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.