Design and synthesis of new substituted pyrazinones and derivatives : peptidomimetic analogues of insect kinins and serine protease inhibitors

In the first part of this work, we are dealing with the use of functionalized 2(1H)-pyrazinones as scaffolds for design and development of peptide β-turn mimetics in solution and on solid support. In the first chapter, we have used the substituted pyrazinone systems as precursors to develop constrained dipeptide Ala-Gly scaffolds for peptide synthesis. In the second chapter, simplified analogues of insect kinins were developed based on the conformationally restricted APC scaffold. In the targets, the sidechain functionality of the receptor binding residues in the parent compound is retained as well as the β-turn conformation of the peptide backbone. Some of these compounds proved to be active in an insect kinin assay. These results show that our minimalistic approach towards insect kinin analogues works: scaffolds bearing the sidechains of residues important for receptor binding together with correct backbone geometry induce a biological effect. We also describe the synthesis of a novel C-terminal pentapeptide analogue of insect kinins using Fmoc strategy on Rink amide resin. This analogue doesn’t appear to induce significant activity in the insect kinin assay. In the second part of this work, we are dealing with the use of the pyrazinone core as a template for the design and synthesis of new peptidomimetic analogues of serine protease inhibitors. In the first chapter, we have used the pyrazinone core for the development of linear analogues of serine protease inhibitors. All the targets were screened for serine protease inhibition. Interestingly, only pyridinyl-containing compounds exhibit effect on chymotrypsin and on thrombin. However, no inhibitory effect on trypsin was observed. Precursors were generated for the synthesis of cyclic analogues of the compounds in chapter 2 In the third chapter, we have developed a novel and very efficient Ugi four-component reaction using readily functionalized pyrazinones. All the Ugi products were screened against thrombin, trypsin and chymotrypsin. In the last chapter, we describe the synthesis of boronic acid-based pyrazinones from the pyrazinone acid systems using standard coupling reaction conditions. These small libraries were synthesized for screening purposes against serine proteases such as thrombin (IIa), chymotrypsin and elastase. However, only the glycine-containing compound showed little inhibitory effect on thrombin.status: publishe