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

Abstract

An approach is described to access 1,2,3‐triazole‐derived peptidyl vinyl sulfones as Trypanosoma brucei brucei inhibitors by using click chemistry, starting from a common azide intermediate. Among the triazole analogues, biotinylated inhibitors 11 and 12 offer possibilities as probes for the elucidation of target proteases for this compound class. The development of two syntheses of a 1,2,3‐triazole‐based vinyl sulfone 5 are also presented. This compound was accessed through a click reaction of a lysine‐derived azide (itself accessed by diazo transfer), and a phenylalanine‐derived alkyne synthesised by both Ohira–Bestmann and Corey–Fuchs‐based alkynylation protocols. Several members of this family of compounds showed promising anti‐trypanosomal activity. Unexpectedly, one of the most active compounds was allyl sulfone 24, which stems from the isomerisation of vinyl sulfone 5, and is presumably a reversible inhibitor. A docking study of the analogues in the active site of the parasitic cysteine protease rhodesain was carried out in order to gain an insight into their likely interactions with these enzymes.

1,5‐Disubstituted 1,2,3‐Triazole‐Containing Peptidotriazolamers: Design Principles for a Class of Versatile Peptidomimetics

“…Although several protocols for the synthesis of chiral propargylamines have been published, most of these publications solely compare the optical rotation of the final product. Recent publications reported partial epimerization upon reaction of the Bestmann–Ohira reagent with chiral α‐amino aldehydes . The risk of epimerization at the aldehyde stage is increased when electron‐withdrawing sidechain residues are present that further increase the acidity in α‐position to the carbonyl group.…”

1,2,3-Triazole Containing Hybrids as Potential Pharmacological Agents: A Review

“…Compounds 120 (IC50 = 18 µm) and 121 (IC50 = 17 µm) were possessing more than 60-fold lower IC50 values compared to acarbose, the reference inhibitor. Some novel benzimidazole grafted 1,2,3-triazole hybrids were reported by Deswal et al [136] using click reaction and their Structure of some 1,2,3-Triazole derivatives (107)(108)(109)(110)(111)(112)(113)(114)(115)(116) as anti-inflammatory agents antidiabetic activity screened. All the compounds exhibited a good-to-moderate α-amylase inhibitory activity as well as αglucosidase inhibitory activity.…”

Design, Synthesis, and Computational Studies with ADMET of Novel Cardiovascular Hybrid Drugs

“…Next, by utilizing the default box size and centered on the ligand, grids were refined and minimized around the structures. Final docking studies were carried out on a generated protein structure grid using the extra-precision (XP) docking mode for all screened compounds [37][38].…”