Discovery, Mode of Action, and Commercialization of Derquantel

Woods, Debra J.; Maeder, Steven; Robertson, Alan P.; Martin, Richard J.; Geary, Timothy G.; Thompson, David P.; Johnson, Sandra S.; Conder, George A.

doi:10.1002/9783527652969.ch18

Cited by 16 publications

(10 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Novel classes of anthelmintics, including an aminoacetonitrile (monepantel), a cyclooctadepsipeptide (emodepside) and a spiroindole (derquantel), have become available relatively recently [10, 11]. Their mode of action involves binding to neural acetylcholine receptors (monepantel) [15], to voltage-/calcium-dependent potassium channels and to G-protein-coupled latrophilin-like receptors (emodepside) [16] or B-subtype nicotinic acetylcholine receptors in muscle cells (derquantel) [17], resulting in spastic (monepantel) or flaccid (emodepside and derquantel) paralysis of sensitive nematodes, leading to death or elimination from the host animal.…”

Section: Introductionmentioning

confidence: 99%

An appraisal of natural products active against parasitic nematodes of animals

Garcia-Bustos

Sleebs

2019

Parasites Vectors

View full text Add to dashboard Cite

Here, the scientific and patent literature on the activities of purified natural compounds has been reviewed, with the aim of assessing their suitability as anthelmintic drug discovery starting points. Only compounds described as active against parasitic nematodes of animals or against the model nematode Caenorhabditis elegans have been analysed. Scientific articles published since 2010 and patents granted from 2000, both inclusive, have been included in this analysis. The results show a scarcity of novel chemical structures, a limited follow-up of compounds disclosed before 2010 and a bias towards the screening of plant products, almost to the exclusion of other sources, when microbial extracts have, historically, provided most starting points for anti-infective drugs. All plant products published in this period were previously known, alerting to the high re-discovery rates of a limited number of chemical classes from this source. The most promising compounds described in the literature reviewed here, namely the linear nemadectin-derivatives, are novel and of bacterial origin. Patented but otherwise unpublished spiroketal structures also appear as interesting scaffolds for future development. The patent literature confirmed that it is possible to patent derivatives of previously known products, making them valid starting points for translational research.

show abstract

Section: Introductionmentioning

confidence: 99%

An appraisal of natural products active against parasitic nematodes of animals

Garcia-Bustos

Sleebs

2019

Parasites Vectors

View full text Add to dashboard Cite

show abstract

“…Another promising combination therapy is derquantel and abamectin [56,57]. Derquantel and abamectin have been used in combination to treat multi-drug resistant Haemonchus contortus [58,59]. However, studies have found monepantel to be more effective than the combined derquantel and abamectin treatment, although monepantel resistance is also prevalent, further exaggerating resistance issues in H. contortus [56,60,61].…”

Section: Resultsmentioning

confidence: 99%

Variation in anthelmintic responses are driven by genetic differences among diverseC. eleganswild strains

Shaver

Wit

Dilks

et al. 2022

Preprint

View full text Add to dashboard Cite

Treatment of parasitic nematode infections in humans and livestock relies on a small arsenal of anthelmintic drugs that have historically reduced parasite burdens. However, anthelmintic resistance (AR) is increasing, and little is known about the molecular and genetic causes of resistance for most drugs. The free-living roundworm Caenorhabditis elegans has proven to be a tractable model to understand AR, where studies have led to the identification of molecular targets of all major anthelmintic drug classes. Here, we used genetically diverse C. elegans strains to perform dose-response analyses across 26 anthelmintic drugs that represent the three major anthelmintic drug classes (benzimidazoles, macrocyclic lactones, and nicotinic acetylcholine receptor agonists) in addition to seven other anthelmintic classes. First, we found that C. elegans strains displayed significant variation in anthelmintic responses across drug classes. Dose-response trends within a drug class showed that the C. elegans strains elicited similar responses within the benzimidazoles but variable responses in the macrocyclic lactones and nicotinic acetylcholine receptor agonists. Next, we compared the effective concentration estimates to induce a 10% maximal response (EC10) and slope estimates of each dose-response curve of each strain to the reference strain, N2, which enabled the identification of anthelmintics with population-wide differences to understand how genetics contribute to AR. Because genetically diverse strains displayed differential susceptibilities within and across anthelmintics, we show that C. elegans is a useful model for screening potential nematicides. Third, we quantified the heritability of responses to each anthelmintic and observed a significant correlation between exposure closest to the EC10 and the exposure that exhibited the most heritable responses. Heritable genetic variation can be explained by strain-specific anthelmintic responses within and across drug classes. These results suggest drugs to prioritize in genome-wide association studies, which will enable the identification of AR genes.

show abstract

“…It is a 2-desoxyparaherquamide, semi-synthetic analogue obtained by chemical reduction of paraherquamide, a fermentation product of Penicillium simplicissimum. 30 Derquantel is the first spiroindole anthelmintic that was marketed in 2010 in veterinary medicine in combination with a macrocyclic lactone, abamectin (Startect ® ).…”

Section: Definition-structurementioning

confidence: 99%

“…Three nicotinic receptors were identified in Ascaris suum : the subtype N (activated by nicotine), the subtype L (activated by levamisole and pyrantel) and the subtype B (activated by bephenium) respectively corresponding to 24pS, 35pS and 45pS channels. 30,33 Derquantel acts as a selective and competitive antagonist of nicotinic acetylcholine receptors by interfering with the 35pS (subtype L) and 45-pS (subtype B) channels leading to flaccid paralysis nematodes that are then expelled from the host. 6 The antagonist effect of Derquantel est plus important in sensitive receiver Pyrantel on the sensitive receiver Levamisole, the Derquantel also remains active on some resistant strains Levamisole.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Pharmacotherapy of gastrointestinal strongylosis of small ruminants: An update

Ouattara¹,

N'guessan

Coulibaly³

2022

IJPCA

View full text Add to dashboard Cite

Gastrointestinal strongylosis, which causes deadly seasonal diarrhea in small ruminants, is a major threat to the livestock population in sub-Saharan Africa. Moreover, livestock is a central component of food security. In addition to this threat, there is a poor veterinary coverage due to the increasing lack of effective anthelmintic drugs against strongyles because of the emergence and proliferation of chemo resistant strains. In this context, and given that the use of a vaccine is not widespread, the establishment of the therapeutic arsenal available to veterinarians to control strongyles will contribute to the food and economic security of rural populations. This review outlines the main pharmacochemical classes of anthelmintics used in the management of strongylosis of small ruminants.

show abstract

Discovery, Mode of Action, and Commercialization of Derquantel

Cited by 16 publications

References 23 publications

An appraisal of natural products active against parasitic nematodes of animals

An appraisal of natural products active against parasitic nematodes of animals

Variation in anthelmintic responses are driven by genetic differences among diverseC. eleganswild strains

Pharmacotherapy of gastrointestinal strongylosis of small ruminants: An update

Contact Info

Product

Resources

About