Arylpyrrole and fipronil analogues that inhibit the motility and/or development of Haemonchus contortus in vitro
- Herath, Dilrukshi, Song, Hongjian, Preston, Sarah, Jabbar, Abdul, Wang, Tao, McGee, Sean, Hofmann, Andreas, Garcia-Bustos, Jose, Chang, Bill, Koehler, Anson, Liu, Yuxiu, Ma, Qiaoqiao, Zhang, Penqxiang, Zhao, Qiqi, Wang, Qingmin, Gasser, Robin
- Authors: Herath, Dilrukshi , Song, Hongjian , Preston, Sarah , Jabbar, Abdul , Wang, Tao , McGee, Sean , Hofmann, Andreas , Garcia-Bustos, Jose , Chang, Bill , Koehler, Anson , Liu, Yuxiu , Ma, Qiaoqiao , Zhang, Penqxiang , Zhao, Qiqi , Wang, Qingmin , Gasser, Robin
- Date: 2018
- Type: Text , Journal article
- Relation: International Journal for Parasitology: Drugs and Drug Resistance Vol. 8, no. 3 (2018), p. 379-385
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- Description: 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 (IC 50 values ranged from 0.04 ± 0.01
- Authors: Herath, Dilrukshi , Song, Hongjian , Preston, Sarah , Jabbar, Abdul , Wang, Tao , McGee, Sean , Hofmann, Andreas , Garcia-Bustos, Jose , Chang, Bill , Koehler, Anson , Liu, Yuxiu , Ma, Qiaoqiao , Zhang, Penqxiang , Zhao, Qiqi , Wang, Qingmin , Gasser, Robin
- Date: 2018
- Type: Text , Journal article
- Relation: International Journal for Parasitology: Drugs and Drug Resistance Vol. 8, no. 3 (2018), p. 379-385
- Full Text:
- Reviewed:
- Description: 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 (IC 50 values ranged from 0.04 ± 0.01
Phenotypic screening of the 'Kurz-box' of chemicals identifies two compounds (BLK127 and HBK4) with anthelmintic activity in vitro against parasitic larval stages of Haemonchus contortus
- Nguyen, Linh, Kurz, Thomas, Preston, Sarah, Brueckmann, Hjoerdis, Lungerich, Beate, Herath, Dilrukshi, Koehler, Anson, Wang, Tao, Skalova, Lenka, Jabbar, Abdul, Gasser, Robin
- Authors: Nguyen, Linh , Kurz, Thomas , Preston, Sarah , Brueckmann, Hjoerdis , Lungerich, Beate , Herath, Dilrukshi , Koehler, Anson , Wang, Tao , Skalova, Lenka , Jabbar, Abdul , Gasser, Robin
- Date: 2019
- Type: Text , Journal article
- Relation: Parasites & Vectors Vol. 12, no. (2019), p. 1-9
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- Description: BackgroundDue to anthelmintic resistance problems, there is a need to discover and develop new drugs for the treatment and control of economically important and pathogenic nematodes of livestock animals. With this focus in mind, we screened 236 compounds from a library (called the Kurz-box') representing chemically diverse classes such as heterocyclic compounds (e.g. thiazoles, pyrroles, quinolines, pyrimidines, benzo[1,4]diazepines), hydoxamic acid-based metalloenzyme inhibitors, peptidomimetics (bis- and tris-pyrimidoneamides, alkoxyamides) and various intermediates on Haemonchus contortus, one of the most important parasitic nematodes of ruminants.MethodsIn the present study, we tested these compounds, and measured the inhibition of larval motility and development of exsheathed third-stage (xL3) and fourth-stage (L4) larvae of H. contortus using an optimised, whole-organism phenotypic screening assay.ResultsOf the 236 compounds, we identified two active compounds (called BLK127 and HBK4) that induced marked phenotypic changes in the worm in vitro. Compound BLK127 induced an eviscerated' phenotype in the xL3 stage and also inhibited L4 development. Compound HBK4 exerted a curved' phenotype in both xL3s and L4s.ConclusionsThe findings from this study provide a basis for future work on the chemical optimisation of these compounds, on assessing the activity of optimised compounds on adult stages of H. contortus both in vitro and in vivo (in the host animal) and against other parasitic worms of veterinary and medical importance.
- Authors: Nguyen, Linh , Kurz, Thomas , Preston, Sarah , Brueckmann, Hjoerdis , Lungerich, Beate , Herath, Dilrukshi , Koehler, Anson , Wang, Tao , Skalova, Lenka , Jabbar, Abdul , Gasser, Robin
- Date: 2019
- Type: Text , Journal article
- Relation: Parasites & Vectors Vol. 12, no. (2019), p. 1-9
- Full Text:
- Reviewed:
- Description: BackgroundDue to anthelmintic resistance problems, there is a need to discover and develop new drugs for the treatment and control of economically important and pathogenic nematodes of livestock animals. With this focus in mind, we screened 236 compounds from a library (called the Kurz-box') representing chemically diverse classes such as heterocyclic compounds (e.g. thiazoles, pyrroles, quinolines, pyrimidines, benzo[1,4]diazepines), hydoxamic acid-based metalloenzyme inhibitors, peptidomimetics (bis- and tris-pyrimidoneamides, alkoxyamides) and various intermediates on Haemonchus contortus, one of the most important parasitic nematodes of ruminants.MethodsIn the present study, we tested these compounds, and measured the inhibition of larval motility and development of exsheathed third-stage (xL3) and fourth-stage (L4) larvae of H. contortus using an optimised, whole-organism phenotypic screening assay.ResultsOf the 236 compounds, we identified two active compounds (called BLK127 and HBK4) that induced marked phenotypic changes in the worm in vitro. Compound BLK127 induced an eviscerated' phenotype in the xL3 stage and also inhibited L4 development. Compound HBK4 exerted a curved' phenotype in both xL3s and L4s.ConclusionsThe findings from this study provide a basis for future work on the chemical optimisation of these compounds, on assessing the activity of optimised compounds on adult stages of H. contortus both in vitro and in vivo (in the host animal) and against other parasitic worms of veterinary and medical importance.
