Search

Gentiana species including G. crassicaulis, G. macrophylla, G. dahurica, and G. straminea are used in traditional Chinese medicine as "Qinjiao" for the treatment of rheumatism, hepatitis, and pain. Four antifungal bisphosphocholines [irlbacholine (2) and three new analogues, gentianalines A-C (1, 3, and 4)] were identified from G. crassicaulis by a bioassay-guided fractionation and structure elucidation approach. Subsequent chemical analysis of 56 "Qinjiao" samples (45 from G. crassicaulis, five from G. macrophylla, three from G. dahurica, and three from G. straminea) showed that bisphosphocholines were present in all four Gentiana species, with irlbacholine as the major compound ranging from 2.0 to 6.2 mg per gram of dried material. Irlbacholine exhibited potent in vitro antifungal activity against Cryptococcus neoformans, Aspergillus fumigatus, Candida albicans, and Candida glabrata with minimum inhibitory concentration (MIC) values of 0.63, 1.25, 10.0, and 5.0 μg/mL, respectively. Identification of the bisphosphocholines, a rare class of antifungal natural products, in these medicinal plants provides scientific evidence to complement their medicinal use. The bisphosphocholines carrying a long aliphatic chain possess amphiphilic molecule-like properties with a tendency of retention in both normal and reversed-phase silica gel column chromatography and thereby may be neglected in natural products discovery. This report may stimulate interest in this class of compounds, which warrant the further study of other biological activities as well.

The phloeodictine-based 6-hydroxy-2,3,4,6-tetrahydropyrrolo[1,2-a]pyrimidinium structural moiety with an n-tetradecyl side chain at C-6 has been demonstrated to be a new antifungal template. Thirty-four new synthetic analogues with modifications of the bicyclic tetrahydropyrrolopyrimidinium skeleton and the N-1 side chain have been prepared and evaluated for in vitro antifungal activities against the clinically important fungal pathogens including Cryptococcus neoformans ATCC 90113, Candida albicans ATCC 90028, Candida glabrata ATCC 90030, Candida krusei ATCC 6258, and Aspergillus fumigatus ATCC 90906. Nineteen compounds (5, 21-31, 34-38, 44, and 48) showed antifungal activities against the aforementioned five fungal pathogens with minimum inhibitory concentrations (MICs) in the range 0.88-10 μM, and all were fungicidal with minimum fungicidal concentrations (MFCs) similar to the respective MIC values. Compounds 24, 36, and 48 were especially active against C. neoformans ATCC 90113 with MIC/MFC values of 1.0/1.0, 1.6/1.6, and 1.3/2.0 μM but exhibited low cytotoxicity with an IC50 > 40 μM against the mammalian Vero cells. The structure and antifungal activity relationship indicates that synthetic modifications of the phloeodictines can afford analogues with potent antifungal activity and reduced cytotoxicity, necessitating further preclinical studies of this new class of antifungal compounds.

The survival rate of Castanopsis kawakamii from seed to seedling is relatively low, leading to difficulties in the regeneration of its natural forests. Forest gaps play a vital role in plant regeneration and biodiversity maintenance in forest ecosystems. Unfortunately, our understanding of the effect of gap size and within-gap position on the seed germination and radicle growth of C. kawakamii is still limited. In particular, our knowledge on the relationship between gap size and environmental factors and their influence on seed germination and radicle growth is incomplete. In the present study, we studied the influence of forest gaps on seed regeneration on the germination and radicle growth of an endangered species C. kawakamii in a subtropical natural forest in China. We selected three large gaps (LG, gap size above 200 m2), three medium gaps (MG, gap size 50–100 m2), three small gaps (SG, gap size 30–50 m2), and non-gap (NG), and planted the seeds of C. kawakamii in five positions within each gap. The results showed that (1) the influence of forest gaps on seed germination rate was, from highest to lowest, medium gaps (51%), non-gap (47%), small gaps (40%) and large gaps (17%), and the seed germination rate was the highest in all positions in medium gaps, with the exception of the east position; (2) radicle length in forest gaps was, from highest to lowest, medium gaps, small gaps, large gaps and non-gap, and it was the highest in the east, south, west and north positions of medium gaps; (3) canopy openness (gap size) and air temperature were the main factors influencing seed germination and radicle growth of C. kawakamii. We concluded that medium-sized gaps were most suitable for seed germination and radicle growth of C. kawakamii, and they promote the regeneration of this endangered species in the investigated natural forest.

