Carbamate 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 No insecticidal activity because it does not penetrate insect cuticle.

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

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)

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

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 250-350 mg/kg Dermal LD50 in rats is ca 2000 mg/kg Chronic: OPIDN-like muscle weakness Temporary, even with continued exposure

Synthesis of Carbamates: Carbaryl 1. using naphthol-1& phosgene

2. Using methyl isocyanate 3. Using methyl carbamoyl chloride

Alternative? Reason for alternative synthesis: Hazard of methyl isocyanate

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

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

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

Aldicarb LD50 : ≤ 1 mg/kg for mammals, fish Degraded by sunlight, but persists in groundwater Chronic effects Immune system depression? Carcinogenicity?

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

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