spinach methyltransferase have been determined from enzyme preparations isolated from fission yeast overexpressing it. Enzyme activity is dependent on SAM and phosphoethanolamine concentrations, hi the presence of these substrates, methyltransferase-containing extracts catalyze the formation of monomethyl- and dimethylphosphoethanolamine as well as phosphocholine. The appearance of these intermediates suggests that they are precursors to phosphocholine.
• a truncated version of the spinach enzyme lacking the second SAM binding site can accomplish the first methylation converting phosphoethanolamine to monomethylphosphoethanolamine, but cannot perform the second and third methylation steps. It is presumed that the C-terminal half can carry out the second and third methylation reactions. The C.
• elegans genome contains two PEAMT-like genes and several homologs are found in other nematode EST datasets suggesting that these genes are widely distributed in Nematoda.
• the nematode proteins and plant homologs are all presumably localized in the cytosol as in the case of the wheat PEAMT as they lack secretion leaders (analyzed by methods available on the internet at cbs.dtu.dk/services/TargetP or transmembrane regions (analyzed by methods available on the internet at dtu.dk/services /TMHHMM.
• secretion leaders analyzed by methods available on the internet at cbs.dtu.dk/services/TargetP
• transmembrane regions analyzed by methods available on the internet at dtu.dk/services /TMHHMM.
• PEAMT2 encodes a polypeptide which is 437 amino acids long (accession number AAB04824.1 , wormbase locus F54D 11.1) and shows significant similarity to the C- terminal half of the spinach PEAMT and other plant homologs with two SAM binding domains.
• the second C. elegans PEAMT gene appears to encode at least to two different splice variants (PEAMTIa and PEAMTIb).
• PEAMTIa and b are 495 and 484 amino acids long, respectively (accession number AAA81102.1 , wormbase locus ZK622.3a and ZK622.3b) and are most similar to the N-terminal half of the plant
• PEAMTs A PFAM analysis (available on the internet at pfam.wustl.edu) supports the blast predictions that whereas the plant PEAMTs contain two canonical methyltransferase domains, the nematode proteins contain an N-terminal MT domain in PEAMTl and a C-terminal MT domain in PEAMT2.
• PEAMTl and PEAMT2 have 30- 40% amino acid identity to their plant homologs in the regions that align. The similarity between PEAMTl and PEAMT2 is low (22 % amino acid identity) and is restricted to a small 127 amino acid region in their C-terminal domains.
• Plasmodium enzyme is inhibited by the phosphocholine analog miltefosine which in turn inhibits parasite proliferation within human erythrocytes suggesting that P. falciparum PEAMT is a potential target for control of this apicomplexan parasite.
• N-substituted and C- substituted ethanolamine analogs e.g., N-ethylaniline, 4-(N-ethyl-N- methylamino)azobenzene, 2-(4-phenylazo-phenylamino)-ethanesulfonyl fluoride, 2-[4- (4-dimethylamino-phenylazo)-phenylamino]-ethanesulfonyl fluoride, 2-(4-phenylazo- phenylamino)-ethanesulfonamide, 2-[4-(4-dimethylamino-phenylazo)-phenylamino]- ethanesulfonamide, C,C,C-Trifluoro-N-(2-phenylamino-ethyl)-methanesulfonamide, 2- (diisopropylamino)ethanol, 2-(tert-buty
• the nematicidal compounds may be supplied to plants exogenously, through sprays for example. These compounds may also be applied as a seed coat. It is also possible to provide the compounds through a host organism or an organism on which the nematode feeds or which the apicomplexan parasite infects. In the case of PMEAT inhibitors, the host organism or organism on which the nematode feeds may or may not be engineered to produce lower amounts of choline. For example, a host cell that does not naturally produce the nematicide can be transformed with genes encoding enzymes capable of making the nematicidal compound and provided with appropriate precursor chemicals exogenously if necessary.
• the active nematicide and precursors can be made endogenously by the expression of the appropriate enzymes.
• yeast or other organisms can be modified to produce nematicides. Nematodes that feed on such organisms would then be exposed to the inhibitors.
• the compounds can be applied to plants or the environment of plants needing nematode control, or to animals or the food of animals needing nematode or apicomplexan parasite control.
