The development of new therapies for leishmaniases (which affeThe development of new therapies for visceral leishmaniasis (affects ~12 million people worldwide) and Chagas disease (~6-7 million people worldwide) is critically dependent on the identification of novel pharmacophores with new modes of action. Current treatments suffer from severe side effects, high cost, patient compliance issues, and emerging resistance; as such, new therapeutic leads are urgently required. Despite significant investment, limited progress has been made with research into new 'synthetic' drugs: no candidates are in clinical trials (although two compounds have recently progressed to preclinical evaluation for VL). In contrast, research into natural product-derived drugs has been largely ignored, despite their track record as frontline treatments for VL (amphotericin B) and the most prominent parasitic disease, malaria (artemisinin). In this project, we challenge this dogma through the exploration of a series of structurally-related alkaloid natural product families, where highly promising antiparasitic bioactivity has been observed in the few examples studied. The selection of these families is additionally based on their accessibility through concise, modular and convergent synthetic strategies, which facilitate modification. We couple this central focus of synthetic chemistry with collaborations to evaluate bioactivity (with expert parasitologist Prof Andre Tempone), and identify pharmacokinetic/dynamic limitations (with expert pharmacologist Prof Kevin Read), thereby informing analogue refinement and synthesis. This multidisciplinary approach will greatly enhance the impact of the synthetic chemistry work by providing 'real-time' feedback into compound design, enhancing project efficiency and progress. Our overarching, long term impact objective is to identify a new pharmacophore (and potentially new parasite target / mode of action) for the potential development of VL/CD therapies.
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