MULTICOMPONENT APPROACHES TO THE SYNTHESIS OF SMALL BIOACTIVE MOLECULES

In this PhD thesis, we exploited the potentialities of four different multicomponent reactions (MCRs), namely Ugi four-component reaction (U-4CR), N-split Ugi reaction (N-split U-4CR), van Leusen three-component reaction (vl-3CR) and Biginelli reaction (Bg-3CR), developing five different approaches to the synthesis of small bioactive molecules. In particular, we successfully applied the build/couple/pair strategy obtaining a small library of ketopiperazine-based minimalist peptidomimetics, by means of diastereoselective U-4CR/post-cyclization sequences, employing optically pure amino acid-derived α-amino aldehydes and α-isocyanoacetates as starting materials. Computer-assisted NMR NOE analysis allowed us to determine the configuration of the newly formed stereocenters, while molecular dynamics simulation and biological evaluation clearly underlined the potentiality of selected compounds to interfere with protein-protein interactions (PPIs). We also focused our attention on another class of peptide-like compounds, namely diamine-based peptidomimetics, by carefully optimizing the N-split U-4CR conditions for the introduction of N-protected amino acids and α-isocyanoacetates components, in a stereoconservative way. This methodology largely simplifies the synthesis of such compounds, opening the way to the use of more complex secondary diamines, able to induce well-defined secondary structures in the related peptidomimetic and hopefully targeting novel PPIs. Furthermore, by combining the same N-split U-4CR with common transformations, a library of dopamine receptor agonists was rapidly obtained, with biological activities in the nanomolar range. Although the desired D2/D3 selectivity was not achieved, structure-activity relationship (SAR) and docking studies allowed us to understand the key pharmacophoric elements in these novel structures, leading the way to the design of improved molecular scaffolds. By employing the vL-3CR in an iterative way, we designed a novel C2-C5’ linked polyimidazole-based minimalist framework, able to mimic the i, i+1, i+2 and i+3 amino acid residues of a β-strand motif. Its conformational behaviour was investigated through solution-phase NMR and molecular dynamics studies, allowing to demonstrate its ability to mimic a poly-alanine β-strand. Finally, we explored the possibility to combine MCRs with organocatalysis, developing the first BINOL-derived phosphoric acid catalysed Biginelli-like reaction on a ketone. In particular, employing N-substituted isatins as carbonyl substrates, we achieved the synthesis of a small library of biologically relevant enantioenriched spiro[indoline-pyrimidine]-diones derivatives. The assignment of the configuration at the new oxindole C-3 stereocenter was assessed through quantum-mechanical methods and NMR spectroscopy, while computational studies on the reaction transition state allowed us to explain the enantioselectivity and the stereochemical outcome.