900 Mini-Reviews in Medicinal Chemistry, 2007, 7, 900-911 1389-5575/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd. Recent Advances in Antifungal Agents Tamás Lóránd 1,* and Béla Kocsis 2 1 University Pécs, Faculty of Medicine, Department of Biochemistry and Medical Chemistry, H-7624 Pécs, Szigeti út 12., Hungary; 2 University Pécs, Faculty of Medicine, Department of Medical Microbiology and Immunology, H-7624 Pécs, Szigeti út 12, Hungary Abstract: New antifungals are needed in the medicine because of more aggressive and invasive diagnostic and therapeu- tic methods used, rapid emergence of resistant and new opportunistic fungi, increasing number of patients suffering from immunosuppressive situations e.g., AIDS, transplantation, cancer, etc. Several classes of new antifungal agents are dis- cussed here including some new members of known families. Voriconazole, posaconazole and ravuconazole, are novel triazoles that inhibit the ergosterol synthesis. These drugs overcome problems associated with the ineffectivity of flucona- zole against some Aspergillus spp. or the variable bioavailability of itraconazole. Echinocandins (caspofungin, anidula- fungin and micafungin) represent a new family of antifungal agents that inhibit 1,3- -glucan synthase. Nikkomycins tar- geting the chitin synthase, show activity against Histoplasma capsulatum and Blastomyces dermatitidis. Sordarin deriva- tives that block the fungal protein synthesis can be considered as a promising new class of antifungal agents for the treat- ment of Candida and Pneumocystis infections. Key Words: Voriconazole, posaconazole, ravuconazole, echinocandins, nikkomycins, sordarins. 1. INTRODUCTION It is a tendency all over the world that the incidence of the mycotic, especially the serious fungal infections (inva- sive candidiasis [1], aspergillosis [2-3], etc.) has increased during the last decades. It is partly due to the fact that the number of immunocompromised persons is growing: HIV infection, bone marrow and organ transplantation, malig- nancy and aggressive anticancer drug therapy, etc. are asso- ciated with immunosuppression and they can induce oppor- tunistic, life-threatening mycotic infections. To save a pa- tients’ life we need quick diagnostic procedures (e.g. galac- tomannantest [4-5], PCR method for detection of fungi [6], antifungal sensitivity tests [7-8], etc.) to start proper therapy as soon as possible. In this struggle we optimally try to use the old antifungal drugs, sometimes in combinations to di- minish the development of antidrug resistance [9]. On the other hand, modification of old drugs to improve their anti- fungal efficiency and the development of new drugs against novel targets, are continuously needed [10-13]. The antifungal armamentarium applies three classes of natural products (griseofulvin, polyenes and echinocandins) and four families of synthetic compounds (allylamines, azoles, flucytosine and phenylmorpholines) with clinical values against fungal infections. The azoles remain the most widely used family of antifungals against a broad range of mycoses. Recently, the search for new molecular targets for antifungal agents by modern genomic methods has brought consider- able knowledge. Some natural antifungal agents were dis- covered with new mode of actions, including inhibition of the synthesis of the fungal cell wall components. Among these compounds are the -(1,3)-glucan synthesis inhibitor *Address correspondence to this author at University Pécs, Faculty of Medicine, Department of Biochemistry and Medical Chemistry, H-7624 Pécs, Szigeti út 12., Hungary; E-mail: tamas.lorand@aok.pte.hu echinocandins, or chitin synthesis inhibitor nikkomycins, or the inhibitors of mannoprotein synthesis such as pradimycin and benanomycin. In addition some other new targets such asprotein synthesis (inhibited by e.g. sordarins), sphingolipid synthesis (inhibitors are e.g. viridofungin or khafrefungin), and mitochondrial electron transport (inhibited by compound UK2) have emerged [14]. This review focuses on some new antifungal azoles and on some new promising classes of antifungal agents (echino- candins, nikkomycins, and sordarins). It should be noted that FDA recently approved three members of the candins (caspo- fungin 10, anidulafungin 11 and micafungin 13) for clinical use. Previously several review articles reported about the developments in this field, one of them written by Vicente and co-workers offered a perspective of this topic [15]. 2. INHIBITORS OF THE FUNGAL STEROL SYN- THESIS The family of antifungal azoles, discovered in the 1960s, is a large class of synthetic compounds that has been ex- tremely popular due to its advantageous properties (broad spectrum, chemical stability, oral applicability). The azoles can be divided into two subfamilies: imidazoles and triazoles. Almost all of the recently developed azoles are triazoles. The azole antifungal agents block the synthesis of ergos- terol, a major component of fungal cytoplasmic membranes. They prevent the 14- -demethylation of lanosterol into er- gosterol in the ergosterol synthetic pathway [16]. Addition- ally, they may also inhibit the post-squalene synthesis seg- ments such as the oxidosqualene cyclase and the C-24- methyltransferase [17]. The latter step can be promising, because the mammalian cholesterol has no methyl group at C-24. In addition the azoles can also inhibit the last step, the 22-desaturase step in some fungal species [18]. Thus expo- sure of fungi to an azole results in the depletion of ergosterol