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.
Highlights
In 1992, it was reported that vinyl sulfones were inhibitors of the cysteine protease papain.[1]
The chemical yields were moderate, a wide range of structurally and electronically diverse analogues of our previously prepared, most active compound have been accessed from one common intermediate
Over the sixteenmember vinyl sulfone dipeptide-based family, most of the structural changes to the P3 substituent were well tolerated in terms of antitrypanosomal activity
Summary
In 1992, it was reported that vinyl sulfones were inhibitors of the cysteine protease papain.[1]. To date, we have not varied the identity of the Cbz substituent This is of interest since substituents in this position protrude into the large P3 region of the cysteinyl protease[7] binding pocket and in principle, additional binding interactions and/or selectivity might be achieved following optimisation of the group penetrating this region. Attempts to improve activity of our lead vinyl sulfone compound 7 involving treatment of 8 with a variety of electrophiles and subsequent biological evaluation of the resultant analogues, is reported
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