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Author: Subject: Structure-Activity Relationship of Chlormephos
Falvin
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[*] posted on 10-3-2021 at 20:00
Structure-Activity Relationship of Chlormephos


According to the book "The Chemistry of Organophosphorus Pesticides" by Dr. Christa Fest and Karl-Julius Schmidt, the insecticide Chlormephos, or S-(Chloromethyl) O,O-diethyl phosphorodithioate, has an oral LD50 in rats of about 7 mg/kg. Also according to the book, parathion has an oral LD50 in rats of 6.4 mg/kg. Interestingly enough, according to Pubchem, the methyl analog of Chlormephos without the chlorine atom has an oral LD50 in rats of 156 mg/kg [1]. Parathion, Chlormephos, O,O-Diethyl S-methyl dithiophosphate all work by inhibiting acetylcholinesterase, and all three of them would require metabolic activation by cytochrome P450 enzymes.

My questions are thus:

1. How and why does the substitution of a methyl group with chloromethyl lead to such a dramatic increase in toxicity?

2. Why do parathion and chlormephos have a similar oral toxicity, and how do their structures contribute to this?

Some people I've talked to regarding the first question have suggested that this can be either due to the presence of a chlorine atom increasing the electrophilicity of the phosphorus atom, or perhaps the substitution of methyl with chloromethyl gives the substance an additional mechanism to react with AChE. Alas, I have not been able to find scientific literature that confirms or disproves these explanations, or which offers an explanation.

[1]: https://pubchem.ncbi.nlm.nih.gov/compound/18682

[Edited on 11-3-2021 by Falvin]
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zinc finger
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[*] posted on 5-5-2021 at 11:51


My thoughts on this:
First I would like to give a little bit background on the biochemical mechanisms:
The described group of toxins share the thiophosphate group. As you said, they get activated by c P450. Now it is important to understand how and why this enzyme does that.

Cytochrome P450 is a very well known "universal" enzyme. This means that it acts inside the organism in many different biochemical reactions with a low substrate specificity. The "task" of c P450 is to (normally) inactivate reagents which would otherwise persist or even accumulate. This can be seen for many drugs and it is exactly the reason why they don't work indefinitely. Now the reactions c P450 catalyses are oxidations and for the stated thiophosphates it oxidatively removes the sulphur and leaves a phosphate group. The metabolite then acts on the Acetylcholinesterase. There it covalently binds to the esteratic site thereby permanently disabling the normal function of AChE.

[img]https://en.wikipedia.org/wiki/Acetylcholinesterase_inhibitor#/media/File:AChe_inhibitors_pic.jpg[/img]

Your questions are very hard to answer with a high certainty and very elaborate experiments would be needed to confirm my answers. Unfortunately I do not have any papers of such experiments on hand right now.

1. Instead of the chlorine affecting the electron density at the phosphorus (it is coupled over one C and one S) I suggest that it is relevant at the anionic site which normally "binds" to the choline. The chlorine will definitely polarise the carbon and this in turn could lead to some polar interaction with the anionic binding region. So this would favour interactions of the toxin with the enzyme and allow more inhibition.

2. Instead of the chloromethyl group Parathion has a nitrophenol group. When I apply the same argumentation as above I can coherently argue: the nitro group allows for polar interaction at the anionic binding region.
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