S2 L3 Insecticides - synthetic Anna Drew with slide contribution from Martin Wilks, Syngenta Diane Alston & Joel Coats

World Insecticide Market

“Old” classes (nerve poisons) ORGANOCHLORINES Most famous DDT »(Dichloro-Diphenyl-Trichloroethane) »4,4'-(2,2,2-trichloroethane -1,1-diyl) bis(chlorobenzene) 1874 synthesized 1939 insecticidal properties discovered 1942 first introduced for malaria control in India

Although useful –tends to accumulate in body fat –not really excreted –tended to build up in food chains »eg birds -> thin egg shells endangering species –resistance developed Banned in the US, UK etc Use: extensive use in developing countries –mosquito, tsetsi fly control – malaria, typhus Action: –delays closing sodium channels –inhibition of axonal Na + -, K + - and Mg 2+ -ATPase –interaction with GABA A receptor chloride ionophores

gamma hexa chloro benzene benzene hexachloride still used in Sri Lanka similar to DDT more rapidly metabolised less stable Other cycloalkanes: dieldrin aldrin [Methoxychlor] Lindane

ORGANOPHOSPHATES Esters of phosphoric acid - examples: eg dichlorvos (orthophosphate) eg parathion eg chlorpyrifos eg diazinon (orthothionphosphate)

Selection: »solubility »volatility »relative toxicity (insects v mammals) »stability Action: –mimic acetylcholine by binding with acetylcholinesterase –prevents ACh breakdown –duration of toxicity depends on how quickly enzyme is rehydrolysed »generally more toxic to vertebrates »persist less in environment Uses: before contact, now systemic –aphids, spiders Problems: –Handling – absorbed through skin –Self-poisoning – major public health problem

Mortality rates of poison admissions at Anuradhapura General Hospital, Sri Lanka ( – ) # Admissions# DeathsMortality Rates (%) Oleander Organophosphate Other Pesticides Medicines Carbamates Hydrocarbons4400 Paraquat Unknown Unknown Pesticides Organochlorines Acid300 Alkali400 TOTAL

Target site

CARBAMATES Derivatives of carbamic acid – examples: Action: –also inhibits AChE resulting in accumulation of ACh at neuromuscular junctions or synapses –causes rapid twitching of voluntary muscles and finally paralysis Use: some contact, some systemic eg propoxureg aldicarbeg methomyleg carbaryl

SUBSTITUTED PHENOLS Good on woody plants and outdoors 1950 fungicide as a winterwash –then acaricide (mites, ticks) –then foliage control of mildew on fruits & mites on apple trees Very toxic, protection for handling Highly toxic to birds, slightly toxic to fish Dinocap Dinitroorthocresol CH 3 CHC 6 H 13

Why preferentially toxic to insects? Ease of access to site of action differs eg pyrethroids –easily absorbed through insect exoskeleton but not skin Action at site differs insect sodium channels 100x more sensitive than mammalian channels –the proportion of sodium channels affected and hence the degree of hyperexcitability is dose-dependent –the duration of the hyperexcitable state and hence the nature of the effect is structure dependent Variability of metabolism eg OPs –insects: convert S -> O forming much more active compounds –mammals: esterase cleaves off ester group and compound is much easier to excrete

INSECT GROWTH REGULATORS Class: benzoylureas »diflubenzuron, lufenuron, novaluron »Cyromazine (triazine) »Use: leafminers in vegetable crops & ornamentals Action: interfere with chitin synthesis »act at the larval stage »greatest value for control of caterpillars, beetle larvae »cause ruptured cuticle or death by starvation »taken up more by ingestion than contact

PYRAZOLES Fipronil Use: –systemic material with contact and stomach activity »control of soil and foliar insects eg rice water weevil »baits for cockroaches, ants, termites –effective against insects resistant or tolerant to pyrethroid, OP and carbamates Action: »inhibitor at the gamma-aminobutyric acid (GABA) receptor »non-competitive blockers at the GABA-gated chloride channels in neurons

OTHERS Since new compounds, 57 brands - Utah Chlorfenapyr –broad-spectrum insecticide –? interferes with oxidative phosphorylation Sulfluramid Buprofezin –inhibits chitin synthesis –similar to benzoyl phenylureas Diafenthiuron (thiourea) –inhibits ATPase in mitochondria

Indoxacarb (oxadiazine) –blocks sodium channel in nerve axon –inhibits propagation of nerve potential Metaflumizone –blocks sodium channel in nerves Pymetrozine (pyridine azomethine) –inhibits feeding of sucking insects – aphids –neuromuscular effects, prevents insertion of insect stylets Flonicamid (nicotine-derived) –antifeedant – mode of action undetermined Clofentezine, Hexythiazox, Etoxazole –mite growth inhibitor – ovicide (kills eggs) – apply early

Pyridazinones –inhibits mitochondrial electron transport –affects respiration –like rotenone Acequinocyl –inhibits mitochondrial electron transport –affects respiration –different site of action to other METI compounds Bifenazate (carbazate) –related to carbamates –neurotoxic but mechanism unknown