SINTESI DI BIOISOSTERI DEGLI OLIGOMANNOSI CON POTENZIALE ATTIVITA’ ANTITUBERCOLARE

Mycobacterium tuberculosis is the cause of the deadly infectious disease, tuberculosis (TB). According to the World Health Organization, nearly one–third of the world's population has been exposed to the tuberculosis pathogen and nearly 1.6 million deaths result every year. TB is, in addition, the leading infectious killer of people living with HIV/AIDS. Recent outbreaks of drug-resistant TB in many industrialized nations have led to a new interest in the disease, and basic research and drug development have again become priorities. The Mycobacterium organism possesses a complex cell wall including glycophospholipids such as phosphatidylinositiol mannosides (PIMs), lipomannan (LM), and lipoarabinomannan (LAM). These glycolipids all contain a common α-1,6-linked mannoside core, and the higher PIMs and LAM possess α-1,2-linked mannosyl residues. It has been shown that simple α-1,6-linked oligomannosides can act as substrates for α-1,6- mannosyltransferases in mycobacterium, i.e. the enzymes that promote the synthesis of the above mentioned PIMs, LM, and LAM This thesis focused on synthesis of potential inhibitors of α-1,6-mannosyltransferases . Iterative and/or a convergent approaches to (1,6)-oligomannoside mimics are reported. These synthetic oligosaccharides display the 1,2,3-triazole ring as a rigid and stable linker between α-D-mannose residues (triazolo-oligomannoses). Moreover the 6-position of the terminal mannosyl residue is deoxygenated. This structural feature is expected to prevent such compounds from acting as substrates for α-1,6-mannosyltransferases in mycobacterium. High stability can be foreseen for these oligomers owing to the resistance of anomeric carboncarbon bond and triazole ring toward chemical and enzymatic degradation. The assembly of the designed triazolo-oligomannoses relied on the great efficiency of the Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition of suitable building blocks duly prepared for his purpose. In this way six triazole-linked oligomannosides with progressive length chain (2-16 mannose units) were prepared in order to evaluate the influence of length on their affinity toward the α-1,6-mannosyltransferases. In vitro assays showed that the hexamannoside and octamannoside were the most active derivatives (95% inhibition at 1 mM concentration) and it was therefore deduced that these compounds were endowed with the optimal chain length for the interaction with α-1,6-mannosyltransferases.