- Jiao, Yaqing, Preston, Sarah, Hofmann, Andreas, Taki, Aya, Baell, Jonathan, Chang, Bill, Jabbar, Abdul, Gasser, Robin
- Authors: Jiao, Yaqing , Preston, Sarah , Hofmann, Andreas , Taki, Aya , Baell, Jonathan , Chang, Bill , Jabbar, Abdul , Gasser, Robin
- Date: 2020
- Type: Text , Book chapter
- Relation: Advances in Parasitology p. 1-45
- Full Text: false
- Reviewed:
- Description: Parasitic roundworms (nematodes) cause substantial morbidity and mortality in animals worldwide. Anthelmintic treatment is central to controlling these worms, but widespread resistance to most of the commercially available anthelmintics for veterinary and agricultural use is compromising control, such that there is an urgency to discover new and effective drugs. The purpose of this article is to review information on parasitic nematodes, the treatment and control of parasitic nematode infections and aspects of discovering new anthelmintics in the context of anthelmintic resistance problems, and then to discuss some progress that our group has made in identifying selected compounds with activity against nematodes. The focus of our recent work has been on discovering new chemical entities and known drugs with anthelmintic activities against Haemonchus contortus as well as other socioeconomically important parasitic nematodes for subsequent development. Using whole worm-based phenotypic assays, we have been screening compound collections obtained via product-development-partnerships and/or collaborators, and active compounds have been assessed for their potential as anthelmintic candidates. Following the screening of 15,333 chemicals from five distinct compound collections against H. contortus, we have discovered one new chemical entity (designated SN00797439), two human kinase inhibitors (SNS-032 and AG-1295), 14 tetrahydroquinoxaline analogues, one insecticide (tolfenpyrad) and two tolfenpyrad (pyrazole-5-carboxamide) derivatives (a-15 and a-17) with anthelmintic activity in vitro. Some of these 20 ‘hit’ compounds have selectivity against H. contortus in vitro when compared to particular human cell lines. In our opinion, some of these compounds could represent starting points for ‘lead’ development. Accordingly, the next research steps to be pursued include: (i) chemical optimisation of representative chemicals via structure-activity relationship (SAR) evaluations; (ii) assessment of the breadth of spectrum of anthelmintic activity on a range of other parasitic nematodes, such as strongyloids, ascaridoids, enoplids and filarioids; (iii) detailed investigations of the absorption, distribution, metabolism, excretion and toxicity (ADMET) of optimised chemicals with broad nematocidal or nematostatic activity; and (iv) establishment of the modes of action of lead candidates. © 2020 Elsevier Ltd
Identification of fromiamycalin and halaminol A from Australian marine sponge extracts with anthelmintic activity against haemonchus contortus
- Herath, Dilrukshi, Preston, Sarah, Jabbar, Abdul, Garcia-Bustos, Jose, Taki, Aya, Addison, Russell, Hayes, Sasha, Beattie, Karren, McGee, Sean, Martin, Sheree, Ekin, Merrick, Hooper, John, Chang, Bill, Hofmann, Andreas, Davis, Rohan, Gasser, Robin
- Authors: Herath, Dilrukshi , Preston, Sarah , Jabbar, Abdul , Garcia-Bustos, Jose , Taki, Aya , Addison, Russell , Hayes, Sasha , Beattie, Karren , McGee, Sean , Martin, Sheree , Ekin, Merrick , Hooper, John , Chang, Bill , Hofmann, Andreas , Davis, Rohan , Gasser, Robin
- Date: 2019
- Type: Text , Journal article
- Relation: Marine Drugs Vol. 17, no. 11 (Nov 2019), p. 14
- Full Text:
- Reviewed:
