Insecticidal Pyrroles

Addor, R. W.; Babcock, T. J.; Black, Bruce C.; Brown, Dean G.; Diehl, R. E.; Furch, Joseph A.; Kameswaran, V.; Kamhi, V. M.; Kremer, Kenneth A. M.; Kuhn, D. G.; Lovell, J. B.; Lowen, Gregory T.; Miller, T. P.; Peevey, R. M.; Siddens, J. K.; Treacy, M. F.; Trotto, S. H.; Wright, Damian P.

doi:10.1021/bk-1992-0504.ch025

Cited by 37 publications

(12 citation statements)

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“…The natural product antibiotic, dioxapyrrolomycin (1) isolated from Streptomyces MG796-AF7, 1 displays moderate insecticidal and acaricidal activity against arachnids, mites and ticks 2 and has been found to be a potent uncoupler of oxidative phosphorylation. 3 Using 1 as a lead compound, 2-arylpyrroles, have been developed through QSAR studies 4 and identified as a novel class of insecticides and acaricides. In particular, Pirate™ 2 has been commercially developed as a broad-spectrum insecticide/ miticide.…”

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Investigations into the Parallel Synthesis of Novel Pyrrole-Oxazole Analogues of the Insecticide Pirate

Loughlin¹,

Henderson²,

Elson³

et al. 2006

Synthesis

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Investigations into the parallel synthesis of selected analogues of a structurally unique pyrrole-oxazole analogue of the pyrrole insecticide pirate, are reported. Acylaminoketone salts were obtained from ketobromides in moderate to high yields and excellent purity. A number of N-tosyl pyrroles were obtained; however, formation of the target acyl tosyl pyrroles was thwarted by the stereoelectronic effects of the pyrrole substituents. During the pyrrole subunit chemistry, an interesting pyrrole derivative, vinyl pyrrole, was isolated. By restricting diversity to the aryl subunit, the parallel synthesis of selected pyrrole-oxazoles in moderate purity, was achieved when electron-donating or no groups were present on the aryl ring.The natural product antibiotic, dioxapyrrolomycin (1) isolated from Streptomyces MG796-AF7, 1 displays moderate insecticidal and acaricidal activity against arachnids, mites and ticks 2 and has been found to be a potent uncoupler of oxidative phosphorylation. 3 Using 1 as a lead compound, 2-arylpyrroles, have been developed through QSAR studies 4 and identified as a novel class of insecticides and acaricides. In particular, Pirate™ 2 has been commercially developed as a broad-spectrum insecticide/ miticide. 3 The N-dealkylated analogue 3, of pirate, is the metabolically active compound, 5 where the activity of the pyrrole insecticides is primarily a function of lipophilicity (Log P) and acidity (pK a ). 2,6 Figure 1 Structures of known insecticides 1-3 and potential lead compounds 4 and 5As part of a study aimed at identifying new potential insecticides, we sought to synthesize novel, structurally unique analogues of pirate 2, that might ultimately deliver improved dosage rates and selectivity in the field, while reducing negative ecological impact. Previously 7 we generated simple pyrrole-oxazoles 4 and 5, and established that they displayed moderate cytotoxicity.During these investigations, 7 we established a viable synthetic route to pyrrole-oxazole 5 via coupling of 6 and 7a and subsequent conversion to the target pyrrole-oxazole 5 (Scheme 1) without any purification steps, in 21% yield (cf. 10% with purification steps). 7 This suggested that the sequence was robust enough for the generation of analogues using solution-phase parallel synthesis. In the present work we wish to report the results of our investigations on the parallel synthesis of selected analogues of pyrrole-oxazole 5. Scheme 1We examined the parallel synthesis of acylaminoketone salts, choosing commercially available ketobromides 10a-k, which varied in the steric and electronic influences of the group a to the ketone. Acylaminoketone salts 7a-k were obtained, in moderate to high yields and excellent purity (with the exception of 7j which, though high yielding, was impure), via a Delépine reaction in which the ketobromides 10a-k were reacted with hexamethylenetetramine 9 followed by cleavage of the resulting salt 11a-k with hydrobromic acid (Scheme 2). 10

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“…In particular, Pirate™ 2 has been commercially developed as a broad-spectrum insecticide/ miticide. 3 The N-dealkylated analogue 3, of pirate, is the metabolically active compound, 5 where the activity of the pyrrole insecticides is primarily a function of lipophilicity (Log P) and acidity (pK a ). 2,6…”

