Preparation, anti-trypanosomal activity and localisation of a series of dipeptide-based vinyl sulfones

Abstract

An improved, Weinreb amide-based, synthesis of anti-trypanosomal lysine-containing vinyl sulfones is described incorporating, as a feature, diversity at the ε-lysine amino group. Members of this family demonstrated moderate to good efficacy as anti-trypanosomal agents and a fluorescent dansyl (19) derivative was used to investigate subcellular localisation of the compound class.

Synthesis and Evaluation of 1,2,3‐Triazole‐Containing Vinyl and Allyl Sulfones as Anti‐Trypanosomal Agents

“…The P 1 region of the Trypanosomal cysteine proteases is located in the periphery of the polypeptide structure, thus, we felt that a range of substituents might be accommodated in this region with a view to increasing inhibitor binding/selectivity. To this end, azide 4 and phenylacetylene/oct‐1‐yne/methyl propiolate/propargyl alcohol were treated with CuSO 4 · 5H 2 O/sodium ascorbate in CH 2 Cl 2 /H 2 O, which generated triazoles 7 – 10 in good to excellent isolated yields. Gratifyingly, biotinylation with the appropriate alkyne‐derived biotin ester and amide also proved possible (compounds 11 and 12 ).…”

“…Fortunately this situation was easily remedied by using substoichiometric amounts of base, which gave triazolyl vinyl sulfone 5 in moderate yield. Removal of the tert ‐butyloxycarbonyl group and N ‐derivatisation was attempted by using a method that had previously been successful for compound 3 , . However, upon addition of an electrophile and a base (Et 3 N), the alkene proved again to have undergone isomerisation, and thus the desired N ‐substituted vinyl sulfone analogues (not shown) were not obtained.…”

“…Binding poses of the azide‐containing compounds 4 (grey) and 25 (white) in the active site of rhodesain. Hashed lines denote hydrogen bonds between the ligand and the cysteine protease.…”

“…We have previously synthesised a range of dipeptidyl vinyl sulfone analogues of 1 in which the groups protruding into the S1′, S1, and S2 regions of the parasitic cysteinyl proteases (i.e., P 1′ , P 1 , and P 2 ) were altered (for example, compound 3 , Figure ) . The ability of this library of compounds to interfere with the life cycle of Trypanosoma brucei brucei was assessed, and as part of the same study azide 4 was also synthesised and evaluated . The copper‐catalysed azide–alkyne click methodology, (CuAAC) has emerged as a powerful chemical tool for the late‐stage manipulation of biologically active structures, within which recognition or reporting elements can be incorporated.…”

A Novel and Efficient Methodology for the Synthesis of Vinylamide Derivatives Using [Ce(L‐Pro)2]2Ox as Heterogeneous Catalyst

“…Vinylamides are known to be effective against a series of disorders, such as malaria, inflammatory, respiratory, and viral diseases . Owing to their pharmacological prospects, new methodologies have been developed to obtain such compounds . However, such methods present several disadvantages, especially a loss of the stereochemistry present in the starting compound, the use of microwave conditions and high temperatures …”