Compounds Interfering with ATP Synthesis

Perry, A. S.; Yamamoto, Ichiro; Ishaaya, I.; Perry, Regina C.

doi:10.1007/978-3-662-03656-3_17

Cited by 2 publications

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“…Although relatively rare, resistance to naphthalophos in parasitic worms has been reported [ 71 , 72 ], yet the use of organophosphates is unwarranted due to a relatively narrow safety margin [ 73 ]. In contrast, although the Insecticide Resistance Action Committee (IRAC) has not assigned flufenerim’s mode of action, another structurally related acaricide, pyrimidifen, is classified as a mitochondrial complex I electron transport inhibitor (METI) [ 74 ]. The conserved 5-chloropyrimidin-4-amine motif does suggest that pyrimidifen and flufenerim share a similar mode of action, namely, as METIs.…”

Section: Discussionmentioning

confidence: 99%

A phenotypic screen of the Global Health Priority Box identifies an insecticide with anthelmintic activity

Shanley,

Taki,

Byrne

et al. 2024

Parasites Vectors

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Background Infection with parasitic nematodes (helminths), particularly those of the order Strongylida (such as Haemonchus contortus), can cause significant and burdensome diseases in humans and animals. Widespread drug (anthelmintic) resistance in livestock parasites, the absence of vaccines against most of these nematodes, and a lack of new and effective chemical entities on the commercial market demands the discovery of new anthelmintics. In the present study, we searched the Global Health Priority Box (Medicines for Malaria Venture) for new candidates for anthelmintic development. Methods We employed a whole-organism, motility-based phenotypic screening assay to identify compounds from the Global Health Priority Box with activity against larvae of the model parasite H. contortus, and the free-living comparator nematode Caenorhabditis elegans. Hit compounds were further validated via dose–response assays, with lead candidates then assessed for nematocidal activity against H. contortus adult worms, and additionally, for cytotoxic and mitotoxic effects on human hepatoma (HepG2) cells. Results The primary screen against H. contortus and C. elegans revealed or reidentified 16 hit compounds; further validation established MMV1794206, otherwise known as ‘flufenerim’, as a significant inhibitor of H. contortus larval motility (half-maximal inhibitory concentration [IC50] = 18 μM) and development (IC50 = 1.2 μM), H. contortus adult female motility (100% after 12 h of incubation) and C. elegans larval motility (IC50 = 0.22 μM). Further testing on a mammalian cell line (human hepatoma HepG2 cells), however, identified flufenerim to be both cytotoxic (half-maximal cytotoxic concentration [CC50] < 0.7 μM) and mitotoxic (half-maximal mitotoxic concentration [MC50] < 0.7 μM). Conclusions The in vitro efficacy of MMV1794206 against the most pathogenic stages of H. contortus, as well as the free-living C. elegans, suggests the potential for development as a broad-spectrum anthelmintic compound; however, the high toxicity towards mammalian cells presents a significant hindrance. Further work should seek to establish the protein–drug interactions of MMV1794206 in a nematode model, to unravel the mechanism of action, in addition to an advanced structure–activity relationship investigation to optimise anthelmintic activity and eliminate mammalian cell toxicity. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

A phenotypic screen of the Global Health Priority Box identifies an insecticide with anthelmintic activity

Shanley,

Taki,

Byrne

et al. 2024

Parasites Vectors

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Comparative toxicity of an acetogenin-based extract and commercial pesticides against citrus red mite

et al. 2014

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Acetogenins, a class of natural compounds produced by some Annonaceae species, are potent inhibitors of mitochondrial electron transport systems. Although the cellular respiration processes are an important biochemical site for the acaricidal action of compounds, few studies have been performed to assess the bioactivity of acetogenin-based biopesticides on spider mites, mainly against species that occur in orchards. Using residual contact bioassays, this study aimed to evaluate the bioactivity of an ethanolic extract from Annona mucosa seeds (ESAM) (Annonaceae) against the citrus red mite Panonychus citri (McGregor) (Acari: Tetranychidae), an important pest of the Brazilian citriculture. ESAM is a homemade biopesticide which was previously characterized by its high concentration of acetogenins. It caused both high mortality of P. citri females (LC50 = 7,295, 4,662, 3,463, and 2,608 mg l(-1), after 48, 72, 96, and 120 h of exposure, respectively) and significant oviposition deterrence (EC50 = 3.194,80 mg l(-1)). However, there was no effect on P. citri female fertility (hatching rate). In addition, the ESAM efficacy (in terms of its LC90) was compared with commercial acaricides/insecticides (at its recommended rate) of both natural [Anosom(®) 1 EC (annonin), Derisom(®) 2 EC (karanjin), and Azamax(®) 1.2 EC (azadirachtin + 3-tigloylazadirachtol)] and synthetic origin [Envidor(®) 24 SC (spirodiclofen)]. Based on all of the analyzed variables, the ESAM exhibited levels of activity superior to other botanical commercial acaricides and similar to spirodiclofen. Thus, our results indicate that ESAM may constitute a biorational acaricide for citrus red mite integrated pest management in Brazilian citrus orchards, particularly for local use.

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Compounds Interfering with ATP Synthesis

Cited by 2 publications

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A phenotypic screen of the Global Health Priority Box identifies an insecticide with anthelmintic activity

A phenotypic screen of the Global Health Priority Box identifies an insecticide with anthelmintic activity

Comparative toxicity of an acetogenin-based extract and commercial pesticides against citrus red mite

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