• the compositions may be applied by, for example . drench or drip techniques. With drip applications compounds can be applied directly to the base of the plants or the soil immediately adjacent to the plants.
• the composition may be applied through existing drip irrigation systems. This procedure is particularly applicable for cotton, strawberries, tomatoes, potatoes, vegetables and ornamental plants.
• a drench application can be used where a sufficient quantity of pesticidal composition is applied such that it drains to the root area of the plants.
• the drench technique can be used for a variety of crops and turf grasses.
• the drench technique can also be used for animals.
• the pesticidal compositions would be administered orally to promote activity against internal parasitic nematodes or apicomplexa. Pesticidal compositions may also be administered in some cases by inj ection of the host animal.
• the concentration of the pesticidal composition should be sufficient to control the parasite without causing significant phototoxicity to the desired plant or undue toxicity to the animal host.
• An important aspect of the invention is the surprising discovery that certain ethanolamine analogs (e.g., N-ethylaniline, 4-(N-ethyl-N-methylamino)azobenzene, 2- (4-phenylazo-phenylamino)-ethanesulfonyl fluoride, 2-[4-(4-dimethylamino- phenylazo)-phenylamino] -ethanesulfonyl fluoride, 2-(4-phenylazo- ⁇ henylamino)- ethanesulfonamide, 2-[4-(4-dimethylamino-phenylazo)-phenylamino]- ethanesulfonamide, C,C,C-Trifiuoro-N-(2-phenylamino-ethyl)-methanesulfonamide, 2- (diisopropylamino)ethanol, 2-(tert-butylamino)ethanol, N-
• pesticidal agents decribed herein can be applied in conjunction with another pesticidal agent.
• the second agent may, for example, be applied simultaneously or sequentially.
• pesticidal agents can include for example, avermectins for animal applications.
• a pesticidal compound may also be coupled to an agent such as glyphosate or polyoxyethylene sorbitan (Tween headgroup) to improve phloem mobility to the roots ofplants.
• an agent such as glyphosate or polyoxyethylene sorbitan (Tween headgroup) to improve phloem mobility to the roots ofplants.
• nematicidal compositions can be used to treat diseases or infestations caused by nematodes of the following non-limiting, exemplary genera: Anguina, Ditylenchus, Tylenchorhynchus, Pratylenchus, Radopholus, Hirschmanniella, Nacobbus, Hoplolaimus, Scutellonema, Rotylenchus, Helicotylenchus, Rotylenchulus, Belonolaimus, Heterodera, other cyst nematodes, Meloidogyne, Criconemoides, Hetnicycliophora, Paratylenchus, Tylenchulus, Aphelenchoides, Bursaphelenchus, Rhadinaphelenchus, Longidorus, Xiphinema, Trichodorus, and Paratrichodorus, Dirofiliaria, Onchocerca, Brugia, Acanthocheilonema, Aelurostrongylus, An
• nematodes including Dirofilaria, Onchocerca, Brugia, Acanthocheilonema, Dipetalonema, Loa, Mansonella, Parafilaria, Setaria, Stephanofilaria, and Wucheria, Pratylenchus, Heterodera, Meloidogyne,
• Paratylenchus Species that are particularly preferred are: Ancylostoma caninum, Haemonchus contortus, Trichinella spiralis, Trichurs muris, Dirofilaria immitis, Dirofilaria tenuis, Dirofilaria repens, Dirofilari ursi, Ascaris suum, Toxocara canis, Toxocara cati, Strongyloides ratti, Parastrongyloides trichosuri, Heterodera glycines, Globodera pallida, Meloidogyne javanica, Meloidogyne incognita, and Meloidogyne arenaria, Radopholus similis, Longidorus elongatus, Meloidogyne hapla, and Pratylenchus penetrans.
• RNA Mediated Interference A double stranded RNA (dsRNA) molecule can be used to inactivate a phosphoethanolamine N-methyl transferase (PEAMT) gene in a cell by a process known as RNA mediated-interference (Fire et al. (1998) Nature 391:806-811, and G ⁇ nczy et al. (2000) Nature 408:331-336).
