Amino acid 1,2,4-triazole mimetics as building blocks of peptides

Therapeutic peptides are a unique drug class due to their high specificity binding with biological targets. However, low bioavailability of peptides, as well as the lack of enzymatic stability, imposes a number of limitations on their biomedical application. A good strategy to overcome the limitations is the use of peptidomimetics, which are able to imitate the binding and activity of peptides in vitro and in vivo. Peptidomimetics can be obtained by combining natural and synthetic amino acids in a peptide sequence. Various five-membered heterocycles are often use as structural fragments of peptide imitators in order to fix the chain in a certain conformation and increase proteolytic stability. The use of 5-aminomethyl-1,2,4-triazole-3-carboxylic acid derivatives as building blocks of peptidomimetic structures may be a very attractive strategy, in which the tautomeric 1,2,4-triazole fragment is capable to flexible forming of hydrogen bonds on protein surface of the target. At proposed work a number of ethyl 5-aminomethyl-1,2,4-triazole-3-carboxylates and their derivatives as mimetics of aliphatic amino acids were synthesized. Their use as building blocks for synthesizing of peptidomimetics was demonstrated. In addition, by use of a panel of pathogenic and model strains of microorganisms and fungi it was not show any independent activity of the amino acid 1,2,4-triazole mimetics synthesized. This similarity of biological properties of the obtained mimetics and their natural analogues reveals in favor of their bioisosterism. Bioisosterism and geometric similarity of 1,2,4-triazole mimetics and natural amino acid encourages their further use as building blocks of therapeutic peptides.