Developments in newer molecules of insecticide the modes of action and structural activity relationships

Developments in newer molecules of insecticide the modes of action and structural activity relationships

1. Developments in newer molecules of insecticide the modes of action and structural activity relationships Submitted To: Dr. Sonaali Professor Department of Entomology Submitted By: P.KRANTHI Ph.D. Scholar ASSIGNMENT ON

2. OUTLINE New Insecticide Classes Neonictinoids Phenyl pyrazoles Oxadiazines Halogenated pyrroles Thiourea derivatives Quinazolines Pyridazinones Thiazolidines Carbazates Diamides IGRs (Benzoyl ureas , Thiadiazines ) Diacylhydrazines New insecticides from microorganisms ( Avermectins , Spinosyns, B . thuringiensis, M. anisopliae ) Pyridine azomethines Tetronic acid derivatives Sulfoximes (Sulfoxaflor)

3. Neo-nicotinoids ( Synthetic analogues of nicotine) Introduction of new nicotine like compounds Chloronicotinyl compounds Thionicotinyl compounds Furanicotinyl compounds Pyridincarboxamides 4 groups

4. Drawbacks of nicotine - Expensiveness Lack of commercially applicable synthesis Extreme toxicity to mammals Limited insecticidal spectrum

5. Chloronicotinyl Compounds Acetamiprid IUPAC: (E)-1-(6-chloro-3-pyridylmethyl)-N- nitroimidazolidin - 2-ylideneamine Acetamiprid Imidacloprid systemic insecticide having good xylem mobility and used as seed treatment and soil application Formulations: 17.8% SL ( Confidor ®), 70% WS (Gaucho®) Effective against sucking pests (aphids, leaf hoppers, plant hoppers, whiteflies, thrips)

6. Thionicotinyl Compounds ( Clothianidin) IUPAC: (E)-1-(2-chloro-1,3-thiazol-5-ylmethyl)-3-methyl-2- nitroguanidine Clothianidin Imidaclothiz Thiacloprid Thiamethoxam Broad spectrum insecticide Formulations: 48% FC (Poncho®) Effective against hemipteran, thysanopteran and coleopteran sucking insect pests

7. Furanicotinyl compounds ( Dinotefuran) IUPAC: (EZ)-(RS)-1-methyl-2-nitro-3-(tetrahydro-3- furylmethyl )guanidine Highly systemic insecticide Formulations: 20% SG (Token®) Effective against sucking pests (hoppers, jassids , aphids

8. Pyridincarboxamides ( Flonicamid ) IUPAC: N-cyanomethyl-4-(trifluoromethyl)nicotinamide Systemic and trans-laminar activity; long time protection; feeding deterrent Formulations: 50% WG ( Ulala ®) Effective against major species of aphids; also controls mealy bugs, whiteflies, plant hoppers

9. Mode Of Action They are nicotinic acetylcholine receptor agonists They bind strongly to nicotinic acetylcholine receptors ( nAChRs ) in the central nervous system of insects, causing nervous stimulation at low concentrations, but receptor blockage, paralysis and death at higher concentrations Neonicotinoids bind more strongly to insect nAChRs than to those of vertebrates, so they are selectively more toxic to insects ( Tomizawa & Casida , 2005)

10. Phenyl pyrazoles ( Fipronil) IUPAC:(RS)-5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4- ( trifluoromethylsulfinyl )-1H-pyrazole-3-carbonitrile Fipronil Flufiprole Pyraclofos Ethiprole Systemic insecticide contact and stomach action Formulations: 5% SP(Regent®) It controls stem borers, gall midges, DBM, thrips, root borers

11. Mode Of Action Acts as an inhibitor at the γ-aminobutyric acid (GABA) receptor as a non-competitive blocker of the GABA-gated chloride channel (similar to lindane and cyclodienes ) Chemical and biological activation producing equally toxic and sometime more persistent metabolites with same mode of action.

12. Oxadiazines ( Indoxacarb) IUPAC: Methyl 7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4- (trifluoromethoxy)phenyl]amino]carbonyl] indeno [1,2-e] [1,3,4]oxadiazine-4a(3H)-carboxylate Formulations: 15.8% EC (Avaunt®) Effective against lepidopteran pests (American boll worm, DBM, Helicoverpa armigera , Plutella xylostella )

13. Mode Of Action This pro-insecticide is bioactivated in the insect by enzymatic (insect esterase) N- decarbomethoxylation changing it to a more active, highly insecticidal metabolite It produces its potent effects at a unique binding site in voltage- gated sodium ion channels of the nervous system of susceptible insects The active metabolite of indoxacarb induces irreversible hyperpolarization of insect nerve cell membranes.

