Synthesis and Optimisation of P3 Substituted Vinyl Sulfone-Based Inhibitors as Anti-Trypanosomal Agents
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1.6 BIOLOGICAL SCIENCES, Cell biology,, Microbiology, Virology, Biochemistry and molecular biology
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.
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