Synthesizing Antifungal Agents

The incidence of fungal infections has increased dramatically in the past two decades due to many factors, for example, patients exposed to immunosuppressive therapeutic regimens, long-term catheterization, and longer survival of immunologically compromised individuals [Hazen, 1995]. Candida albicans, associated with human bloodstream infections [Wisphnghoff et al., 2004], and Aspergillus fumigatus, associated with bone marrow transplant infections, are among the most common forms of fungal infection [Wald et al., 1998]. Despite the discovery of antifungal agents such as azoles [Sheehan et al., 1999], polyenes [Ellis, 2002], the nucleoside analog flucytosine [Vernes et al., 2000], and the echinocandins [Denning, 2003], resistance to these antifungal agents is a serious health concern that is only going to increase. Interestingly, the study of enzymes in fungi suggests to medicinal chemists a way to exploit the overexpression of these enzymes, particularly orotidine monophosphate decarboxylase (OMP decarboxylase), as a novel means to treat fungal infections. OMP decarboxylase catalyzes the decarboxylation of orotidine monophosphate to uridine monophosphate. Furthermore, the concentration of OMP decarboxylase in fungi is 10 to 100 times greater than in mammals [Victor et al., 1979]. The present project aims to use the high concentration of OMP decarboxylase in fungi to design compounds that are selectively activated by OMP decarboxylase and can be applied to the treatment of fungal infections with a high safety profile