14. Halogenated pyrroles ( Chlorfenapyr ) IUPAC: 4-Bromo-2-(4-chlorophenyl)-1-ethoxymethyl-5-trifluoromethyl-1H-pyrrole-3-carbonitrile Formulations: 10% SC (Intrepid®) Effective against DBM in cabbage and cauliflower, mites in chilli

15. Mode Of Action Chlorfenapyr works by disrupting the production of ATP, specifically, Oxidative removal of the N- ethoxymethyl group of chlorfenapyr by MFO forms the compound CL 303268 which uncouples oxidative phosphorylation at the mitochondria, resulting in disruption of production of ATP, cellular death, and ultimately organism mortality Oxidative phosphorylation Unco u ple rs

16. Thiourea derivatives ( Diafenthiuron ) IUPAC: 1-tert-butyl-3-(2,6-diisopropyl-4phenoxyphenyl)thiourea Formulations: 50% WP (Polo®) Effective against sucking insects (whiteflies, aphids, jassids ), mites, capsule borers Mode of Action of Diafenthiuron : Diafenthiuron inhibition of oxidative phosphorylation i.e specifically they inhibit ATP synthase.

17. Quinazolines ( Fenazaquin ) IUPAC: 4-tert-butylphenethyl quinazolin-4-yl ether Formulations: 10% EC (Magister®) Mode of action: Broad spectrum acaricide; It inhibits mitochondrial electron transport chain by binding with complex I at co-enzyme Q Effective against mites in tea and chilli

18. Pyridazinones ( Fenpyroximate ) IUPAC: tert-butyl (E)- α-(1,3- dimethyl-5-phenoxypyrazol-4 ethylmethyleneamino -oxy)-p-toluate) Fenpyroximate Pyridaben Pyridalyl Formulations: 5% EC (Mitigate®) Effective against red spider mites and two spotted mites

19. Mode Of Action It is photochemically converted in sunlight to its carbodiimide derivative, which is a more powerful toxicant than diafenthiuron (Steinmann et al., 1990) The carbodiimide acts as an adenosine triphosphatase (ATPase) inhibitor following metabolic activation to the corresponding carbodiimide ( Petroske and Casida , 1995) The carbodiimide metabolite inhibits mitochondrial respiration by selective and covalent binding to the proteolipid ATPase (Ruder et al., 1992; Kayser and Eilinger , 2001)

20. Thiazolidines ( Hexythiazox ) IUPAC: (4RS,5RS)-5-(4-chlorophenyl)-N-cyclohexyl-4-methyl-2-oxo- 1,3-thiazolidine-3-carboxamide Formulations: 5.45% EC (Maiden®) Mode of action : Unknown or non-specific mode of action(mite growth inhibitors) Effective against red spider and yellow mites in tea and chilli

21. Carbazates ( Bifenazate ) IUPAC: Isopropyl 2-(4-methoxybiphenyl-3 yl ) hydrazinoformate Selective acaricide Formulations: 24% SC ( Floramite ®) Mode of action: Neuroactive; exact mode of action is unclear Effective against spider mite

22. Diamides ( Flubendiamide ) Flubendiamide Chlorantraniliprole Cyantraniliprole Cyclaniliprole Tetraniliprole Pthalic diamide Formulations: 20% WG (Takumi®), 39.35% SC (Fame®) Effective against insect pests of rice (stem borer. Leaf folder) and cotton ( Helicoverpa armigera , spotted boll worm)

23. Cyantraniliprole IUPAC: 3-bromo-1-(3-chloro-2-pyridyl)-4′-cyano-2′-methyl-6′- ( methylcarbamoyl )pyrazole-5-carboxanilide Anthranilic diamide Formulations: 20% SC ( Cyazypyr ®) Effective against key chewing and sucking insects (Homopterans and lepidopterans)

24. Mode Of Action Ryanodine receptors are intracellular channels specialized for the rapid and massive release of Ca2+ from intracellular stores, which is an essential step in the muscle contraction process Pthalic diamides interacts with a site distinct from the ryanodine binding site and disrupts the Ca2+ regulations of the ryanodine receptor completely by an allosteric mechanism

