Design and synthesis of novel natural product inspired trypanosomatid inhibitors
Abstract
Chamuvarinin is a natural product known to have low micromolar activity against Trypanosoma
brucei, causative agent of Human African Trypanosomiasis (HAT). Having completed the total
synthesis of chamuvarinin in 2010, the Florence group started a phenotypic screening-based drug
discovery campaign to identify simplified analogues of chamuvarinin with trypanocidal activity. The
ideal lead compounds sought after need to have retained or improved activity in Trypanosoma
brucei compared to chamuvarinin, as well as being >10 times more potent in parasitic cells than in
mammalian cells. An additional desirable property is broad range activity across a panel of
trypanosomes - Trypanosoma brucei, Trypanosoma cruzi and Leishmania major.
The work described in this thesis is a contribution towards this campaign, looking to expand the
chemical space occupied by the inhibitors synthesised in the group. Two series of inhibitors were
designed and synthesised, one based on THP-furan-THP scaffold and another on the previously
established biphenyl motif-containing lead. The design of inhibitors was partially informed by in
silico studies of the target protein identified in the group using proteomics experiments. This thesis
details the synthesis of the inhibitors and discusses their biological profiles and how the findings can
inform future directions the drug discovery campaign can undertake.
Type
Thesis, PhD Doctor of Philosophy
Rights
Embargo Date: 2024-04-29
Thesis restricted in accordance with University regulations. Print copy restricted until 29th April 2021. Electronic copy restricted until 29th April 2024
Thesis restricted in accordance with University regulations. Print copy restricted until 29th April 2021. Electronic copy restricted until 29th April 2024
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Description of related resources
Data Underpinning Design and Synthesis of Novel Natural Product Inspired Trypanosomatid Inhibitors (PhD Thesis) Zacharova, M.K., University of St Andrews, DOI: https://doi.org/10.17630/338b4dbf-6503-4e8c-a00e-823274d01dc2Related resources
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