Synthesis and biological potential of new active β-lactam based compounds

This thesis is divided in three main chapters and reports the research work performed during a three year-PhD programme under the supervision of Prof. Daria Giacomini. The main subject of this dissertation concerns the design and synthesis of new classes of monocyclic β-lactam compounds and their biological potential. β-lactams in fact are really evergreen bioactive molecules, primarily known for their efficiency as antibiotics, but more recently considered also for a great number of diverse activities. The search for novel active azetidinone compounds has been deeply studied and pioneered within my research group since more than 10 years, and with this thesis work we aim at demonstrating how a wide structural variability on a fixed monocyclic azetidinone scaffold could give rise to novel candidates displaying different biological activities and innovative promising applications. Specifically, Chapter 2 comprises the synthesis of new β-lactam-based antimicrobial agents against multidrug-resistant pathogens. Different classes of 4-alkylidene-azetidinones and N-thio-substituted β-lactams were successfully developed, resulting strong antibacterial compounds toward Gram-positive resistant bacterial strains. Chapter 3 concerns the design of novel β-lactam derivatives designed to target integrins. Ligands that displayed an agonist behaviour were then derivatized with fluorophore or cytotoxic residues in order to develop a drug-delivery system for selectively targeting cancer cells. In addition, some novel active hydroxyapatite (HA)- and Poly-(L)-lactic-acid (PLLA)-based biomaterials were prepared, by loading selected antibacterial and integrin ligands- β-lactams, respectively. Finally, Chapter 4 covers other more variegated projects including biocatalytic approaches for the synthesis of enantiomerically pure azetidinones, and studies toward oxidative processes mediated by enzymes or metal-free oxidants. The work performed during a three months-exchange period at Karl Franzens University of Graz under the supervision of Prof. Kurt Faber is also included in this section, regarding a study on biocatalytic kinetic resolution for the enantioselective synthesis of ortho-substituted biphenyl compounds.