Synthesis and testing of a natural product derived library against trypanosomatid parasites

Abstract

Neglected tropical diseases caused by trypanosomatid parasites are a continuing and escalating problem, which devastate the less economically developed cultures in which they are endemic by impairing both human and animal health. Current drugs for these diseases are regarded as out-of-date, expensive, with unacceptable side-effects and mounting parasite resistance, meaning there is an urgent need for new therapeutics. In this work, we capitalise on the longstanding reputation of natural products as a resource of potent and structurally diverse bioactive molecules. We have explored four new, easily accessible drug scaffolds inspired by prevalent motifs from reported trypanocidal natural products, developing their chemical synthesis and investigating structure-activity relationships. All four scaffolds have produced promising lead compound structures through potency-based optimisation, which will benefit the development of new trypanocidal agents against T. brucei, T. cruzi and L. major. Many of the compounds give promising evidence for trypanosome-specific biological activity, and surpass external guidelines for the identification of novel lead structures. This work provides a solid platform for further development of the potency and selectivity of these trypanocidal core structures, as well as for the identification of their cellular targets. We have already begun work to identify the targets of a few select lead scaffolds, facilitated by biochemical assays, as well as metabolomic and proteomic analyses.