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confidence: 99%

Investigations into the Parallel Synthesis of Novel Pyrrole-Oxazole Analogues of the Insecticide Pirate

Loughlin¹,

Henderson²,

Elson³

et al. 2006

Synthesis

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“…The founding member of insecticidal and acaricidal arylpyrroles was a natural product, dioxapyrrolomycin, first identified as a metabolite from Streptomyces fumanus (see Carter et al, 1987 ). The structure of dioxapyrrolomycin was modified to yield the commercial product chlorfenapyr ( Addor et al, 1992 ), a compound that is effective against a range of parasitic arthropods of plants, including the southern armyworm ( Persectania ewingii ), tobacco budworm ( Heliothis virescens -Fabricius), western potato leafhopper ( Empoasca abrupta ) and red spider mite ( Tetranychus urticae ) ( Kuhn, 1997 ). Chlorfenapyr is a pro-drug that is metabolically converted to the active compound (CL303268) by N-dealkylation inside the pathogen ( Black et al, 1994 ).…”

Section: Discussionmentioning

confidence: 99%

Arylpyrrole and fipronil analogues that inhibit the motility and/or development of Haemonchus contortus in vitro

Herath

Song

Preston

et al. 2018

International Journal for Parasitology: Drugs and Drug Resistan

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Due to widespread drug resistance in parasitic nematodes, there is a need to develop new anthelmintics. Given the cost and time involved in developing a new drug, the repurposing of known chemicals can be a promising, alternative approach. In this context, we tested a library (n = 600) of natural product-inspired pesticide analogues against exsheathed third stage-larvae (xL3s) of Haemonchus contortus (barber's pole worm) using a whole-organism, phenotypic screening technique that measures the inhibition of motility and development in treated larvae. In the primary screen, we identified 32 active analogues derived from chemical scaffolds of arylpyrrole or fipronil. The seven most promising compounds, selected based on their anthelmintic activity and/or limited cytotoxicity, are arylpyrroles that reduced the motility of fourth-stage larvae (L4s) with significant potency (IC50 values ranged from 0.04 ± 0.01 μM to 4.25 ± 0.82 μM, and selectivity indices ranged from 10.6 to 412.5). Since the parent structures of the active compounds are uncouplers of oxidative phosphorylation, we tested the effect of selected analogues on oxygen consumption in xL3s using the Seahorse XF24 flux analyser. Larvae treated with the test compounds showed a significant increase in oxygen consumption compared with the untreated control, demonstrating their uncoupling activity. Overall, the results of the present study have identified natural product-derived molecules that are worth considering for chemical optimisation as anthelmintic drug leads.

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“…The pyrrole ring system is an attractive target since it is the central scaffold in a variety of known agrochemicals and pharmaceutical drugs. − We were particularly interested in 3-carboxypyrrolinones based on the similarity of these structures to known chemical hybridizing agents. − …”

Section: Introductionmentioning

confidence: 99%

A Novel Solid-Phase Synthesis of Carboxypyrrolinones

et al. 1999

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A solid-phase organic synthesis method has been developed for the preparation of 3-carboxypyrrolinones 9. Treatment of polymer-bound malonic acid with amino alcohols afforded the malonamide resin products 6. Benzyl and alkyl amino alcohols were prepared in solution via a two-step procedure without purification and were coupled to the resin directly using a resin capture strategy. Polymer loadings and product conversions were determined by direct cleavage of resin-bound materials and analysis by 1H NMR spectroscopy with an internal standard. Treatment of the polymer-bound malonamides with TFA released the malonamic acids, 10, which underwent further reaction to afford the trifluoroacetate derivatives 11. Secondary amides underwent an additional cyclization to afford oxazoles 12. The malonamide resins 6 can be oxidized to the corresponding ketones 7 by treatment with CrO2(O-t-Bu)2, which can in turn be cyclized in the presence of LDA or LHMDS to afford the carboxypyrrolinones 8. TFA treatment releases the free carboxypyrrolinones, 9, in 43−80% overall yield.

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Insecticidal Pyrroles

Cited by 37 publications

References 0 publications

Investigations into the Parallel Synthesis of Novel Pyrrole-Oxazole Analogues of the Insecticide Pirate

Investigations into the Parallel Synthesis of Novel Pyrrole-Oxazole Analogues of the Insecticide Pirate

Arylpyrrole and fipronil analogues that inhibit the motility and/or development of Haemonchus contortus in vitro

A Novel Solid-Phase Synthesis of Carboxypyrrolinones

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