• the dsRNA molecule can have the nucleotide sequence of a PEAMT nucleic acid (preferably exonic) or a fragment thereof.
• the molecule can comprise at least 50, at least 100, at least 200, at least 300, or at least 500 or more contiguous nucleotides of a PEAMT-like gene.
• the dsRNA molecule can be delivered to nematodes via direct injection, by soaking nematodes in aqueous solution containing concentrated dsRNA, or by raising bacteriovorous nematodes on E. coli genetically engineered to produce the dsRNA molecule (Kamath et al. (2000) Genome Biol. 2; Tabara et al. (1998) Science 282:430- 431).
• C. elegans can be grown on lawns of E. coli genetically engineered to produce double-stranded RNA (dsRNA) designed to inhibit PEAMTl or PEAMT2 expression.
• dsRNA double-stranded RNA
• E. coli were transformed with genomic fragments encoding portions of the C. elegans PEAMTl or the PEAMT2 gene.
• a 960 nucleotide fragment was amplified from the PEAMTl gene using oligo-nucleotide primers containing the sequences 5'-ATGGTGAACGTTCGTCGTGC-S' and 5'-
• RNAi was initiated from C. elegans larvae at 23 °C on NGM plates containing IPTG and E. coli expressing the C. elegans PEAMTl or PEAMT2, or GFP dsRNA. If the starting worm (the PO) was an Ll, or a dauer larva, the phenotype of both the PEAMTl and PEAMT2 RNAi- generated mutants was complete or almost complete sterility. One the other hand, if the PO animal was an L4 larva, then the phenotype of both the PEAMTl and PEAMT2 RNAi-generated mutants was L1/L2 larval arrested development and lethality.
• the sequence of the PEAMTl and PEAMT2 genes is of sufficiently high complexity (i.e., unique) such that the RNAi is not likely to represent cross reactivity with other genes.
• PEAMTl, PEAMT2, actin, or GFP along with specific chemicals (EA, MME, DME or Cho).
• Chemicals were added to NGM plates at various concentrations and negative (GFP dsRNA) and positive (actin dsRNA) controls were performed for each chemical or chemical mixture at each concentration.
• agar plates containing NGM and the chemicals specified in Table 1 were seeded with bacteria expressing double-stranded RNA homologous to either PEAMTl or PEAMT2.
• a single Ll or dauer larva was placed on each plate, and the PO and the Fl were examined for the next 5 days.
• a single L4 C. elegans hermaphrodite was placed on each plate.
• the hermaphrodite was allowed to lay eggs for 24 hours and the phenotype of the Fl progeny was scored 48 hours after the initial 24-hour egg-laying period. At the time of scoring, 4 individual Fl progeny were cloned to separate plates containing the same chemical and bacteria they were grown on. The Fl and F2 progeny were examined over the next 4-5 days for the presence of a phenotype.
• Table 1 C. elegans PEAMTl and PEAMT2 RNAi feeding phenotypes (starting with C. elegans Ll, dauer, or L4 larva as the PO animal).
• the C. elegans phosphoethanolamine N-methyltransferase proteins PEAMTl and PEAMT2 together catalyze the conversion of phosphoethanolamine to phosphocholine.
• the RNAi-generated mutants of PEAMTl or PEAMT2 are both predicted to have decreased levels of choline which leads to sterility, or L1/L2 larval arrested development and death. Addition of 25 mM choline rescues the larval arrest associated with both PEAMTl and PEAMT2 RNAi phenotypes. However, only the PEAMTl mutants are rescued by the addition of 5 mM monoethanolamine (MME) or 5 mM dimethylethanolamine (DME) while the PEAMT2 mutants are not (see Table 1). These data are consistent with the prediction that PEAMTl catalyzes the first methylation while PEAMT2 catalyzes the second and third methylations in the conversion of pEAto pCho:
• PEAMTl PEAMT2 PEAMT2 Five mM DME rescues the sterility associated with PEAMTl RNAi . The rescue by DME strongly suggests the sterility is due to a reduction in choline production and not due to other changes caused by the PEAMT mutations.
• a single C. elegans L4 larva (the PO animal) was placed on a lawn of E. coli that had been spotted onto NGM plates containing various concentrations of the ethanolamine-like compounds.
