Natural Products & Metabolomics

Leishmaniasis and schistosomiasis are neglected tropical diseases (NTDs) infecting the world’s poorest populations. Effectiveness of the current antileishmanial and antischistosomal therapies are significantly declining, which calls for an urgent need of new effective and safe drugs. In Ethiopia fresh leaves of Ranunculus multifidus Forsk. are traditionally used for the treatment of various ailments including leishmaniasis and eradication of intestinal worms. In the current study, anemonin isolated from the fresh leaves of R. multifidus was assessed for its in vitro antileishmanial and antischistosomal activities. Anemonin was isolated from the hydro-distilled extract of the leaves of R. multifidus. Antileishmanial activity was assessed on clinical isolates of the promastigote and amastigote forms of Leishmania aethiopica and L. donovani clinical isolates. Resazurin reduction assay was used to determine antipromastigote activity, while macrophages were employed for antiamastigote and cytotoxicity assays. Antischistosomal assays were performed against adult Schistosoma mansoni and newly transformed schistosomules (NTS). Anemonin displayed significant antileishmanial activity with IC50 values of 1.33 nM and 1.58 nM against promastigotes and 1.24 nM and 1.91 nM against amastigotes of L. aethiopica and L. donovani, respectively. It also showed moderate activity against adult S. mansoni and NTS (49% activity against adult S. mansoni at 10 µM and 41% activity against NTS at 1 µM). The results obtained in this investigation indicate that anemonin has the potential to be used as a template for designing novel antileishmanial and antischistosomal pharmacophores.

Meroterpenoids are secondary metabolites formed due to mixed biosynthetic pathways which are produced in part from a terpenoid co-substrate. These mixed biosynthetically hybrid compounds are widely produced by bacteria, algae, plants, and animals. Notably amazing chemical diversity is generated among meroterpenoids via a combination of terpenoid scaffolds with polyketides, alkaloids, phenols, and amino acids. This review deals with the isolation, chemical diversity, and biological effects of 452 new meroterpenoids reported from natural sources from January 2016 to December 2020. Most of the meroterpenoids possess antimicrobial, cytotoxic, antioxidant, anti-inflammatory, antiviral, enzyme inhibitory, and immunosupressive effects.

An extensive phytochemical study of a foliose lichen from Indonesia, Parmelia cetrata, resulted in the successful isolation of 13 phenol and depside derivatives (1–13) including the previously unreported depsides 3′-hydroxyl-5′-pentylphenyl 2,4-dihydroxyl-6-methylbenzoate (7), 3′-hydroxyl-5′-propylphenyl 2,4-dihydroxyl-6-methylbenzoate (8) and 3′-hydroxyl-5′-methylphenyl 2-hydroxyl-4-methoxyl-6-propylbenzoate (9). The anti-infective activity of isolated compounds was evaluated against the gram-negative bacterium Aliivibrio fischeri and the nematode Caenorhabditis elegans. 2,4-Dihydroxyl-6-pentylbenzoate (5) and lecanoric acid (6) induced growth inhibition of A. fischeri with inhibition values of 49% and 100% at a concentration of 100 µM, respectively. The antibacterial activity might be due to their free carboxyl group. A phenolic group at C4 also contributed to the antimicrobial activity of the depsides as shown for compounds 7 and 8, which caused 89% and 96% growth inhibition at 100 µM, respectively. Lecanoric acid (6) in addition possesses significant anthelmintic effects causing 80% mortality of C. elegans at 100 µg/mL.

Ozoroa insignis Del. is an ethnobotanical plant widely used in traditional medicine for various ailments, including schistosomiasis, tapeworm, and hookworm infections. From the so far not investigated fruits of Ozoroa insignis, the anthelmintic principles could be isolated through bioassay-guided isolation using Caenorhabditis elegans and identified by NMR spectroscopic analysis and mass spectrometric studies. Isolated 6-[8(Z)-pentadecenyl] anacardic (1), 6-[10(Z)-heptadecenyl] anacardic acid (2), and 3-[7(Z)-pentadecenyl] phenol (3) were evaluated against the 5 parasitic organisms Schistosoma mansoni (adult and newly transformed schistosomula), Strongyloides ratti, Heligmosomoides polygyrus, Necator americanus, and Ancylostoma ceylanicum, which mainly infect humans and other mammals. Compounds 1–3 showed good activity against Schistosoma mansoni, with compound 1 showing the best activity against newly transformed schistosomula with 50% activity at 1µM. The isolated compounds were also evaluated for their cytotoxic properties against PC-3 (human prostate adenocarcinoma) and HT-29 (human colorectal adenocarcinoma) cell lines, whereby compounds 2 and 3 showed antiproliferative activity in both cancer cell lines, while compound 1 exhibited antiproliferative activity only on PC-3 cells. With an IC50 value of 43.2 µM, compound 3 was found to be the most active of the 3 investigated compounds.