- Description: There is an urgent need to discover and develop new anthelmintics for the treatment of parasitic nematodes of veterinary importance to circumvent challenges linked to drug resistant parasites. Being one of the most diverse natural ecosystems, the marine environment represents a rich resource of novel chemical entities. This study investigated 2000 extracts from marine invertebrates, collected from Australian waters, for anthelmintic activity. Using a well-established in vitro bioassay, these extracts were screened for nematocidal activity against Haemonchus contortus - a socioeconomically important parasitic nematode of livestock animals. Extracts (designated Mu-1, Ha-1 and Ha-2) from two marine sponges (Monanchora unguiculata and Haliclona sp.) each significantly affected larvae of H. contortus. Individual extracts displayed a dose-dependent inhibition of both the motility of exsheathed third-stage larvae (xL3s) and the development of xL3s to fourth-stage larvae (L4s). Active fractions in each of the three extracts were identified using bioassay-guided fractionation. From the active fractions from Monanchora unguiculata, a known pentacyclic guanidine alkaloid, fromiamycalin (1), was purified. This alkaloid was shown to be a moderately potent inhibitor of L4 development (half-maximum inhibitory concentration (IC50) = 26.6 +/- 0.74 mu M) and L4 motility (IC50 = 39.4 +/- 4.83 mu M), although it had a relatively low potency at inhibiting of xL3 motility (IC50 >= 100 mu M). Investigation of the active fractions from the two Haliclona collections led to identification of a mixture of amino alcohol lipids, and, subsequently, a known natural product halaminol A (5). Anthelmintic profiling showed that 5 had limited potency at inhibiting larval development and motility. These data indicate that fromiamycalin, other related pentacyclic guanidine alkaloids and/or halaminols could have potential as anthelmintics following future medicinal chemistry efforts.
- Authors: Herath, Dilrukshi , Preston, Sarah , Jabbar, Abdul , Garcia-Bustos, Jose , Taki, Aya , Addison, Russell , Hayes, Sasha , Beattie, Karren , McGee, Sean , Martin, Sheree , Ekin, Merrick , Hooper, John , Chang, Bill , Hofmann, Andreas , Davis, Rohan , Gasser, Robin
- Date: 2019
- Type: Text , Journal article
- Relation: Marine Drugs Vol. 17, no. 11 (Nov 2019), p. 14
- Full Text:
- Reviewed:
- Description: There is an urgent need to discover and develop new anthelmintics for the treatment of parasitic nematodes of veterinary importance to circumvent challenges linked to drug resistant parasites. Being one of the most diverse natural ecosystems, the marine environment represents a rich resource of novel chemical entities. This study investigated 2000 extracts from marine invertebrates, collected from Australian waters, for anthelmintic activity. Using a well-established in vitro bioassay, these extracts were screened for nematocidal activity against Haemonchus contortus - a socioeconomically important parasitic nematode of livestock animals. Extracts (designated Mu-1, Ha-1 and Ha-2) from two marine sponges (Monanchora unguiculata and Haliclona sp.) each significantly affected larvae of H. contortus. Individual extracts displayed a dose-dependent inhibition of both the motility of exsheathed third-stage larvae (xL3s) and the development of xL3s to fourth-stage larvae (L4s). Active fractions in each of the three extracts were identified using bioassay-guided fractionation. From the active fractions from Monanchora unguiculata, a known pentacyclic guanidine alkaloid, fromiamycalin (1), was purified. This alkaloid was shown to be a moderately potent inhibitor of L4 development (half-maximum inhibitory concentration (IC50) = 26.6 +/- 0.74 mu M) and L4 motility (IC50 = 39.4 +/- 4.83 mu M), although it had a relatively low potency at inhibiting of xL3 motility (IC50 >= 100 mu M). Investigation of the active fractions from the two Haliclona collections led to identification of a mixture of amino alcohol lipids, and, subsequently, a known natural product halaminol A (5). Anthelmintic profiling showed that 5 had limited potency at inhibiting larval development and motility. These data indicate that fromiamycalin, other related pentacyclic guanidine alkaloids and/or halaminols could have potential as anthelmintics following future medicinal chemistry efforts.