• the growth and development of the PO and its Fl progeny at 23 0 C was monitored by visual observation over several days.
• Four of the compounds tested [2-(diisopropylamino)ethanol, 2-(tert-butylamino)ethanol, D- phenylalaninol and N-(2-hydroxyethyl)aniline], showed nematicidal activity against C. elegans.
• the phenotype of worms treated with the nematicidal ethanolamine-like compounds mimicked the RNAi-phenotype of PEAMTl and PEAMT2. That is, the Fl progeny of the treated worm did not develop beyond the Ll /L2 stage and died.
• Treatment of C. elegans with the Cl -substituted compound 2- aniino-1-phenylethanol showed no nematicidal effect.
• Table 3 Nematicidal activity of ethanolamine-like compounds against C. elegans.
• Table 4 Nematicidal activity of ethanolamine-like compounds against other nematodes.
• ethanolamine-like compounds noted above are also nematicidal against Acrobiloides ellesmerensis and Cephalobus sp. Assays were done as those described for C. elegans L4 larvae. Three of the four compounds that were nematicidal against C. elegans were tested and were found to be nematicidal against A. ellesmerensis and Cephalobus sp.
• EC50's of compounds against C. elegans were measured in a contact assay.
• Compounds were solubilized in acetone, ethanol or water (in that order of preference) at 10Ox the desired concentration.
• Dilution series of 10x, 3x, 2x or square root-2x were accomplished by serial dilution with identical solvent. Between 6 and 12 concentration points were assayed. For each concentration, 50 microliters of 10Ox compound solution were added to 5 ml NGM-agar at 50 to 60 0 C. Four wells of a 24-well plate each received approximately 1 ml of the the NGM-agar-compound mixture.
• each well was scored for number of adults, number of eggs and number of larvae present, as well as for presence or absence of crystallized compound, cloudiness of plates, and depletion of bacterial food source. Most plates were also scored at 120 or 144 hours following challenge. For determination of an EC50, the average number of adults present in the 4 replicate wells 96 hours after challenge was determined, and an EC50 interpolated.
• 2-(4-phenylazo-phenylamino)-ethanesulfonyl fluoride shows nematode control approaching that of the commercial nematicides fenamiphos (Nemacur) in drench (soil based) assays against root knot nematode infections of tomato plants in the greenhouse.
• 2-(4-phenylazo-phenylarnino)- ethanesulfonyl fluoride shows no phytoxicity at any of the rates tested.
• 2-(4-phenylazo-phenylamino)-ethanesulfonyl fluoride is not toxic to several arthropods.
• test compounds were solubilized in DMSO at 10 mg/ml to create 10Ox stock solutions. A dilution series was created by diluting the stock solution with DMSO. For each well assay 4 ⁇ l of the appropriate dilution was added to a well of a test plate.
• Ll worms and L4 worms were used in the assay.
• Ll worms were prepared by plating eggs on a plate without a bacterial feeding layer. The eggs hatched and arrested at the Ll stage. This Ll stage population was used to create a stock for the experiments.
• To create an L4 stage stock a small number of worms were taken from an overgrown and starved plate of worms and seeded on a plate with a bacterial feeder layer. A 25 ⁇ l aliquot of worms was added to each well in the assay.
• test compounds Dilutions of test compounds were prepared as described above for the well assay. An 80 ⁇ l of the appropriate dilution was added to a 15 ml tube along with 8 ml of 60 °C NGM agar. The contents of the tube were mixed and divided to two tubes (4 ml each) to create a pair of test plates.
• a 25 ⁇ l aliquot of a freshly grown bacterial culture was spotted in each plate as a feeder layer.
• Worms were prepared as described above. One plate from each pair received 10-20 eggs and the other plate received a single L4 worm. Plates were incubated at A 20 0 C and scored at at 4 hrs, 24 hrs, 48 hrs and 72.
• Cucumber seeds are sprouted for 3 days in moist paper towels. Acceptable sprouts should be 3-4 cm long with several lateral roots just emerging.