New indole alkaloids streptoprenylindoles A–C (1–3) and diterpenoids 18-acetyl-cyclooctatin (8), 5,18-dedihydroxy-cyclooctatin (9), and 5-dehydroxy-cyclooctatin (10) were isolated from the culture of marine-derived Streptomyces sp. ZZ820, along with known 3-cyanomethyl-6-[3-methyl-2-butenyl]indole (4), N-(2-(1H-indol-3-yl)ethylacetamide (5), 1-acetyl-β-carboline (6), indole-3-methylethanoate (7), cyclooctatin (11), and chromomycin A3 (12). Their structures were elucidated by a combination of extensive spectroscopic analyses, ECD calculation, and the Mosher's method. Streptoprenylindoles A (1) and B (2) are enantiomers that were separated through the preparation of their Mosher esters. Three new diterpenoids (8–10) showed antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli with MIC values of 24.11–55.12 μM, while chromomycin A3 (12) showed potent antibacterial activities against MRSA (MIC: 0.59 μM) and E. coli (MIC 0.04 μM).

Penicipyrrodiether A, an adduct of GKK1032 analogue and phenol A derivative, was isolated from a culture of marine-associated fungus Penicillium sp. ZZ380 and represents the first example of this type of fungal metabolite. Its structure was elucidated by extensive spectroscopic analyses, including 1D- and 2D-NMR, HRESIMS, MS/MS, and electronic circular dichroism calculation as well as single-crystal X-ray diffraction. Penicipyrrodiether A showed antibacterial activity in inhibiting the growth of methicillin-resistant Staphylococcus aureus with a MIC value of 5.0 μg/mL. Its plausible pathway for biosynthesis has been proposed.

Forest gaps affect the soil microbial community structure and soil function by altering the ambient environment. This study aimed to explore the effects of environmental factors on soil microbial communities and enzyme activities in Castanopsis kawakamii forest gaps. The soil properties, soil enzyme activities, and microbial composition inferred by high-throughput sequencing were determined to quantify the soil eco-physiological functions. A redundancy analysis and linear model (LM) were further used to test the significance of forest-gap effects on soil microbial community structure and its function. The formation of gaps significantly increased the canopy openness (CO) and soil temperature (ST), and the small gaps (GS) and large gaps (GL) were the most conducive to the accumulation of soil total nutrients. Soil characteristics in GS provided a favorable environment for microbial growth, which promoted the soil microbes and function in these forest gaps. The soil physical–chemical properties in GM were relatively low and influenced its soil function, resulting in this gap size having the lowest enzyme activities. Forest gaps govern the soil microbiomes and soil function by regulating gap characteristics and soil properties. Meanwhile, the presence of dominant microorganisms promoted enzyme activities. These results could help further our understanding of the impact of forest gaps on the soil process and forest succession.

Five new diterpenoids, named euphorfischerins A-E, were isolated from the roots of Euphorbia fischeriana. Their chemical structures and absolute configurations were determined by interpretation of NMR, HR-ESI-MS, ECD and X-ray diffraction data. Euphorfischerin A showed cytotoxicity against the human cancer cell lines HeLa, H460 and Namalwa with IC50 values of 4.6, 11.5 and 16.4 μM, respectively, while euphorfischerin B gave comparable IC50 values of 9.5, 17.4 and 13.3 μM against the three cancer cell lines, respectively.

