Synthesis, nematocidal activity and SAR study of novel difluoromethylpyrazole carboxamide derivatives containing flexible alkyl chain moieties

Liu, Xinghai; Zhao, Wen; Shen, Zhonghua; Xing, Jia-Hua; Xu, Tian‐Ming; Peng, Wei‐Li

doi:10.1016/j.ejmech.2016.10.017

Cited by 57 publications

(25 citation statements)

References 38 publications

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“…Therefore, the identification and characterization of cholinergic agonist receptors from nematodes have driven important research efforts during the last decades [ 10 – 13 ]. Although nicotinic agonists are not currently used in the treatment or prevention of plant parasitic or filarial worms, recent reports of their in vitro efficacy further highlight the importance of elucidating their pharmacological targets [ 14 – 18 ].…”

Section: Introductionmentioning

confidence: 99%

Deciphering the molecular determinants of cholinergic anthelmintic sensitivity in nematodes: When novel functional validation approaches highlight major differences between the model Caenorhabditis elegans and parasitic species

et al. 2018

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Cholinergic agonists such as levamisole and pyrantel are widely used as anthelmintics to treat parasitic nematode infestations. These drugs elicit spastic paralysis by activating acetylcholine receptors (AChRs) expressed in nematode body wall muscles. In the model nematode Caenorhabditis elegans, genetic screens led to the identification of five genes encoding levamisole-sensitive-AChR (L-AChR) subunits: unc-38, unc-63, unc-29, lev-1 and lev-8. These subunits form a functional L-AChR when heterologously expressed in Xenopus laevis oocytes. Here we show that the majority of parasitic species that are sensitive to levamisole lack a gene orthologous to C. elegans lev-8. This raises important questions concerning the properties of the native receptor that constitutes the target for cholinergic anthelmintics. We demonstrate that the closely related ACR-8 subunit from phylogenetically distant animal and plant parasitic nematode species functionally substitutes for LEV-8 in the C. elegans L-AChR when expressed in Xenopus oocytes. The importance of ACR-8 in parasitic nematode sensitivity to cholinergic anthelmintics is reinforced by a ‘model hopping’ approach in which we demonstrate the ability of ACR-8 from the hematophagous parasitic nematode Haemonchus contortus to fully restore levamisole sensitivity, and to confer high sensitivity to pyrantel, when expressed in the body wall muscle of C. elegans lev-8 null mutants. The critical role of acr-8 to in vivo drug sensitivity is substantiated by the successful demonstration of RNAi gene silencing for Hco-acr-8 which reduced the sensitivity of H. contortus larvae to levamisole. Intriguingly, the pyrantel sensitivity remained unchanged thus providing new evidence for distinct modes of action of these important anthelmintics in parasitic species versus C. elegans. More broadly, this highlights the limits of C. elegans as a predictive model to decipher cholinergic agonist targets from parasitic nematode species and provides key molecular insight to inform the discovery of next generation anthelmintic compounds.

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Section: Introductionmentioning

confidence: 99%

Deciphering the molecular determinants of cholinergic anthelmintic sensitivity in nematodes: When novel functional validation approaches highlight major differences between the model Caenorhabditis elegans and parasitic species

et al. 2018

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“…The fluorine atom with a small radius and strong electronegativity has simulation, electronic, blocking, and penetration effects. Fluorine atoms are frequently introduced into herterocycles to obtain strong bioactivity in medicinal chemistry and pesticide chemistry.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and in vivo fungicidal activity of some new quinoline derivatives against rice blast

Liu

Fang

Xie

et al. 2017

Pest Management Science

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“…The crystal structure of SDH (PDB entry: 2fbw) was downloaded from the RCSB Protein Data Bank. The molecular docking procedures were carried out by Discovery Studio 3.5 (Liu et al, ; Wu, Robertson, Iii, & Vieth, ).…”

Section: Methodsmentioning

confidence: 99%

Design, synthesis, and antifungal activity of novel cinnamon–pyrazole carboxamide derivatives

Ren

Liu

Jiao

et al. 2018

Drug Development Research

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Hit, Lead & Candidate Discovery To discover succinate dehydrogenase inhibitors with a novel structure, we introduced cinnamic acid structure to optimize the lead structure 1 and synthesized four series of cinnamon–pyrazole carboxamide derivatives. The bioassay data showed that compounds (E)‐N‐(1‐[4‐chlorophenyl]‐4‐cyano‐1H‐pyrazol‐5‐yl)‐3‐(2‐fluorophenyl) acrylamide (5III‐d) and (E)‐3‐(2‐chlorophenyl)‐N‐(1‐[4‐chlorophenyl]‐4‐cyano‐1H‐pyrazol‐5‐yl) acrylamide (5III‐f) showed the significant antifungal activity against three fungi. In addition, 5III‐d and 5III‐f exhibited the excellent inhibitory effect against succinate dehydrogenase (SDH) enzymes with IC50 values ranging from 19.4 to 28.7 μM. The study demonstrates that the chlorine substituent group is present on both the phenyl and pyrazole rings that have a very good effect on the antifungal effect, and the compounds 5III‐d and 5III‐f can act as potential SDH inhibitors (SDHI) and throw a sprat for a new generation of SDHI.

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Synthesis, nematocidal activity and SAR study of novel difluoromethylpyrazole carboxamide derivatives containing flexible alkyl chain moieties

Cited by 57 publications

References 38 publications

Deciphering the molecular determinants of cholinergic anthelmintic sensitivity in nematodes: When novel functional validation approaches highlight major differences between the model Caenorhabditis elegans and parasitic species

Deciphering the molecular determinants of cholinergic anthelmintic sensitivity in nematodes: When novel functional validation approaches highlight major differences between the model Caenorhabditis elegans and parasitic species

Synthesis and in vivo fungicidal activity of some new quinoline derivatives against rice blast

Design, synthesis, and antifungal activity of novel cinnamon–pyrazole carboxamide derivatives

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