Recent Advances in the Medicinal Chemistry of Antifungal Agents

The need for new antifungal agents has never been greater. Over the last 10 years the incidence of life-threatening fungal infections has increased dramatically as the population of immunocompromised individuals induding cancer, organ transplant, and AIDS patients has increased. Present therapeutic options for· the treatment of these infections are limited to compounds in two classes, the polyenes and the azoles. Some polyene research still continues with analogs of amphotericin B in the hopes of decreasing toxicity. Much work continues in the azole area with follow-up compounds to fluconazole and itraconazole in order to expand the spectrum and provide oral and iv formulation potential. A newer class of cell wall active agents that has been developed to the point of seeing clinical candidates is the cyclic lipopeptide echinocandin family. This group has the potential of providing broad spectrum fungicidal activity with a much lower toxicity level than .the current agents. Another newer class of natural products known as the aureobasidins has potent, oral fungicidal activity against Candida spp. Research has continued with the pradimicins to produce several new semisynthetic derivatives with comparable activity and spectrum to the parent compound but with improved water-solubility. Work with the nikkomycin class has delineated points of the SAR but has not produced compounds of sufficient potency for clinical use. The allylamines have been examined further to provide analogs of terbinafine with increased Candida activity but are still most highly potent versus dermatophytes. Several other newer classes with unique mechanisms of action have also been identified.