Although stripped from hydroxyl-groups, deoxygenated hygrophorones remain highly active against severe phytopathogens. The synthesis to these natural product congeners is achieved in rearrangement sequences, with an optimized deprotection strategy avoiding retro-aldol reactions. The activities are comparable to fungicides used in agriculture. Based on naturally occurring hygrophorones, racemic di- and mono-hydroxylated cyclopentenones bearing an aliphatic side chain have been produced in short synthetic sequences starting from furfuryl aldehyde. For the series of dihydroxylated trans-configured derivatives, an Achmatowicz-rearrangement and a Caddick-ring contraction were employed, and for the series of trans-configured mono-hydroxylated derivatives a Piancatelli-rearrangement. All final products showed good to excellent fungicidal activities against the plant pathogens B. cinerea, S. tritici and P. infestans.

The antioxidant and enzyme inhibitory potential of fifteen cycloartane-type triterpenes’ potentials were investigated using different assays. In the phosphomolybdenum method, cycloalpioside D (6) (4.05 mmol TEs/g) showed the highest activity. In 1,1-diphenyl-2-picrylhydrazyl (DPPH*) radical and 2,2′-azino-bis(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS) cation radical scavenging assays, cycloorbicoside A-7-monoacetate (2) (5.03 mg TE/g) and cycloorbicoside B (10) (10.60 mg TE/g) displayed the highest activities, respectively. Oleanolic acid (14) (51.45 mg TE/g) and 3-O-β-d-xylopyranoside-(23R,24S)-16β,23;16α,24-diepoxycycloart-25(26)-en-3β,7β-diol 7-monoacetate (4) (13.25 mg TE/g) revealed the highest reducing power in cupric ion-reducing activity (CUPRAC) and ferric-reducing antioxidant power (FRAP) assays, respectively. In metal-chelating activity on ferrous ions, compound 2 displayed the highest activity estimated by 41.00 mg EDTAE/g (EDTA equivalents/g). The tested triterpenes showed promising AChE and BChE inhibitory potential with 3-O-β-d-xylopyranoside-(23R,24S)-16β,23;16α,24-diepoxycycloart-25(26)-en-3β,7β-diol 2′,3′,4′,7-tetraacetate (3), exhibiting the highest inhibitory activity as estimated from 5.64 and 5.19 mg GALAE/g (galantamine equivalent/g), respectively. Compound 2 displayed the most potent tyrosinase inhibitory activity (113.24 mg KAE/g (mg kojic acid equivalent/g)). Regarding α-amylase and α-glucosidase inhibition, 3-O-β-d-xylopyranoside-(23R,24S)-16β,23;16α,24-diepoxycycloart-25(26)-en-3β,7β-diol (5) (0.55 mmol ACAE/g) and compound 3 (25.18 mmol ACAE/g) exerted the highest activities, respectively. In silico studies focused on compounds 2, 6, and 7 as inhibitors of tyrosinase revealed that compound 2 displayed a good ranking score (−7.069 kcal/mole) and also that the ΔG free-binding energy was the highest among the three selected compounds. From the ADMET/TOPKAT prediction, it can be concluded that compounds 4 and 5 displayed the best pharmacokinetic and pharmacodynamic behavior, with considerable activity in most of the examined assays.

The chemical investigation of the root barks leaves and stem barks of Brucea antidysenterica J. F. Mill. (Simaroubaceae) led to the isolation of a new pregnane glycoside, named Bruceadysentoside A or 3-O-β-L-arabinopyranosyl-pregn-5-en-20-one (1) together with seventeen known compounds. Their structures were established from spectral data, mainly HRESIMS, 1 D and 2 D NMR and by comparison with literature data. Compounds 1, 2, 5, 6, 8, 10, 12 and 13 were tested in vitro for their effects on the viability of two different human cancer cell lines, namely prostate PC-3 adenocarcinoma cells and colorectal HT-29 adenocarcinoma cells. No substantial activities were recorded for 2, 10, 12 and 13 (up to 10 μM concentration). 1, 5 and 8 did not show strong anti-proliferative effects up to 100 μM, however, 6 exhibited a stronger anti-proliferative effect with IC50 values of ∼ 100 μM against PC-3 and ∼ 200 μM against HT-29.

