Discovery of new chemicals with anthelmintic activity against the barber’s pole worm and other parasitic nematodes
Document TypePhD thesis
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© 2018 Dr Yaqing Jiao
Parasitic nematodes cause a substantial disease burden on humans and animals worldwide. A review of the literature (Chapter 1) showed that, on one hand, neglected tropical diseases caused by parasitic nematodes have a devastating, long-term impact on human health; on the other hand, gastrointestinal nematodes are a major constraint to the livestock industries, causing subclinical infections and diseases in animals and leading to a substantial reduction in meat, milk and fibre production. Currently, anthelmintic treatment remains the mainstay of controlling parasitic nematode infections. However, the massive and widespread resistance to the limited number of commercial anthelmintics, particularly in the veterinary and agricultural contexts, demonstrates an urgency to discover new and effective anthelmintics to sustain the economic and health benefits from the application of anthelmintics. Thus, the key focus of this thesis was to discover new chemical entities and/or known drugs with anthelmintic activities against Haemonchus contortus and/or other socioeconomically important parasitic nematodes for subsequent development. Whole worm-based phenotypic screening assays were employed, compound collections were obtained via product-development-partnerships and/or collaborators, and active compounds were assessed for their potential as anthelmintic candidates. In this thesis, one new chemical entity (designated SN00797439), two human kinase inhibitors (SNS-032 and AG-1295), 14 AG-1295 (tetrahydroquinoxaline) analogues, one insecticide (tolfenpyrad) and two tolfenpyrad (pyrazole-5-carboxamide) derivatives (a-15 and a-17) with anthelmintic activity in vitro were discovered following the screening of a total of 15,333 chemicals from five distinct compound collections against H. contortus. In Chapter 2, a new chemical entity, SN00797439, was identified with activity against a range of parasitic nematodes, including H. contortus, Ancylostoma ceylanicum, Brugia malayi, Dirofilaria immitis and/or Trichuris muris in vitro, offering a novel, lead-like scaffold for the development of a relatively broad-spectrum anthelmintic. In Chapter 3, two human kinase inhibitors under pharmaceutical development, SNS-032 (piperidinecarboxamide) and AG-1295 (quinoxaline), were identified to have inhibitory activity on the motility and development of parasitic larvae of H. contortus in vitro. AG-1295 had limited cytotoxicity against a normal mammalian epithelial cell line (designated MCF10A). In Chapters 4 and 5, three pyrazole-5-carboxamides (tolfenpyrad, a-15 and a-17) were shown to possess significant inhibitory effects on H. contortus without detectable toxicity on a human neonatal foreskin fibroblast (NFF) cell line in vitro. All three of these chemicals were shown to inhibit the oxygen consumption in H. contortus larvae, a finding that was consistent with the known, specific inhibition of complex I of the respiratory electron transport chain by selected pyrazole-5-carboxamides in arthropods. The evaluation of these hit compounds using various technologies employed in parasitology, drug discovery, chemistry, histology, toxicology, molecular biology and bioinformatics should offer data to support their potential as leads for future drug development and to facilitate the exploration of their mode(s) of action in this and related nematodes. Encouraged by the findings in Chapter 3 and the detection of a non-wildtype phenotype in treated worms in vitro, Chapter 6 investigated the activities of 14 additional tetrahydroquinoxaline (AG-1295) analogues on H. contortus. Qualitative and quantitative assessments of larval motility, development and morphological alterations showed that these 14 chemicals all affected the viability of parasitic larvae and, interestingly, induced an eviscerated larval phenotype and led to cuticular damage and/or stunted growth in in vitro H. contortus. Taken together, Chapters 2 to 6 identified a series of 20 hit compounds, some of which have selectivity against H. contortus compared with selected human cell lines tested. In Chapter 7, the research achievements are summarised, and the next steps to be pursued in future research are outlined, including (i) the chemical optimisation of representative chemicals via structure-activity relationship (SAR) evaluations; (ii) assessment of the breadth of spectrum of anthelmintic activity on other parasitic nematodes, such as other 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; (iv) establishment of the modes of action of lead candidates. The findings from the thesis are then put into a broad context and discussed. In conclusion, the present thesis contributes to the fields of parasitology and anthelmintic discovery by identifying compounds with in vitro anthelmintic activity that represent sound starting points for ‘lead’ discovery.
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