Abstract
A straightforward and convenient approach for the first total syntheses of chromanone A and a related 7-OMe substituted natural product is reported. These unique C-3 substituted 2-hydroxymethyl chromones were recently isolated as fungal metabolites. Chromanone A was synthesized in 25.3% overall yield from the readily available pyrocatechol, whereas the second natural product was prepared in 39.7% global yield. A small library of chromones, including both natural products and some of their synthetic heterocyclic precursors, was evaluated against Candida albicans ATCC 10231, a biofilm forming agent. It was found that 8-methoxy-3-methyl-4-oxo-4H-chromene-2-carbaldehyde, a partially oxidized form of chromanone A, exhibited a minimum inhibitory concentration of 7.8 μg mL−1 and significantly inhibited the yeast's virulence factors, including the adherence to buccal epithelial cells and the secretion of phospholipases, as well as the formation of germ tubes and the generation of the hyphal pseudomycelium. In addition, despite the heterocycle exhibiting non-significant inhibition of the formation of the Candida biofilm, it completely inhibited the growth of C. albicans in preformed biofilms at 62.5 μg mL−1.
Highlights
Bio lms are structured microbial communities, embedded in a self-produced polymeric matrix of protein and polysaccharides. They are frequently found on interfaces or attached to surfaces, and are the scenario of complex interactions. These enduring structures are elusive to the defense system of the host, reluctant to undergo phagocytosis, and offer the producing microorganism a markedly increased resistance to antibiotics and chemical disinfectants.1a bio lms are an important form of microbial resistance and transmission of chronic infections.1b
Our work is focused on the synthesis of structurally unique heterocyclic natural products,[6] as well as in their evaluation.7a,b Further, among chromone derivatives, we have developed the total synthesis of the structure assigned to aspergillitine,7c a 2,3dimethyl chromone derivative isolated from a marine Aspergillus species
These results clearly indicated that the amount of adhered fungal cells to buccal epithelial cells (BEC) was signi cantly lower (Wilcoxon test, p < 0.0001) in yeasts treated with both aldehydes than in the untreated cells, suggesting that the presence of these heterocycles causes some degree of resistance to the colonization of BEC by C. albicans
Summary
Bio lms are structured microbial communities, embedded in a self-produced polymeric matrix of protein and polysaccharides. Our work is focused on the synthesis of structurally unique heterocyclic natural products,[6] as well as in their evaluation.7a,b Further, among chromone derivatives, we have developed the total synthesis of the structure assigned to aspergillitine,7c a 2,3dimethyl chromone derivative isolated from a marine Aspergillus species. In pursuit of these interests, here we report an efficient approach to the rst total syntheses of chromanone A (A) and of its isomer, the related natural product B. The results of the evaluation of both natural products and their heterocyclic synthetic intermediates, as antifungal agents against the bio lm forming yeast Candida albicans ATCC 12031, are discussed
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