Potent Antifungal Properties of Dimeric Acylphloroglucinols from Hypericum mexicanum and Mechanism of Action of a Highly Active 3′Prenyl Uliginosin B

Abstract

The success of antifungal therapies is often hindered by the limited number of available drugs. To close the gap in the antifungal pipeline, the search of novel leads is of primary importance, and here the exploration of neglected plants has great promise for the discovery of new principles. Through bioassay-guided isolation, uliginosin B and five new dimeric acylphloroglucinols (uliginosins C-D, and 3′prenyl uliginosins B-D), besides cembrenoids, have been isolated from the lipophilic extract of Hypericum mexicanum. Their structures were elucidated by a combination of Liquid Chromatography - Mass Spectrometry LC-MS and Nuclear Magnetic Resonance (NMR) measurements. The compounds showed strong anti-Candida activity, also against fluconazole-resistant strains, with fungal growth inhibition properties at concentrations ranging from 3 to 32 µM, and reduced or absent cytotoxicity against human cell lines. A chemogenomic screen of 3′prenyl uliginosin B revealed target genes that are important for cell cycle regulation and cytoskeleton assembly in fungi. Taken together, our study suggests dimeric acylphloroglucinols as potential candidates for the development of alternative antifungal therapies.

Antioxidant activity and phenolic acid constituents of two andean Hypericum L. species from Colombia

“…For H. mexicanum, it was reported that the presence of caffeic and cinnamic acids in leaves but not in stems and roots. They also did not detect chlorogenic acid in any of the organs analysed (18). In comparison with our results, we did not detect caffeic acid, but we could determine the presence of p-coumaric, chlorogenic and ferulic acids in aerial parts of H. mexicanum.…”

“…Furthermore, the presence of quercitrin and rutin was also established in the ethyl acetate fraction of H. juniperinum by means of HPLC (15). More recently, a complete characterization of the phenolic profile from stems, roots and leaves of H. mexicanum has been described (18).…”

“…Furthermore, the butanol extract was the second most active in the tests, suggesting the presence of more polar compounds, such as quercetin and kaempferol glycosyl derivatives (38). Likewise, the most polar extract (aqueous) was the least active in most of the assays, which might be because this extract could present a low content of reactive antioxidants, such as glycosyl flavonoids like rutin, hyperoside, isoquercitrin and quercitrin, which are recognized compounds in H. perforatum, rutin and quercitrin in H. juniperinum and isorhamnetin-3-O-glucoside and quercetin-3-O-glucoside in H. mexicanum (15,18,39).…”

“…Likewise, the methanolic extract showed antibacterial activity against S. aureus, E. coli and S. epidermidis and the total extract and the methanolic and chloroform fractions displayed a low minimum inhibitory concentration value in comparison with the H. perforatum extract against S. aureus (17). Moreover, dimeric acylphloroglucinols isolated from the chloroform fraction of leaves from H. mexicanum displayed strong anti-candidal activity (18). Recently, the essential oils (EOs) of these 2 Hypericum species were chemically characterized and evaluated against the maize weevil.…”

Hypericum Genus as a Natural Source for Biologically Active Compounds

“…The following supporting information can be downloaded at: , Table S1: Biological activity of secondary metabolites identified in Hypericum genus plants [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ,…”