Síntese de inibidores potenciais de glicosamina-6-fosfato sintase e de (1,3)--D-glicana sintase e de análogos da neamina

Abstract

The spread of infections caused by pathogenic fungi remains a serious problem for contemporary medicine and the need to develop new antifungal agents is evident in view of the limitations of the drugs of the currently available therapeutic arsenal. The exploitation of selective molecular targets has proved to be an effective strategy in identifying new potent compounds. Thus, in the present work the synthesis and antimicrobial evaluation of lipophilic analogs of Lglutamine, potential inhibitors of GlcN-6-P synthase, enzyme that catalyzes the synthesis of glucosamine-6-phophate, precursor of chitin, important structural constituent of the fungal cell wall is proposed Eleven analogs of L-glutamine were successfully synthesized. Another enzyme which has been investigated as a target for the development of new antifungal agents is 1.3-b-D-glucan synthase responsible for catalyzing the synthesis of 1,3- b-D-glucans. The papulacandins are naturally occurring substances that inhibit the action of this enzyme. A new analogue of papulacandin D planned by simplification molecular was achieved successfully. Finally, the synthesis of three new neamine analogues, prepared by metathesis reaction was also proposed. In the present work the synthesis of one of these compounds was accomplished. Besides, there were important advances in the synthetic route to the two other compounds, including a successful preparation of the key intermediate prepared by cross methathesis.