- Ruan, Banfeng, Zhang, Yuezhou, Tadesse, Solomon, Preston, Sarah, Taki, Aya, Jabbar, Abdul, Hofmann, Andreas, Jiao, Yaqing, Garcia-Bustos, Jose, Harjani, Jitendra, Le, Thuy, Varghese, Swapna, Teguh, Silvia, Xie, Yiyue, Odiba, Jephthah, Hu, Min, Gasser, Robin, Baell, Jonathan
- Authors: Ruan, Banfeng , Zhang, Yuezhou , Tadesse, Solomon , Preston, Sarah , Taki, Aya , Jabbar, Abdul , Hofmann, Andreas , Jiao, Yaqing , Garcia-Bustos, Jose , Harjani, Jitendra , Le, Thuy , Varghese, Swapna , Teguh, Silvia , Xie, Yiyue , Odiba, Jephthah , Hu, Min , Gasser, Robin , Baell, Jonathan
- Date: 2020
- Type: Text , Journal article
- Relation: European Journal of Medicinal Chemistry Vol. 190, no. (2020), p.
- Full Text: false
- Reviewed:
- Description: Parasitic roundworms (nematodes) are significant pathogens of humans and animals and cause substantive socioeconomic losses due to the diseases that they cause. The control of nematodes in livestock animals relies heavily on the use of anthelmintic drugs. However, their extensive use has led to a widespread problem of drug resistance in these worms. Thus, the discovery and development of novel chemical entities for the treatment of parasitic worms of humans and animals is needed. Herein, we describe our medicinal chemistry optimization efforts of a phenotypic hit against Haemonchus contortus based on a pyrrolidine-oxadiazole scaffold. This led to the identification of compounds with potent inhibitory activities (IC50 = 0.78–22.4 μM) on the motility and development of parasitic stages of H. contortus, and which were found to be highly selective in a mammalian cell counter-screen. These compounds could be used as suitable chemical tools for drug target identification or as lead compounds for further optimization. © 2020 Elsevier Masson SAS
Advances in the discovery and development of anthelmintics by harnessing natural product scaffolds
- Herath, H. M. P. Dilrukshi, Taki, Aya, Sleebs, Brad, Hofmann, Andreas, Nguyen, Nghi, Preston, Sarah, Davis, Rohan, Jabbar, Abdul, Gasser, Robin
- Authors: Herath, H. M. P. Dilrukshi , Taki, Aya , Sleebs, Brad , Hofmann, Andreas , Nguyen, Nghi , Preston, Sarah , Davis, Rohan , Jabbar, Abdul , Gasser, Robin
- Date: 2021
- Type: Text , Book chapter
- Relation: Advances in Parasitology p. 203-251
- Full Text: false
- Reviewed:
- Description: Widespread resistance to currently-used anthelmintics represents a major obstacle to controlling parasitic nematodes of livestock animals. Given the reliance on anthelmintics in many control regimens, there is a need for the continued discovery and development of new nematocides. Enabling such a focus are: (i) the major chemical diversity of natural products; (ii) the availability of curated, drug-like extract-, fraction- and/or compound-libraries from natural sources; (iii) the utility and practicality of well-established whole-worm bioassays for Haemonchus contortus—an important parasitic nematodes of livestock—to screen natural product libraries; and (iv) the availability of advanced chromatographic (HPLC), spectroscopic (NMR) and spectrometric (MS) techniques for bioassay-guided fractionation and structural elucidation. This context provides a sound basis for the identification and characterisation of anthelmintic candidates from natural sources. This chapter provides a background on the importance and impact of helminth infections/diseases, parasite control and aspects of drug discovery, and reviews recent work focused on (i) screening well-defined compound libraries to establish the methods needed for large-scale screening of natural extract libraries; (ii) discovering plant and marine extracts with nematocidal or nematostatic activity, and purifying bioactive compounds and assessing their potential for further development; and (iii) synthesising analogues of selected purified natural compounds for the identification of possible ‘lead’ candidates. The chapter describes some lessons learned from this work and proposes future areas of focus for drug discovery. Collectively, the findings from this recent work show potential for selected natural product scaffolds as candidates for future development. Developing such candidates via future chemical optimisation, efficacy and safety evaluations, broad spectrum activity assessments, and target identification represents an exciting prospect and, if successful, could pave the way to subsequent pre-clinical and clinical evaluations. © 2021 Elsevier Ltd
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