1. Carbamate Insecticides

2. 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.

3. 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

4. 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)

5. 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

6. 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

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

8. 2. Using methyl isocyanate
3. Using methyl carbamoyl chloride

9. Alternative? Reason for alternative synthesis:
Hazard of methyl isocyanate

10. 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

11. 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

12. 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

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

14. 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

15. 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