Insecticides Physostigmine Occurs naturally in calabar bean Physostigma venenosum 1st isolated in 1864 Structure identified in 1923 Synthesized by Julian Percy in 1930s Used against glaucoma myasthenia gravis ID: 341675
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Slide1
Carbamate
Insecticides Slide2
Physostigmine
Occurs naturally in calabar bean
Physostigma venenosum1st isolated in 1864; Structure identified in 1923Synthesized by Julian Percy in 1930sUsed against glaucoma, myasthenia gravisNo insecticidal activity because it does not penetrate insect cuticle.Slide3
General Structure of Carbamate Insecticides
Fukuto
and MetcalfStructure-Activity Relationships of carbamatesUncharged N-methyl carbamates can penetrate insect cuticle5Å [0.5 nM] separate anionic from
esteratic
site of insect AChE
All insecticidal carbamates are N-methyl carbamatesR = CH3 or HX = leaving groupUsually bulkyAlkyl aldicarbAromaticcarbaryl
PhysostigmeneSlide4
Mechanism of Action
Resemble OPs because they
Inhibit AChEHave a leaving group that is hydrolyzed in forming the AChE-carbamate complexDiffer from OPs becauseAChE-carbamate complex dissociates readilyAging does not occurAtropine is a more effective antidote than the oximes (e.g., 2-PAM)Slide5
Biotransformation of Carbamates
Insecticidal carbamates
Are N-methyl estersWith R = H or CH3X = bulky leaving groupActivationRequires cleaving of leaving group by carboxyesterase
Alternative metabolism
N-demethylation
Produces formaldehyde as byproductEpoxide metaboliteMediated by CYP 1A1Slide6
Toxicity
Aldicarb
Oral LD50 in rats is 0.9 mg/kgDermal LD50 in rats is 5 mg/kgCarbofuranHuman oral LD50 is 11 mg/kg
Oral LD
50
in rats is 5-8 mg/kgDermal LD50 in rats is 120 mg/kgCarbarylOral LD50 in rats is 250-350 mg/kgDermal LD50 in rats is ca 2000 mg/kgChronic: OPIDN-like muscle weaknessTemporary, even with continued exposureSlide7
Synthesis of Carbamates: Carbaryl
1. using naphthol-1& phosgeneSlide8
2. Using methyl isocyanate
3. Using methyl carbamoyl chlorideSlide9
Alternative?
Reason for alternative synthesis:
Hazard
of methyl
isocyanate Slide10
Methyl Isocyanate
Properties
ReactiveExothermic polymerization Precursor for carbamate insecticidesCarbarylMethomyl
Aldicarb
Carbofuran
Bhopal, 12/3/84Union Carbide plant in Madya PradeshSafety deficits ---> explosion8,000 dead immediatelyPermanent sequelae in survivorsToxicitiesPulmonaryReproductive
Synthesis of carbaryl from carbamoyl chloride and MICSlide11
Long-term Effects of Carbamates
Carcinogenicity?
N-methyl carbamates form nitroso-carbamates at pH 3These compounds are probable carcinogensRisk is unquantified and disputedReproductive/Developmental toxicity?CarbarylDogsEpidemiologyImmunotoxicity?AldicarbSlide12
Carbaryl (Sevin
TM
) LD50 : 250 mg/kg in ratsEnvironmental persistence: brief to moderateRepro and developmental toxicity: ???Carcinogenicity: ??Delayed neurotoxicity?Reversible muscle weakness
Precursor, MIC, extremely dangerousSlide13
Aldicarb
LD50 : ≤ 1 mg/kg for mammals, fishDegraded by sunlight, but persists in groundwaterChronic effectsImmune system depression?Carcinogenicity? Slide14
Carbofuran
Corn rootworm insecticide
Oral LD50 ≤ 8 mg/kg in rats (po)11 mg/kg in humans~ 1 mg/kg in birdsEnvironmental Effects: Loses effectiveness due to increasingly rapid microbial degradationSlide15
Procarbamates
Substitute more complex group for N-CH
3 or N-HCleaving of this group ---> active carbamateComplex group may have its own insecticidal activityFormamidine-carbamatesProcarbamates often have Better acaricidal activityLower mammalian toxicity
Example:
Carbosulfan
Carbosulfan: a procarbamate