• Stock solutions are prepared in acetone (16.5 mg of compound in 10 ml acetone); or DMSO (10 mg of compound in 1 ml DMSO).
• acetone 16.5 mg of compound in 10 ml acetone
• DMSO 10 mg of compound in 1 ml DMSO.
• Plant seedlings slant vial, lay in seedling in correct orientation and so that cotyledons will be just above sand, then tilt back to cover radicle with sand.
• Add 3.3 ml water to each vial and place the vial racks under the fluorescent light racks.
• Gall 200, Gall 40, Ptox 200 and Ptox 40 are gall ratings at 200 ppm and 40 ppm and phytotoxicity ratings at 200 ppm and 40 ppm, respectively. The results are reported below. Rows with the same superscript (e.g., a, b or c) correspond to compounds assayed in the same test.
• Azobenzenes nitrobenzenes, stilbenes, and chalcones having nematicidal activity
• Various azobenzenes, nitrobenzenes, stilbenes, and chalcones were tested for their effectiveness against: Meloidogyne incognita infecting tomatoes growing in a greenhouse (Tomatoes/Greehouse; 21 days); Meloidogyne incognita infecting cucumber growing a laboratory (Cucumber/Laboratory; 10 days); and Meloidogyne incognita in an in vitro well assay ⁇ In vitro; 4 days).
• the results of these studies are presented in the table below.
• a "+" indicates strong efficacy of the compound; "-" indicates weak efficacy of the compound; and "+/-" indicates intermediate or variable efficacy.
• Non-mutagenic azobenzenes having nematicidal activity Azobenzenes analogs do not in general show significant acute mammalian toxicity. However, mutagenicity is often seen with this class of chemistry and in one published study the aromatic azo group was associated with mutagenicity - the ability to cause errors in DNA replication — in 77% of molecules surveyed (J Med Chem. 2005 48(1):312-20). Non-mutagenic pesticidal analogs are desireable for both human and animal health and crop chemistry applications.
• the most commonly used mutagenicity assay is the Ames test which looks for reverse mutations in histidine-requiring strains of Salmonella typhimurium. This procedure evaluates the mutagenic potential of test chemicals by their effect on histidine requiring strains of the bacterium in the absence and presence of a rat liver metabolising systems (S9 extract). When the bacterial cultures are exposed to mutagens some of the bacteria undergo genetic changes resulting in reversion of the bacteria to a non-histidine- requiring state. The reverted bacteria will then grow in the absence of exogenous histidine thus providing an indication of the potential of the chemical to cause mutation.
• S9 extract rat liver metabolising systems
• Commonly used salmonella strains often have additional mutations to increase their sensitivity to mutational effects including error-prone DNA repair systems (e.g., the loss of the excision repair system) and the loss of the lipopolysaccharide barrier that coats the surface of the bacteria.
• error-prone DNA repair systems e.g., the loss of the excision repair system
• lipopolysaccharide barrier that coats the surface of the bacteria.
• the COOH and SO 3 H substitutents are two electron withdrawing groups that deactivate azobenzene mutagenicity.
• the COOH and SO 3 H groups have a net negative charge at pH 7 which will tend to impede cellular and transcuticular and uptake (MoI Biochem Parasitol. 1990 41(2):153-65).
• these deactivating groups include but are not limited to COCF 3 , CCl 3 , CBr 3 , CI 3 , N(CF 3 ) 2 , SO 2 CF 3 , SO 2 CH 3 , SO 2 CHF 2 , SO 2 CN, SO 2 N(OB) 2 , SO 2 NHCH 3 , SO 2 NH 2 , SO 2 C 6 H 5 .
• DC4299, DC4350, DC4356 Three CF 3 containing azobenzenes (DC4299, DC4350, DC4356) have been tested in the Ames assay using the TA98 (frame-shift mutations) and TAlOO (point mutation) tester strains. Compounds were dissolved in a dimethylsulfoxide (DMSO) vehicle and tested in duplicate at the concentrations 1.5, 5, 15, 50, 150, 500, 1500 and 5000 ug/plate. DC4299, DC4350 and DC4356 were all Ames negative (i.e., non- mutagenic) either with or without rat liver S9 activation.
• DMSO dimethylsulfoxide

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