Medicinal Chemistry Approaches to Widen Therapeutic Potential for Melatonin and Temozolomide Derivatives

The work described in this thesis was primarily focused on the design, synthesis, physicochemical characterization and biological evaluation of small molecules of pharmaceutical interest. The thesis consists of two sections, one concerning the development of new melatonin derivatives and the other regarding the expansion of the structure-activity relationships of the anticancer agent temozolomide. Specifically, part of the melatoninergic work has been dedicated to the design and synthesis of different MLT receptor ligands structurally characterized by a tetrahydroquinoline scaffold. The semi rigid THQ ring was found to be a good synthetically accessible template for the design of potent MLT ligands with different topology. In the second part of this first section, new dual-acting compounds have been designed and synthesized by combining the interesting properties of melatonin derivatives with other, potentially synergistic, pharmacological activities. The new dual-acting compounds have showed a promising antiglaucoma activity. The second section of the thesis, conducted during my visiting period at University of Illinois at Urbana-Champaign, has been carried out in a different research field concerning the anticancer agent temozolomide. To understand the relationship between its structure, hydrolytic stability and anticancer activity, new imidazotetrazines derivatives bearing previously unexplored functionalities at the C8 position have been synthetized and tested against a panel of human GBM cell lines showing interesting anticancer activities.