Two rare polyketides, named as janthinopolyenemycins A (1) and B (2), were isolated from a co-culture of two marine-sourced bacteria Janthinobacterium spp. ZZ145 and ZZ148. Their structures were established by a combination of extensive NMR spectroscopic analyses, HRESIMS data, and ECD calculation. Both janthinopolyenemycins A and B showed activity in inhibiting the growth of Candida albicans with a MIC value of 15.6 μg/mL and a MBC value of 31. 25 μg/mL.

WOS: 000425841300009, In the present work, fruits of Prangos platychlaena Boiss. ex Tchihat. ssp. platychlaena (Apiaceae) collected from eastern (sample A) and central (sample B) parts of Turkey were subjected to hydrodistillation to yield essential oils (EOs). The chemical composition of P. platychlaena ssp. platychlaena fruit oil was analyzed by gas chromatography-flame ionization detector (GC-FID) and gas chromatography-mass spectrometry (GC-MS) techniques. An unknown compound with m/z 178 [M](+) in high percentages was detected in both EOs (45.8% and 11.2% in samples A and B, respectively). Column chromatography on silica gel was subsequently followed by the sample A and yielded a new acetylenic derivative (1), which was characterized by spectroscopic techniques as (2S)-3,5-nonadiyne-2-yl acetate. Samples A and B oils were characterized by a series of acetylenic derivatives like 3,5-nonadiyne (24.5% and 5.8% in A and B, respectively), (Z)-3,5-nonadiyne-7-ene (0.2% in A), and (E)-3,5-nonadiyne-7-ene (0.5% in A). Monoterpenes alpha-pinene (6.8% and 12.8%), alpha-phellandrene (0.1% and 17.1%), and beta-phellandrene (4.2% and 22.4%) were found to be the major components in P. platychlaena ssp. platychlaena EOs in samples A and B, respectively. The components of P. platychlaena ssp. platychlaena EOs were separated on the overpressured layer chromatography (OPLC) plates, and the plates were subsequently subjected to direct-bioautography assays using three plant pathogens such as Colletotrichum acutatum, C. fragariae, and C. gloeosporioides; however, no antifungal activity was observed. Due to a high yield, sample A was evaluated for its repellent activity against female mosquito Aedes aegypti and attraction of sterile male Mediterranean fruit fly Ceratitis capitata. Sample A demonstrated good repellency against Ae. aegypti in human-based cloth patch bioassays and no attraction to C. capitata in short range bioassays.

The first synthesis of 2-methyl-6-pentadecyl-Δ1,6-piperideine (1), a major alkaloid of the piperideine chemotype in fire ant venoms, and its analogues, 2-methyl-6-tetradecyl-Δ1,6-piperideine (2) and 2-methyl-6-hexadecyl-Δ1,6-piperideine (3), was achieved by a facile synthetic method starting with glutaric acid (4) and urea (5). Compound 1 showed in vitro antifungal activity against Cryptococcus neoformans and Candida albicans with IC50 values of 6.6 and 12.4 μg/mL, respectively, and antibacterial activity against vancomycin-resistant Enterococcus faecium with an IC50 value of 19.4 μg/mL, while compounds 2 and 3 were less active against these pathogens. All three compounds strongly inhibited the parasites Leishmania donovani promastigotes and Trypanosoma brucei with IC50 values in the range of 5.0–6.7 and 2.7–4.0 μg/mL, respectively.

The essential oils (EOs) derived from aromatic plants such as Piper species are considered to play a role in alleviating neuronal ailments that are associated with inhibition of acetylcholinesterase (AChE). The chemical compositions of 23 EOs prepared from 16 Piper spp. were analyzed by both gas chromatography with a flame ionization detector (GC-FID) and gas chromatography–mass spectrometry (GC-MS). A total of 76 compounds were identified in the EOs from the leaves and stems of 19 samples, while 30 compounds were detected in the EOs from the fruits of four samples. Sesquiterpenes and phenylpropanoids were found to be rich in these EOs, of which asaricin, caryophyllene, caryophyllene oxide, isospathulenol, (+)-spathulenol, and β-bisabolene are the major constituents. The EOs from the leaves and stems of Piper austrosinense, P. puberulum, P. flaviflorum, P. betle, and P. hispidimervium showed strong AChE inhibitory activity with IC50 values in the range of 1.51 to 13.9 mg/mL. A thin-layer chromatography (T...

