Novel HEIA-Type Trazasterols as Potential Antifungal Agents

Research project P 14758 Novel HEIA-type Triazasterols as Potential Antifungal Agents Edith GRÖSSNITZER 27.11.2000 In recent times the demand for novel antiflangal drugs for the treatment of fungal deseases has dramatically increased. Immunocompromised patients, whose number is constantly rising because of chronic infections by environmental pollution, organ transplants, cancer therapy and AIDS, are seriously endangered by fungal infections. In such cases, fungal infections, e. g. with Candida albicans, Aspergillus or Cryptococcus neoformans, can easily. develop to deep-seated systemic mycoses spreading over lungs, brain and spinal cord. Safe systemic treatments are hard with the small choice of potent, presently available antimycotic drugs due to severe side effects or a restricted antifungal spectrum. Moreover, some substances produce regularly and rapidly resistant fungal mutants. In order to overcome this insufficient situation we want to intensify our research in this field by the now submitted project dealing with the development of new enzyme inhibitors of the ergosterol biosynthesis representing t,riazaanalogous high energy intermediates with specific target sites in the pathogenic fungal metabolism. With respect to the fact, that ergosterol is an essential component of the fungal cell membrane, the lack of ergosterol (and/or the accumulation of precursors) causes serious misfbnctions of the cell membrane, inhibition of the fungal growth and cell death. The design of the planned new antimycotics presented in this project is guided by biochemical considerations and bases on the knowledge that some enzymes involved in the ergosterol biosynthesis are known to create carbocationic high energy intermediates (HEI) and to bind these intermediates more tightly than the substrates. Hence these HEls are promising models for the design of potentially highly active and powerful antifungal agents. In contrast to the known drugs the potential novel antimycotics will represent analogues of substrate intermediates occurring in the ergosterol biosynthesis with integrated guanidinium moiety. in particular they represent partly hydrogenated imidazo[l`,2`:1,2] pyrimido [4,3-a]isoquinolin-8-ols, decahydro-6H-pyrrolo [1`,2`:3,4] pyrimido[1,2-a]quinazolines and 24,26,27- or 23,25,28-triaza-28-homolanosterols (shortly designated as triazasterols) and are designed as inhibitors of 2,3-oxidosqualene lanosterol cyclase, e-methyl transferase, 14- reductase and 8 - 7 -isomerase. On account of their special structural features and the steady positive charge they could act as so called high energy intermediate analogues (HEIA) and should possess strong and possibly multiple inhibitory effects on the target enzymes. Due to the much higher stability as cations under physiological conditions and their much more closer resemblance to the structute of the naturally substrates, the planned triazasterols with guanidine moiety are expected to be more potent inhibitors than those of the amine type like allylamines (e.g. naftifine) and morpholines (e.g. amorolfine). The ambitious aim of our project is the development of novel antifungal agents, which possess, in comparison with the currently available drugs, increased activity and at least reduced side effects. But the research in sterol biosynthesis inhibitors is not limited to the development of fungicides and antimycotics. It also promotes the basic research and knowledge on the function and biosynthesis of fungal sterols as well as the possibility of the development of hypocholesterolemic drugs, antiprotozoal drugs, plant growth regulators and even anticancer agents.