Non‐natural Acetogenin Analogues as Potent Trypanosoma brucei Inhibitors

Abstract

A series of novel bis-tetrahydropyran 1,4-triazole analogues based on the acetogenin framework display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei, the causative agent of African sleeping sickness. A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediates to enable rapid access to diastereochemical variation either side of the 1,4-triazole core. The resulting diastereomeric analogues displayed varying degrees of trypanocidal activity and selectivity in structure activity relationship studies.

Exploring the Antiplasmodial 2‐Aminopyridines as Potential Antitrypanosomal Agents

“…brucei growth at an IC 50 of 3.2 μM. However, values in this range are typical of antitrypanosomal compounds in early development …”

Structure‐Based Design, Synthesis and Biological Evaluation of Bis‐Tetrahydropyran Furan Acetogenin Mimics Targeting the Trypanosomatid F1 Component of ATP Synthase

“…Starting from our established THP building block syn ‐ 16 and anti ‐ 17 ,, Swern oxidation followed by diastereoselective Carreira alkynylation gave the corresponding propargyl alcohols 18 and 19 , respectively. While the stereochemical control of the alkynylation reactions was inconsequential for the downstream synthesis, these conditions proved more efficient compared with lithium TMS‐acetylide addition to the respective aldehydes .…”

“…We have since described a series of bis‐tetrahydropyran 1,4‐triazole analogues based on the chamuvarinin polyether core and assembled from a pool of readily accessible chiral tetrahydropyran (THP) building blocks linked by different heterocyclic spacers including 1,4‐triazoles of type 2 (Figure ). Many of these simplified analogues displayed low micromolar trypanocidal activities but more significantly excellent selectivities relative to mammalian cell lines …”

Development of Simplified Heterocyclic Acetogenin Analogues as Potent and Selective Trypanosoma brucei Inhibitors

“…Inspired by chamuvarinin, we sought to design a series of simplified acetogenin‐like analogues retaining key structural and stereochemical features of the parent natural product. These simplified analogues were assembled from a pool of readily accessible chiral tetrahydropyran (THP) building blocks via copper‐mediated click chemistry . These 1,4‐triazole linked analogues, including 2 , maintained high trypanocidal activity with modest selectivity profiles when compared against the human HeLa cell line.…”

“…Oximes 3 – 5 were rapidly accessed from the corresponding THP alcohols by Swern oxidation and condensation with hydroxylamine (Scheme ). Synthesis of the required alkyne‐substituted THP precursors 6 – 8 have been previously described …”