Design, Synthesis And Biological Evaluation Of Novel Coumarin Derivatives As Potential Chitin Synthase Inhibitors

Chitin is a natural polysaccharide chain that is composed of thousands of N-acetyl-D-glucosamine (GlcNAc) residues joined by β-1,4 glycosidic bonds and is an essential component of the fungal cell wall. It is absent in mammalian cells and plant. The biosynthesis of chitin is catalyzed by chitin synthase (CHS). Thus the chitin synthase signifies an ideal target for the development of antifungal agents.Coumarin and its derivatives are a large class of quite important lactones with a fused structure of benzene ring and a-pyrone. Coumarin skeleton contains π-π conjugated system with rich electron, good charge-transport and photochemical properties and thermodynamic stability. This kind of rigid fused ring endues coumarin derivatives with wide potential applications in the fields of bromatology, material and supramolecular chemistry as well as medicinal chemistry. In this thesis,piperazine tartrate derivatives and phosphoramidate derivatives of coumarin were synthesized as chitin synthase inhibitors and their inhibition activity against the chitin synthase were tested and their antifungal and antibacterial activities were evaluated as well.In the first chapter, studies on chitin synthase inhibitors were summarized.In the second chapter, a series of piperazine tartrate derivatives as chitin synthase inhibitors have been obtained through the condensation, rearrangement,nitration, reduction, protection, hydrolysis reaction using substituted phenol as the starting material. Compound l0o possessed excellent activity against chitin synthase, with IC50 of 0.10mM, was more effective than polyoxins B with IC50 of 0.18mM.In the third chapter, a series of phosphoramidate derivatives as chitin synthase inhibitor have been obtained through the condensation, chloride,alkylation,acyl reaction using substituted phenol as the starting material.The tested enzyme were determined the michaelis constant and Compound 7t were tested the inhibition constant. Furthermore, compound 7t possessed excellent activity against chitin synthase,with IC50 of 0.08mM.All the target compounds were screened for their in vitro antimicrobial and antifungal activity. Results showed that the antifungal activity of target compounds was superior to their antibacterial activity.They can be used as seclective antifungal agents.