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
- 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
- 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
Metabolic profiling and in vitro assessment of anthelmintic fractions of Picria fel-terrae Lour
- Kumarasingha, Rasika, Karpe, Avinash, Preston, Sarah, Yeo, Tiong-Chia, Lim, Diana, Tu, Chu-Lee, Luu, Jennii, Simpson, Kaylene, Shaw, Jillian, Gasser, Robin, Beale, David, Morrison, Paul, Palombo, Enzo, Boag, Peter
- Authors: Kumarasingha, Rasika , Karpe, Avinash , Preston, Sarah , Yeo, Tiong-Chia , Lim, Diana , Tu, Chu-Lee , Luu, Jennii , Simpson, Kaylene , Shaw, Jillian , Gasser, Robin , Beale, David , Morrison, Paul , Palombo, Enzo , Boag, Peter
- Date: 2016
- Type: Text , Journal article
- Relation: International Journal for Parasitology: Drugs and Drug Resistance Vol. 6, no. 3 (2016), p. 171-178
- Full Text:
- Reviewed:
- Description: Anthelmintic resistance is widespread in gastrointestinal nematode populations, such that there is a consistent need to search for new anthelmintics. However, the cost of screening for new compounds is high and has a very low success rate. Using the knowledge of traditional healers from Borneo Rainforests (Sarawak, Malaysia), we have previously shown that some traditional medicinal plants are a rich source of potential new anthelmintic drug candidates. In this study, Picria fel-terrae Lour. plant extract, which has previously shown promising anthelmintic activities, was fractionated via the use of a solid phase extraction cartridge and each isolated fraction was then tested on free-living nematode Caenorhabditis elegans and the parasitic nematode Haemonchus contortus. We found that a single fraction was enriched for nematocidal activity, killing ≥90% of C. elegans adults and inhibiting the motility of exsheathed L3 of H. contortus, while having minimal cytotoxic activity in mammalian cell culture. Metabolic profiling and chemometric analysis of the effective fraction indicated medium chained fatty acids and phenolic acids were highly represented. Image 1 •Chemical fractionation of Picria fel-terrae Lour. plant extract.•Anthelmintic activity against Caenorhabditis elegans and Haemonchus contortus.•Metabolic profiling and chemometric analysis of active fraction.•Active fraction has minimal mammalian cytotoxicity.
- Authors: Kumarasingha, Rasika , Karpe, Avinash , Preston, Sarah , Yeo, Tiong-Chia , Lim, Diana , Tu, Chu-Lee , Luu, Jennii , Simpson, Kaylene , Shaw, Jillian , Gasser, Robin , Beale, David , Morrison, Paul , Palombo, Enzo , Boag, Peter
- Date: 2016
- Type: Text , Journal article
- Relation: International Journal for Parasitology: Drugs and Drug Resistance Vol. 6, no. 3 (2016), p. 171-178
- Full Text:
- Reviewed:
- Description: Anthelmintic resistance is widespread in gastrointestinal nematode populations, such that there is a consistent need to search for new anthelmintics. However, the cost of screening for new compounds is high and has a very low success rate. Using the knowledge of traditional healers from Borneo Rainforests (Sarawak, Malaysia), we have previously shown that some traditional medicinal plants are a rich source of potential new anthelmintic drug candidates. In this study, Picria fel-terrae Lour. plant extract, which has previously shown promising anthelmintic activities, was fractionated via the use of a solid phase extraction cartridge and each isolated fraction was then tested on free-living nematode Caenorhabditis elegans and the parasitic nematode Haemonchus contortus. We found that a single fraction was enriched for nematocidal activity, killing ≥90% of C. elegans adults and inhibiting the motility of exsheathed L3 of H. contortus, while having minimal cytotoxic activity in mammalian cell culture. Metabolic profiling and chemometric analysis of the effective fraction indicated medium chained fatty acids and phenolic acids were highly represented. Image 1 •Chemical fractionation of Picria fel-terrae Lour. plant extract.•Anthelmintic activity against Caenorhabditis elegans and Haemonchus contortus.•Metabolic profiling and chemometric analysis of active fraction.•Active fraction has minimal mammalian cytotoxicity.
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
- 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.
- 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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