The fungal cell wall as a drug discovery target: SAR of novel echinocandin analogs

Serious fungal infections are an escalating problem due to the increase in the immunocompromised patient population. Amphotericin B remains the drug of choice for life-threatening infections despite a high incidence of severe adverse reactions. While the newer azoles represent a class of safer drugs, they are fungistatic and are not ideal for deep-seated mycoses. There is a need for safer agents with a novel mode of action. The echinocandins and pneumocandins belong to a class of fungicidal lipopeptides that inhibit the synthesis of β-1,3-D-glucan in a number of pathogenic fungi, most importantly, Candida and Aspergillus species. Cationic derivatives of the pneumocandins such as L-733560, are nanomolar inhibitors of β-1,3-D-glucan synthesis and potent agents in vivo. Optimization of their properties led to identification of L-743872 which is under clinical investigation.