Selected alpha-pyrones from the plants Cryptocarya novoguineensis (Lauraceae) and Piper methysticum (Piperaceae) with activity against Haemonchus contortus in vitro
- Herath, Dilrukshi, Preston, Sarah, Jabbar, Abdul, Garcia-Bustos, Jose, Addison, Russell, Hayes, Sasha, Rali, Topul, Wang, Tao, Koehler, Anson, Chang, Bill, Hofmann, Andreas, Davis, Rohan, Gasser, Robin
- Authors: Herath, Dilrukshi , Preston, Sarah , Jabbar, Abdul , Garcia-Bustos, Jose , Addison, Russell , Hayes, Sasha , Rali, Topul , Wang, Tao , Koehler, Anson , Chang, Bill , Hofmann, Andreas , Davis, Rohan , Gasser, Robin
- Date: 2019
- Type: Text , Journal article
- Relation: International Journal for Parasitology-Drugs and Drug Resistance Vol. 9, no. (2019), p. 72-79
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- Description: Due to the widespread occurrence and spread of anthelmintic resistance, there is a need to develop new drugs against resistant parasitic nematodes of livestock animals. The Nobel Prize-winning discovery and development of the anti-parasitic drugs avermectin and artemisinin has renewed the interest in exploring natural products as anthelmintics. In the present study, we screened 7500 plant extracts for in vitro-activity against the barber's pole worm, Haemonchus contortus, a highly significant pathogen of ruminants. The anthelmintic extracts from two plants, Cryptocarya novoguineensis and Piper methysticum, were fractionated by high-performance liquid chromatography (HPLC). Subsequently, compounds were purified from fractions with significant biological activity. Four alpha-pyrones, namely goniothalamin (GNT), dihydrokavain (DHK), desmethoxyyangonin (DMY) and yangonin (YGN), were purified from fractions from the two plants, GNT from C. novoguineensis, and DHK, DMY and YGN (= kavalactones) from P. methysticum. The three kavalactones induced a lethal, eviscerated (Evi) phenotype in treated exsheathed third-stage larvae (xL3s), and DMY and YGN had moderate potencies (IC50 values of 31.7 +/- 0.23 mu M and 23.7 +/- 2.05 mu M, respectively) at inhibiting the development of xL3s to fourth-stage larvae (L4s). Although GNT had limited potency (IC50 of 200-300 mu M) at inhibiting L4 development, it was the only compound that reduced L4 motility (IC50 of 6.25-12.50 mu M). The compounds purified from each plant affected H. contortus in an irreversible manner. These findings suggest that structure-activity relationship studies of alpha-pyrones should be pursued to assess their potential as anthelmintics.
- Authors: Herath, Dilrukshi , Preston, Sarah , Jabbar, Abdul , Garcia-Bustos, Jose , Addison, Russell , Hayes, Sasha , Rali, Topul , Wang, Tao , Koehler, Anson , Chang, Bill , Hofmann, Andreas , Davis, Rohan , Gasser, Robin
- Date: 2019
- Type: Text , Journal article
- Relation: International Journal for Parasitology-Drugs and Drug Resistance Vol. 9, no. (2019), p. 72-79
- Full Text:
- Reviewed:
- Description: Due to the widespread occurrence and spread of anthelmintic resistance, there is a need to develop new drugs against resistant parasitic nematodes of livestock animals. The Nobel Prize-winning discovery and development of the anti-parasitic drugs avermectin and artemisinin has renewed the interest in exploring natural products as anthelmintics. In the present study, we screened 7500 plant extracts for in vitro-activity against the barber's pole worm, Haemonchus contortus, a highly significant pathogen of ruminants. The anthelmintic extracts from two plants, Cryptocarya novoguineensis and Piper methysticum, were fractionated by high-performance liquid chromatography (HPLC). Subsequently, compounds were purified from fractions with significant biological activity. Four alpha-pyrones, namely goniothalamin (GNT), dihydrokavain (DHK), desmethoxyyangonin (DMY) and yangonin (YGN), were purified from fractions from the two plants, GNT from C. novoguineensis, and DHK, DMY and YGN (= kavalactones) from P. methysticum. The three kavalactones induced a lethal, eviscerated (Evi) phenotype in treated exsheathed third-stage larvae (xL3s), and DMY and YGN had moderate potencies (IC50 values of 31.7 +/- 0.23 mu M and 23.7 +/- 2.05 mu M, respectively) at inhibiting the development of xL3s to fourth-stage larvae (L4s). Although GNT had limited potency (IC50 of 200-300 mu M) at inhibiting L4 development, it was the only compound that reduced L4 motility (IC50 of 6.25-12.50 mu M). The compounds purified from each plant affected H. contortus in an irreversible manner. These findings suggest that structure-activity relationship studies of alpha-pyrones should be pursued to assess their potential as anthelmintics.
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