Synthesis and optimisation of P 3 substituted vinyl sulfone-based inhibitors as anti-trypanosomal agents.

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 P ₃ position, were accessed in a divergent manner from a common intermediate (ammonium salt 8). Several P ₃ analogues exhibited sub-micromolar EC ₅₀ 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.
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