Synthesis and Optimisation of P3 Substituted Vinyl Sulfone-Based Inhibitors as Anti-Trypanosomal Agents

Authors

William Doherty, University College Dublin
Nikoletta Adler, Trinity College Dublin, Ireland
Andrew Knox, Technological University DublinFollow
Thomas J. Butler, Technological University DublinFollow
Paul Evans, University College Dublin

Document Type

Article

Rights

Available under a Creative Commons Attribution Non-Commercial Share Alike 4.0 International Licence

Disciplines

1.6 BIOLOGICAL SCIENCES, Cell biology,, Microbiology, Virology, Biochemistry and molecular biology

Publication Details

• December 2020
• Bioorganic & Medicinal Chemistry 28(23):115774

Abstract

A series of lysine-based vinyl sulfone peptidomimetics were synthesised and evaluated for anti-trypanosomal activity against bloodstream forms of T. brucei. This focused set of compounds, varying in the P3 position, were accessed in a divergent manner from a common intermediate (ammonium salt 8). Several P3 analogues exhibited sub-micromolar EC50 values, with thiourea 14, urea 15 and amide 21 representing the most potent anti-trypanosomal derivatives of the series. In order to establish an in vitro selectivity index the most active anti-trypanosomal compounds were also assessed for their impact on cell viability and cytotoxity effects in mammalian cells. Encouragingly, all compounds only reduced cellular metabolic activity in mammalian cells to a modest level and little, or no cytotoxicity, was observed with the series.

DOI

https://doi.org/10.1016/j.bmc.2020.115774

Recommended Citation

Doherty, W. et al. (2020) Synthesis and Optimisation of P3 Substituted Vinyl Sulfone-Based Inhibitors as Anti-Trypanosomal Agents, Bioorganic & Medicinal Chemistry, 28(23):115774 DOI:10.1016/j.bmc.2020.115774