Metabolomics and lipidomics reveal perturbation of sphingolipid metabolism by a novel anti-trypanosomal 3-(oxazolo[4,5-b]pyridine-2-yl)anilide

Introduction: Trypanosoma brucei is the causative agent of human African trypanosomiasis, which is responsible for thousands of deaths every year. Current therapies are limited and there is an urgent need to develop new drugs. The anti-trypanosomal compound, 3-(oxazolo[4,5-b]pyridine-2-yl)anilide (OXPA), was initially identified in a phenotypic screen and subsequently optimized by structure–activity directed medicinal chemistry. It has been shown to be non-toxic and to be active against a number of trypanosomatid parasites. However, nothing is known about its mechanism of action. Objective: Here, we have utilized an untargeted metabolomics approach to investigate the biochemical effects and potential mode of action of this compound in T. brucei. Methods: Total metabolite extracts were analysed by HILIC-chromatography coupled to high resolution mass spectrometry. Results: Significant accumulation of ceramides was observed in OXPA-treated T. brucei. To further understand drug-induced changes in lipid metabolism, a lipidomics method was developed which enables the measurement of hundreds of lipids with high throughput and precision. The application of this LC–MS based approach to cultured bloodstream-form T. brucei putatively identified over 500 lipids in the parasite including glycerophospholipids, sphingolipids and fatty acyls, and confirmed the OXPA-induced accumulation of ceramides. Labelling with BODIPY-ceramide further confirmed the ceramide accumulation following drug treatment. Conclusion: These findings clearly demonstrate perturbation of ceramide metabolism by OXPA and indicate that the sphingolipid pathway is a promising drug target in T. brucei.No Full Tex

Structure-Property Optimization of a Series of Imidazopyridines for Visceral Leishmaniasis

Leishmaniasis is a collection of diseases caused by more than 20 Leishmania parasite species that manifest as either visceral, cutaneous, or mucocutaneous leishmaniasis. Despite the significant mortality and morbidity associated with leishmaniasis, it remains a neglected tropical disease. Existing treatments have variable efficacy, significant toxicity, rising resistance, and limited oral bioavailability, which necessitates the development of novel and affordable therapeutics. Here, we report on the continued optimization of a series of imidazopyridines for visceral leishmaniasis and a scaffold hop to a series of substituted 2-(pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles with improved absorption, distribution, metabolism, and elimination properties

A diverse view of science to catalyse change

Valuing diversity leads to scientific excellence, the progress of science and, most importantly, it is simply the right thing to do. We must value diversity not only in words, but also in actions

A diverse view of science to catalyse change:Valuing diversity leads to scientific excellence, the progress of science and, most importantly, it is simply the right thing to do. we must value diversity not only in words, but also in actions

No abstract available.publishe

Novel heterocyclic inhibitors for human African trypanosomiasis

Human African trypanosomiasis (HAT), more commonly known as African sleeping sickness is caused by the protozoan Trypanosoma brucei. There are two subspecies of the parasite that are responsible for human infection; T.b. rhodesiense and T.b. gambiense. These parasites differ in that T.b. rhodesiense results in an acute infection whilst T.b. gambiense results in a chronic infection. HAT was recently named by the World Health Organisation in a list of 17 of the world’s neglected tropical diseases. HAT affects approximately 10,000 people in the remotest parts of Africa with the disease ultimately affecting the central nervous system, resulting in disrupted sleep patterns, brain damage and eventual death. The current treatments for this disease often involve complex therapeutic regimens, lead to the development of long term health issues, and even death in some patients. Reports of resistance developing to some of these treatment options are also becoming more frequent and as a result new treatments are urgently needed. A whole organism high-throughput screen of 87,296 compounds from the WEHI/Bio21 Stage 1 screening library was conducted against T.b. brucei and led to the identification of a number of new compound series. This thesis describes the synthesis and structure-activity relationships (SAR) around four of these series. The first body of work presented centres around the oxazolopyridines and details the initial SAR studies that were conducted. Whilst an increase in the potency of these analogues was achieved there were limiting physicochemical properties that hindered the progression of the series, namely metabolic stability and solubility. A number of analogues were designed and synthesised that particularly focused on improving the metabolic stability of the series. The pyrazine carboxamides are the next series of compounds to be presented in this thesis. Much of the preliminary SAR had already been explored by previous researchers and a number of limitations were uncovered. Notably the metabolism of the series was rapid and the solubility was limiting. In order to address the solubility issue a number of analogues were designed and synthesised with a greater percentage of sp3 carbons and these results are detailed. A number of analogues of the core pyrazine ring were also envisioned and synthesised in order to further probe the SAR around this series. The pyridyl benzamides were chosen for progression as a result of their highly optimisable structure, despite their low micromolar activity against T.b. brucei. The work presented in this chapter demonstrates a significant boost in the activity of the series, down to low nanomolar inhibition as well as the identification of a related series, the thiazole benzamides. Finally, a discussion around the phenyl thiazoles will be presented. A significant SAR exploration had already been conducted by other researchers and potent inhibitors of T.b. brucei had been identified, though the metabolism of the series was rapid and prevented progression of the series. As such a number changes to the core thiazole were envisioned and synthesised as well as modifications to the ethyl linker. The synthesis and results of this work has been detailed herein