25. Anthranilic diamides cause death of insects by disruption of Ca2+ within muscle tissue. The anthranilic diamide insecticides bind to ryanodine receptors locking them partially open. Ca2+ leaks out of muscle tissues which results in the inability to regulate muscle function which causes paralysis and death (Cordova et al., 2006)

26. Benzoyl Urea IUPAC name : 1-(4-chlorophenyl)-3- (2,6-difluorobenzoyl)-urea Dichlorbenzuron Diflubenzuron Flucycloxuron Flufenoxuron Formulations: 10% DC (Cascade) Effective against immature stages of many phytophagous mites and insects pests of, citrus, tea and ornamentals Effective against immature stages of many phytophagous

27. Mode Of Action It acts as a chitin synthesis inhibitor by blocking terminal polymerization step catalysed by chitin synthase enzyme. They might affect the insect hormonal site, thereby resulting in physiological disturbances such as inhibition of DNA synthesis, alter carbohydrase and phenoloxidase activities, or suppress microsomal oxidase activity ( Ishaaya & Ascher, 1977; Van Eck,1979; Soltani et al., 1984) These compounds alters cuticle composition—especially that of chitin—thereby affecting the elasticity and firmness of the endo-cuticle ( Grosscurt & Anderson, 1980)

28. Thiadiazines Buprofezin IUPAC: (Z)-2-tert-butylimino-3-isopropyl-5-phenyl-1,3,5- thiadiazinan-4-one Insect growth regulator Formulations: 44% SC (Applaud®) Effective against homopteran insects (hoppers, jassids , whiteflies)

29. Mode Of Action It acts as a chitin synthesis inhibitor having both contact and vapour phase activity It acts on the nymph stages of leaf hoppers, scales, plant hoppers,and whiteflies ( Ishaaya et al., 1988) It inhibits incorporation of 3H- glucosamin into chitin (Uchida et al., 1985) As a result of chitin deficiency, the pro-cuticle of the nymphs loses its elasticity and the insect is unable to complete the moulting process (De Cock and Degheele , 1998)

30. Diacylhydrazines ( Chromafenozide ) IUPAC: N′-tert-butyl-5-methyl-N′-(3,5-xyloyl)chromane-6- carbohydrazide Chromafenozide Halofenozide Methoxyfenozide Tebufenozide Insect growth regulator Formulations: 5% SC (Virtu®) Effective against lepidopteran insects on top fruits

31. Mode Of Action These compounds bind to the ecdysteroid receptors, accelerating the molting process and thereby disrupting the insect hormonal balance (Wing, 1988; Palli et al., 1996)

32. New Insecticides From Microorganisms ( Avermectins ) Source : Streptomyces avermitilis A series of 16-membered macrocyclic lactone derivatives with potent anthelmintic and insecticidal properties

33. Abamectin ( Avermectin B1) Agri- Mek ® 15% EC Used against sucking pests, phytophagous mites, dipterans, psyllidae , leaf miners Ivermectin (22,23-dihydroavermectin) Ivomec ® 1% SC Used to control parasites of cattle Emamectin benzoate Proclaim® 5% WSG Used against lepidopteran insects. Mode of action They block the transmittance of electrical activity in nerves and muscle cells by stimulating the release and binding of GABA at nerve endings. This causes an influx of chloride ions into the cells, leading to hyperpolarisation and subsequent paralysis of the neuromuscular systems.

34. Source: Saccharopolyspora spinosa Mixture of 2 most active metabolites :Spinosyn A and Spinosyn D Formulations: 45% SC (Tracer ®) Mode of action They primarily target binding sites on nicotinic acetylcholine receptors ( nAChRs ) of the insect nervous system that are distinct from those at which other insecticides have their activity. Spinosoid binding leads to disruption of acetylcholine neurotransmission. Spinosad also has secondary effects as a GABA neurotransmitter agonist Spinosyns

35. Entomopathogenic Bacteria ( Bacillus thuringiensis) Bacillus thuringiensis ( Bt ), a gram-positive, motile, rod shaped bacterium produces a parasporal crystal composed of one or more proteins The strains of Bt characterized so far affect members of 3 insect orders: Lepidoptera (butterflies & moths), Diptera (mosquitoes & biting flies) and Coleoptera (beetles)

