Abstract
Systemic fungal infections are a growing problem in contemporary medicine and few drugs are licensed for therapy of invasive fungal infections. Differences between fungi and humans, like the presence of a cell wall in fungal cells, can be explored for designing new drugs. (1,3)-β-D-glucan synthase, an enzyme that catalyzes the synthesis of (1,3)-β-D-glucan, a structural and essential component of the fungal cell wall, is absent in mammals and this makes it an excellent target for the development of new antifungal agents. Papulacandins are a family of natural antifungal agents targeting (1,3)-β-D-glucan synthase. In this study we describe the synthesis and biological evaluation of two new Papulacandin analogs as potential (1,3)-β-D-glucan synthase inhibitors.
Highlights
(1,3)-β-D-glucan synthase represents an important molecular target for the development of new antifungal drugs, as this enzyme is essential for fungi and is absent in mammalian cells
Papulacandins constitute a family of natural antifungal agent inhibitors of (1,3)-β-D-glucan synthase whose isolation and characterization were initially reported by Traxler and coworkers (Traxler, Gruner, Auden, 1977)
The papulacandins have demonstrated potent in vitro antifungal activity against several pathogenic fungi: Candida albicans, Candida tropicalis, Microsporum canis, Geotrichum lactis, Saccharomyces cerevisae and Pneumocystis carinii (Denmark, Kobayashi, Regens, 2010; Barret, Pena, Willardsen, 1996; Schmatz et al, 1990)
Summary
(1,3)-β-D-glucan synthase represents an important molecular target for the development of new antifungal drugs, as this enzyme is essential for fungi and is absent in mammalian cells. This enzyme catalyzes the synthesis of (1,3)-β-D-glucan, a structural component of the fungal cell wall. Based on antifungal potential of papulacandins combined with the lower structural complexity of Papulacandin D, we planned and synthesized new analogs of this compound employing the molecular simplification method and using a more complex acyl chain, containing unsaturations and different functional groups. Removal of the chiral centers of the fatty acid chains eliminates difficulties encountered in the stereocontrolled synthesis of chiral compounds
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