Synthesis and optimisation of P3 substituted vinyl sulfone-based inhibitors as anti-trypanosomal agents. Issue 23 (1st December 2020)

• Record Type: Journal Article
• Authors: Doherty, William; Adler, Nikoletta; Butler, Thomas J.; Knox, Andrew J.S.; Evans, Paul
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 23(2020)
• Publication Date: 2020-12-01
• Subjects: Cysteinyl protease -- Anti-parasitic -- Peptidomimetic -- S-conjugate addition -- Chemoselective functionalisation; Ac acetyl -- [α]D specific rotation (measured at 589 nm) -- app apparent -- Ar aromatic -- Bu butyl -- Cbz carboxybenzyl (benzyloxycarbonyl) -- d doublet -- dd doublet of doublets -- DIPEA diisopropylethylamine -- DMSO dimethylsulfoxide -- c-Hex cyclohexane -- CI confidence interval -- clogP calculated partition coefficient (log10) -- EC50 effective concentration half maximal -- EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide -- ES electrospray -- Et ethyl -- EtOAc ethyl acetate -- equiv equivalent -- g/mg gram/milligram -- GI50 growth inhibition half maximal -- H hour(s) -- HaCaT human keratinocyte cells -- HOBt hydroxybenzotriazole -- HRMS high resolution mass spectrometry -- IR infrared (spectroscopy) -- J coupling constant -- LD50 lethal dose half maximal -- LDH lactate dehydrogenase -- M molarity (moldm−3) -- m multiplet -- Me methyl -- mL/μL millilitre/microlitre -- M.p melting point -- MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- NMR nuclear magnetic resonance -- Ph phenyl -- ppm parts per million -- q quartet -- Rf retention factor -- rt room temperature (approx. 18 °C) -- S.D standard deviation -- t triplet; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115774
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 P 3 position, were accessed in a divergent manner from a common intermediate (ammonium salt 8 ). Several P 3 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.