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

Autor: Doherty W; Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Dublin D04 N2E2, Ireland., Adler N; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland., Butler TJ; School of Biological and Health Sciences, Technological University Dublin, Dublin City Campus, Kevin St., Dublin D08 NF82, Ireland., Knox AJS; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland; School of Biological and Health Sciences, Technological University Dublin, Dublin City Campus, Kevin St., Dublin D08 NF82, Ireland. Electronic address: andrew.knox@tudublin.ie., Evans P; Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Dublin D04 N2E2, Ireland. Electronic address: paul.evans@ucd.ie.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2020 Dec 01; Vol. 28 (23), pp. 115774. Date of Electronic Publication: 2020 Sep 20.
DOI: 10.1016/j.bmc.2020.115774
Abstrakt: 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.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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