36. 3 Bt products registered in India B.t. israelensis ( diptera )—frequently used for mosquitoes B.t. kurstaki (lepidoptera)—frequently used for gypsy moth, spruce budworm, and many vegetable pests B.t. galleriae (lepidoptera)—frequently used for leaf beetle, Colorado potato beetle B.t. kurstaki is the most commonly used Bt formulation

37. Mode Of Action Bacillus thuringiensis strains produce crystalline proteins (called δ- endotoxins) Caterpillar consumes the Bt spore (diagram 1) & crystalline toxin-treated leaf The Bt crystalline toxin (diamond shapes in diagram 2) binds to gut wall receptors, and the caterpillar stops feeding Within hours, the gut wall breaks down, allowing spores (oval tube shapes) and normal gut bacteria (circular shapes) to enter body cavity, where the toxin dissolves The caterpillar dies in 24 to 48 hours from septicemia, as spores and gut bacteria proliferate in its blood (diagram 3)

38. Entomopathogenic Fungi ( Metarhizium anisopliae ) They cause green muscardine disease in various insect pests Mode of action Fungi have virulent spores adsorbed to the carrier/neutral material that remain either dormant or active on the carrier particles and start multiplying when congenial environmental conditions are met with The soil borne insect like termites come in contact with the fungus and the mycelia of fungus starts growing on the body of termites and starts feeding on the body fluid of insects and results in disease and death of the insect pest.

39. Conidia Different cultures of M. anisopliae Cockroach killed by M. anisopliae

40. Pyridine azomethines ( Pymetrozine ) IUPAC: (E)-4,5-dihydro-6-methyl-4-(3-pyridylmethyleneamino)-1,2,4-triazin-3(2H)-one Formulations: 50% WDG (Fulfill®) Mode of action: It has no direct toxicity against insects but it blocks stylet penetration of sucking insects which may cause immediate cessation of feeding after exposure to this insecticide Effective against sucking pests (whiteflies, hoppers and aphids)

41. Tetronic Acid Derivatives Spiromesifen IUPAC: 3-mesityl-2-oxo-1-oxaspiro[4.4]non-3-en-4-yl 3,3-dimethylbutyrate Formulations : 24% SC (Oberon®) Mode of action: Prevent Lipid biosynthesis by inhibiting acetyl CoA carboxylase Effective against mites and moth scale insects

42. Sulfoximines IUPAC:[methyl(oxo){1-[6-(trifluoromethyl)-3-pyridyl]ethyl}- λ6 sulfanylidene ] cyanamide Systemic insect neuro-toxin Formulations: 24% SC (Transform®) Effective against major species of sap feeding insects

43. Mode Of Action It causes a blockage in the nicotinergic neuronal pathway leading to the accumulation of acetylcholine, an important neurotransmitter, resulting in the insect's paralysis and eventually death Sulfoxaflor is stable to monooxygenases that are known to readily metabolize other insecticides such as organochlorines and the neonicotinoids (Zhu et al ., 2011)

44. Other Insecticidal Groups

45. Future Challenges To develop more and more new molecules having Low dose compounds High efficacy and quick knockdown effect Low mammalian toxicity Relatively safer formulations Less leaching potential New chemistry Less harmful to beneficial species More discoveries in macromolecular pesticides More innovations required for new neo-nicotinoids

46. More biotechnological innovations to be directed in transgenic plants etc. More innovative technology to be developed in application of pesticides Minimization of residue load in ecosystem More emphasis shall be given in bio-control agents Research emphasis shall be given in innovations of more plant derived bio-pesticides

47. Conclusion Scientific community has been involved in approaches towards the developments of newer molecules which could be easily biodegradable, target-specific with very low mammalian toxicity A distinct division in scientific opinion was made to decide whether to go for bio-based products or for using synthetic chemicals for protecting the crops A new horizon of analytical chemistry was evolved as pesticide residue analysis to judge the residue level of these harmful chemicals in food grains

48. Researches were carried out to develop safer molecules which could undergo photo-degradation, microbial degradation as well as chemical degradation leaving very less amount of residues in the environment The prime motto for this development is to give protection to the crops along with safety to the natural enemies of different pests as a whole safety to environment

49. “If you're not part of the solution, Y o u ’ r e p a r t o f t h e p r e c i p it a t e …”