We present the first major survey of regional diversity, distribution and host-association of Sepedonium. Whereas the rather scarce worldwide records of this mycoparasitic fungus suggested no specific distribution pattern of most species before, we provide new evidence of endemic and specific host-parasite guilds of Sepedonium in Southern South America, including the description of a new species. The corresponding inventory was performed in temperate central Chile. The regional landscape, a mosaic of exotic timber plantations and remnants of native Nothofagus forests, facilitates a unique combination of endemic and adventitious Boletales hosts. During a two-year survey, 35 Sepedonium strains were isolated and cultured from infected basidiomata of allochthonous Chalciporus piperatus, Paxillus involutus, Rhizopogon spp. and Suillus spp., as well as from the native Boletus loyita, B. loyo, B. putidus and Gastroboletus valdivianus. Taxonomic diagnosis included morphology of conidia and conidiophores, sequences of ITS, RPB2 and EF1 molecular markers and characteristics of in vitro cultures. Phylogenetic reconstructions were performed using Bayesian methods. Four Sepedonium species could be identified and characterized, viz.: S. ampullosporum, S. chrysospermum, S. laevigatum and the newly described species S. loyorum. The most frequent species on introduced Boletales was S. ampullosporum, followed by S. chrysospermum and S. laevigatum. S. loyorum sp. nov. was found exclusively on native boletacean hosts, separated from its closest relative S. chalcipori by micromorphological and molecular attributes. Species descriptions and identification keys are provided. Ecological and biogeographical aspects of endemic and allochthonous symbiotic units consisting of mycoparasite, ectomycorrhizal fungal host and respective mycorrhizal tree are discussed.

Background: Natural products acquire vast and intriguing structural diversity and have been recognized as a tremendously diverse source of new lead compounds. Numerous bioactive secondary metabolites are present in the form of glycosylated molecules in which the sugar parts are normally associated with the interaction along with molecular recognition of the cellular target.Scope and approach: The presence of sugar entities are crucial as well as in some cases necessary, for therapeutic effects. Establishing novel and potent glycosylated secondary metabolites has formed a main goal in the natural product field from fungi and bacteria. These compounds possess a diverse range of sugar units.Key findings and conclusions: Fungi is considered one of the important sources for approved drugs with a diverse range of mode of action. The sugar part in numerous pharmacologically active natural products enhances bioavailability, biological potential, reduce toxicity, and improve stability. The vast majority of glyocosides showed antimicrobial effects, cytotoxic, antiviral and antiinflammatory effects. Notably, numerous fungal glycosides presented in this review illustrate significant antimicrobial effects towards various microorganisms especially against plant pathogens. The antimicrobial effects of these fungal glycosides indicate that these metabolites could be employed as natural preservatives in food in order to abolish or control the growth of pathogenic and spoilage microorganisms.

Functional food defined as dietary supplements that in addition to their nutritional values, can beneficially modulate body functions becomes more and more popular but the reaction of the intestinal microbiota to it is largely unknown. In order to analyse the impact of functional food on the microbiota itself it is necessary to focus on the physiology of the microbiota, which can be assessed in a whole by untargeted metabolomics. Obtaining a detailed description of the gut microbiota reaction to food ingredients can be a key to understand how these organisms regulate and bioprocess many of these food components. Extracts prepared from seven chief functional foods, namely green tea, black tea, Opuntia ficus-indica (prickly pear, cactus pear), black coffee, green coffee, pomegranate, and sumac were administered to a gut consortium culture encompassing 8 microbes which are resembling, to a large extent, the metabolic activities found in the human gut. Samples were harvested at 0.5 and 24 h post addition of functional food extract and from blank culture in parallel and analysed for its metabolites composition using gas chromatography coupled to mass spectrometry detection (GC-MS). A total of 131 metabolites were identified belonging to organic acids, alcohols, amino acids, fatty acids, inorganic compounds, nitrogenous compounds, nucleic acids, phenolics, steroids and sugars, with amino acids as the most abundant class in cultures. Considering the complexity of such datasets, multivariate data analyses were employed to classify samples and investigate how functional foods influence gut microbiota metabolisms. Results from this study provided a first insights regarding how functional foods alter gut metabolism through either induction or inhibition of certain metabolic pathways, i.e. GABA production in the presence of higher acidity induced by functional food metabolites such as polyphenols. Likewise, functional food metabolites i.e., purine alkaloids acted themselves as direct substrate in microbiota metabolism.