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Carbamate Insecticides
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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 No insecticidal activity because it does not penetrate insect cuticle.
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General Structure of Carbamate Insecticides
Fukuto and Metcalf Structure-Activity Relationships of carbamates Uncharged N-methyl carbamates can penetrate insect cuticle 5Å [0.5 nM] separate anionic from esteratic site of insect AChE All insecticidal carbamates are N-methyl carbamates R = CH3 or H X = leaving group Usually bulky Alkyl aldicarb Aromatic carbaryl Physostigmene
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Mechanism of Action Resemble OPs because they Inhibit AChE
Have a leaving group that is hydrolyzed in forming the AChE-carbamate complex Differ from OPs because AChE-carbamate complex dissociates readily Aging does not occur Atropine is a more effective antidote than the oximes (e.g., 2-PAM)
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Biotransformation of Carbamates
Insecticidal carbamates Are N-methyl esters With R = H or CH3 X = bulky leaving group Activation Requires cleaving of leaving group by carboxyesterase Alternative metabolism N-demethylation Produces formaldehyde as byproduct Epoxide metabolite Mediated by CYP 1A1
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Toxicity Aldicarb Oral LD50 in rats is 0.9 mg/kg
Dermal LD50 in rats is 5 mg/kg Carbofuran Human oral LD50 is 11 mg/kg Oral LD50 in rats is 5-8 mg/kg Dermal LD50 in rats is 120 mg/kg Carbaryl Oral LD50 in rats is mg/kg Dermal LD50 in rats is ca 2000 mg/kg Chronic: OPIDN-like muscle weakness Temporary, even with continued exposure
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Synthesis of Carbamates: Carbaryl 1. using naphthol-1& phosgene
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2. Using methyl isocyanate
3. Using methyl carbamoyl chloride
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Alternative? Reason for alternative synthesis:
Hazard of methyl isocyanate
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Methyl Isocyanate Properties Reactive Exothermic polymerization
Precursor for carbamate insecticides Carbaryl Methomyl Aldicarb Carbofuran Bhopal, 12/3/84 Union Carbide plant in Madya Pradesh Safety deficits ---> explosion 8,000 dead immediately Permanent sequelae in survivors Toxicities Pulmonary Reproductive Synthesis of carbaryl from carbamoyl chloride and MIC
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Long-term Effects of Carbamates
Carcinogenicity? N-methyl carbamates form nitroso-carbamates at pH 3 These compounds are probable carcinogens Risk is unquantified and disputed Reproductive/Developmental toxicity? Carbaryl Dogs Epidemiology Immunotoxicity? Aldicarb
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Carbaryl (SevinTM) LD50 : 250 mg/kg in rats
Environmental persistence: brief to moderate Repro and developmental toxicity: ??? Carcinogenicity: ?? Delayed neurotoxicity? Reversible muscle weakness Precursor, MIC, extremely dangerous
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Aldicarb LD50 : ≤ 1 mg/kg for mammals, fish
Degraded by sunlight, but persists in groundwater Chronic effects Immune system depression? Carcinogenicity?
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Carbofuran Corn rootworm insecticide Oral LD50 ≤ 8 mg/kg in rats (po)
11 mg/kg in humans ~ 1 mg/kg in birds Environmental Effects: Loses effectiveness due to increasingly rapid microbial degradation
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Procarbamates Cleaving of this group ---> active carbamate
Substitute more complex group for N-CH3 or N-H Cleaving of this group ---> active carbamate Complex group may have its own insecticidal activity Formamidine-carbamates Procarbamates often have Better acaricidal activity Lower mammalian toxicity Example: Carbosulfan Carbosulfan: a procarbamate
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