Novel heterocyclic inhibitors for human African trypanosomiasis

Human African trypanosomiasis (HAT), more commonly known as African sleeping sickness is caused by the protozoan Trypanosoma brucei. There are two subspecies of the parasite that are responsible for human infection; T.b. rhodesiense and T.b. gambiense. These parasites differ in that T.b. rhodesiense results in an acute infection whilst T.b. gambiense results in a chronic infection. HAT was recently named by the World Health Organisation in a list of 17 of the world’s neglected tropical diseases. HAT affects approximately 10,000 people in the remotest parts of Africa with the disease ultimately affecting the central nervous system, resulting in disrupted sleep patterns, brain damage and eventual death. The current treatments for this disease often involve complex therapeutic regimens, lead to the development of long term health issues, and even death in some patients. Reports of resistance developing to some of these treatment options are also becoming more frequent and as a result new treatments are urgently needed. A whole organism high-throughput screen of 87,296 compounds from the WEHI/Bio21 Stage 1 screening library was conducted against T.b. brucei and led to the identification of a number of new compound series. This thesis describes the synthesis and structure-activity relationships (SAR) around four of these series. The first body of work presented centres around the oxazolopyridines and details the initial SAR studies that were conducted. Whilst an increase in the potency of these analogues was achieved there were limiting physicochemical properties that hindered the progression of the series, namely metabolic stability and solubility. A number of analogues were designed and synthesised that particularly focused on improving the metabolic stability of the series. The pyrazine carboxamides are the next series of compounds to be presented in this thesis. Much of the preliminary SAR had already been explored by previous researchers and a number of limitations were uncovered. Notably the metabolism of the series was rapid and the solubility was limiting. In order to address the solubility issue a number of analogues were designed and synthesised with a greater percentage of sp3 carbons and these results are detailed. A number of analogues of the core pyrazine ring were also envisioned and synthesised in order to further probe the SAR around this series. The pyridyl benzamides were chosen for progression as a result of their highly optimisable structure, despite their low micromolar activity against T.b. brucei. The work presented in this chapter demonstrates a significant boost in the activity of the series, down to low nanomolar inhibition as well as the identification of a related series, the thiazole benzamides. Finally, a discussion around the phenyl thiazoles will be presented. A significant SAR exploration had already been conducted by other researchers and potent inhibitors of T.b. brucei had been identified, though the metabolism of the series was rapid and prevented progression of the series. As such a number changes to the core thiazole were envisioned and synthesised as well as modifications to the ethyl linker. The synthesis and results of this work has been detailed herein

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Anilinoquinoline based inhibitors of trypanosomatid proliferation.

We recently reported the medicinal chemistry re-optimization of a series of compounds derived from the human tyrosine kinase inhibitor, lapatinib, for activity against Plasmodium falciparum. From this same library of compounds, we now report potent compounds against Trypanosoma brucei brucei (which causes human African trypanosomiasis), T. cruzi (the pathogen that causes Chagas disease), and Leishmania spp. (which cause leishmaniasis). In addition, sub-micromolar compounds were identified that inhibit proliferation of the parasites that cause African animal trypanosomiasis, T. congolense and T. vivax. We have found that this set of compounds display acceptable physicochemical properties and represent progress towards identification of lead compounds to combat several neglected tropical diseases