Antiviral Agents: 3,5-Disubstituted 1,2,4-Oxadiazole Derivatives and Novel Peptidomimetics Containing Hydroxyethyl Isostere and Imidazolidinone Structures.

摘要

The search for new compounds with biological activity is the major goal of medicinal research.;One way to discover new lead compounds is the screening of large compound libraries, followed by the optimization of the found compounds. With this method, A3 was recently identified as a lead compound showing activity against a variety of viruses, including influenza. The reoccurrence of seasonal and pandemic influenza makes this disease a major thread to human life and economic productivity.;This dissertation is concerned with the development of a small library of derivatives exploring possible optimization of the A3 scaffold. The presence of an indole moiety is seen as a main reason for stability issues with the lead compound. Therefore, the second goal is the finding of a suitable bioisosteric replacement for this residue.;Four new lead compounds (SKB-126, SKB-134, SKB-136 and SKB-150) have been identified from this library, containing new substitution on the indole moiety as well as replacement of the indole with naphthalene and aromatic urea unit.;With continuous development in biochemical research, the understanding of biological mechanisms on the cellular level has brought attention to peptides as means to manipulate those mechanisms in order to treat diseases. Peptidomimetics are compounds with behavior similar to that of the peptide they mimic, but typically have structural enhancements that prevent quick metabolism or excretion from the system.;A new class of peptidomimetics derived from both imidazolidinones and hydroxyethylene isosteres is described herein. The key step of their synthesis is the opening of a fused ring aziridine with amino acids or small peptides to form an oxazolidinone, followed by rearrangement to the target imidazolidinone. A chain elongation on the resulting diol with a second amino acid or peptide fragment provides the novel peptidomimetics containing hydroxyethylene isosteres and imidazolidinone structures.