Selective toxicity of N,N'-thiodicarbamates

Ma, Fahmy; Nm, Mallipudi; Tr, Fukuto

doi:10.1021/jf60217a021

Cited by 45 publications

(37 citation statements)

References 5 publications

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“…log P of 4.07, whereas for methoprene this value is 5.21 (Tomlin, 1994), indicating that the carbamate analog is less lipophilic than the sesquiterpenoid ester. For structurally diverse groups of neurotoxic carbamate insecticides the replacement of the acidic proton of the carbamate moiety with a nonpolar sulfenylcarbamate or sulfinylcarbamate group renders the molecule more lipophilic and substituent-dependent increases in lipophilicity by log P increments of 1.5 to 4.0 are observed (Fahmy et al, 1978;Fukuto, 1983). Consequently, analog derivatizations of fenoxycarb should afford compounds with log P values significantly higher than that of the parent carbamate.…”

Section: Discussionmentioning

confidence: 99%

“…Bissulfonylcarbamate 6 was prepared by acylation of the appropriate bissulfonamide (McDermott and Spillane, 1984). Unsymmetrical derivatives 11-13 were obtained in 45-7070 yields according to known procedures (Fahmy et al, 1978;Brown and Kohn, 1974) by reacting fenoxycarb with the N-chlorosulfenyl derivative (Brown, 1972) of the corresponding carbamates. The following procedures are typical for the synthesis of representative projuvenoids (Fig.…”

Section: Chemicalsmentioning

confidence: 99%

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Projuvenoids: Synthesis and biological evaluation of sulfenylated, sulfinylated, and sulfonylated carbamates

Ujváry¹,

Matolcsy²,

Bélai³

et al. 1996

Arch. Insect Biochem. Physiol.

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Applying the proinsecticide principle developed earlier for neurotoxic carbamate insecticides, a series of new N‐sulfenylated, N‐sulfinylated, and N‐sulfonylated derivatives of fenoxycarb were synthesized and evaluated for juvenile hormone mimicking activity. Laboratory evaluations of the compounds using Pieris brassicae and Sitophilus oryzae, as well as field experiments using Bemisia tabaci, showed that several symmetrical biscarbamates with either a sulfenyl or sulfinyl bridge possessed higher activity than the parent carbamate. From the unsymmetrical compounds containing biologically inert derivatizing moieties, one of the sulfenylated biscarbamates also showed improved activity against P. brassicae. The changes in the biological activity of the sulfur‐containing derivatives compared to that of the parent compound are attributed to the modified physicochemical characteristics, i.e., increased lipophilicity facilitating penetration, transport, as well as protection of the compound from metabolism. © 1996 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Section: Chemicalsmentioning

confidence: 99%

Projuvenoids: Synthesis and biological evaluation of sulfenylated, sulfinylated, and sulfonylated carbamates

Ujváry¹,

Matolcsy²,

Bélai³

et al. 1996

Arch. Insect Biochem. Physiol.

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“…Armed with knowledge that monomethyl substitution on the carbamyl nitrogen of carbamate insecticides was required for anticholinesterase activity, and inspired by the discovery that malathion achieved its high degree of safety to mammals by being a proinsecticide that was selectively degraded in mammals before bioactivation, Fukuto and coworkers proposed a proinsecticide strategy of replacing the hydrogen on the carbamyl nitrogen of the methyl carbamate ester with various substituents to reduce mammalian toxicity . This approach led to what is unquestionably the largest proinsecticide design program ever, in many academic and industrial labs, from which many commercial products resulted .…”

Section: Examples Of Proinsecticides (Organized By Irac Group)mentioning

confidence: 99%

Chance and design in proinsecticide discovery

Salgado

David

2017

Pest Management Science

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Many insecticides are inactive on their target sites in the form that is sold and applied, needing first to be bioactivated. This proinsecticide strategy has often been achieved by design, through systematic derivatization of intrinsically active molecules with protecting groups that mask their toxic effects until their selective removal in target insects by metabolic enzymes generates the toxiphore. Proinsecticides can be designed to gain selectivity between target and non-target organisms, or to improve bioavailability by enhancing plant or insect uptake. In most cases, however, chance trumps design in proinsecticide discovery: most first-in-class products that we now know to be proinsecticides were only discovered a posteriori to be such, often after having been on the market for years. Knowing the active form of an insecticide is essential to mode of action identification, and early mode of action studies on novel chemotypes should take into account the possibility that the compounds might be proinsecticides. This paper reviews examples of proinsecticides in the marketplace, strategies for making proinsecticides and techniques for unmasking proinsecticides in mode of action studies. Our analysis of global agrochemical sales data shows that 34% of the dollar value of crop insecticides used in 2015 were proinsecticides. © 2016 Society of Chemical Industry.

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“…Carbofuran (2,3-dihydro-2,2-dimethylbenzofuran-7-yl methylcarbamate), an N-methyl carbamate pesticide, is highly toxic (LD 50 = 2 mg kg 31 in mice) [1] and a potent inhibitor of acetylcholinesterase, an enzyme vital for functioning of the central nervous system. Accumulation of carbofuran and its metabolites in the environment could potentially pose health hazards.…”

Section: Introductionmentioning

confidence: 99%

Induction of carbofuran oxidation to 4-hydroxycarbofuran by Pseudomonas sp. 50432

Chaudhry¹

2002

FEMS Microbiology Letters

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Pseudomonas sp. 50432 biotransformed a highly toxic pesticide, carbofuran (2,3-dihydro-2,2-dimethylbenzofuran-7-yl methylcarbamate) to 7-phenol (2,3-dihydro-2,2-dimethyl-7-hydroxy benzofuran) and several unknown metabolites. One of the unknown metabolites identified by gas chromatography/mass spectroscopy was 4-hydroxycarbofuran (2,3-dihydro-2,2-dimethyl-4-hydroxybenzofuran-7-yl methylcarbamate). It had a mass (237) similar to 3-hydroxycarbofuran and 5-hydroxycarbofuran but different fragmentation patterns. This is the first report in which an inducible oxidative enzyme, hydroxylase, mediated the conversion of carbofuran to 4-hydroxycarbofuran. A second constitutively synthesized enzyme hyrolase transformed carbofuran to 7-phenol. ß

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Selective toxicity of N,N'-thiodicarbamates

Cited by 45 publications

References 5 publications

Projuvenoids: Synthesis and biological evaluation of sulfenylated, sulfinylated, and sulfonylated carbamates

Projuvenoids: Synthesis and biological evaluation of sulfenylated, sulfinylated, and sulfonylated carbamates

Chance and design in proinsecticide discovery

Induction of carbofuran oxidation to 4-hydroxycarbofuran by Pseudomonas sp. 50432

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