The natural product phloroglucinol-based derivatives representing monoacyl-, diacyl-, dimeric acyl-, alkylated monoacyl-, and the nitrogen-containing alkylated monoacylphloro- glucinols were synthesized and evaluated for inhibitory activities against the inflammatory mediators such as inducible nitric oxide synthase (iNOS) and nuclear factor kappaB (NF-&kappa, B). The diacylphloroglucinol compound 2 and the alkylated acylphloroglucinol compound 4 inhibited iNOS with IC50 values of 19.0 and 19.5 &micro, M, respectively, and NF-&kappa, B with IC50 values of 34.0 and 37.5 &micro, M, respectively. These compounds may serve as leads for the synthesis of more potent anti-inflammatory compounds for future drug discovery.

In the present study, 45 maleimides have been synthesized and evaluated for anti-leishmanial activities against L. donovani in vitro and cytotoxicity toward THP1 cells. All compounds exhibited obvious anti-leishmanial activities. Among the tested compounds, there were 10 maleimides with superior anti-leishmanial activities to standard drug amphotericin B, and 32 maleimides with superior anti-leishmanial activities to standard drug pentamidine, especially compounds 16 (IC50 &lt, 0.0128 &mu, g/mL) and 42 (IC50 &lt, g/mL), which showed extraordinary efficacy in an in vitro test and low cytotoxicities (CC50 &gt, 10 &mu, g/mL). The anti-leishmanial activities of 16 and 42 were 10 times better than that of amphotericin B. The structure and activity relationship (SAR) studies revealed that 3,4-non-substituted maleimides displayed the strongest anti-leishmanial activities compared to those for 3-methyl-maleimides and 3,4-dichloro-maleimides. 3,4-dichloro-maleimides were the least cytotoxic compared to 3-methyl-maleimides and 3,4-non-substituted maleimides. The results show that several of the reported compounds are promising leads for potential anti-leishmanial drug development.

Sixty-three amide alkaloids, including three new, piperflaviflorine A (1), piperflaviflorine B (2), and sarmentamide D (4), and two previously synthesized ones, (1E,3S)-1-cinnamoyl-3- hydroxypyrrolidine (3) and N-[7′-(4′-methoxyphenyl)ethyl]-2-methoxybenzamide (5), were isolated from the aerial parts of Piper flaviflorum and Piper sarmentosum. Their structures were elucidated by detailed spectroscopic analysis and, in case of 3, by single-crystal X-ray diffraction. Most of the isolates were tested for their antifungal and antibacterial activities. Ten amides (6–15) showed antifungal activity against Cryptococcus neoformans ATCC 90 113 with IC50 values in the range between 4.7 and 20.0 µg/mL.

In spectroscopy, redundant information makes the number of input variables for a prediction model larger than required. We present a method based on the physarum network to select the variable with the least correlation. This method transforms the variable selection problem into a path finding problem and then solves the problem based on the mechanism of foraging of Physarum polycephalum. Experimental results show that the physarum network, combined with other feature selection or extraction methods, can select the least number of wavelengths without sacrificing the prediction performance.

Two new compounds, (Z,R)-1-phenylethylcinnamate (1) and (1R,2R,3R,6S)-pipoxide (2) were isolated from the aerial part of Piper hainanense, along with 12 known compounds, including nine benzene derivatives (4-11), one isobutylamide (12), and two polyoxygenated cyclohexene derivatives (13-14). Their structures were elucidated on the basis of the HRESIMS, 1D and 2D NMR spectroscopic analyses, and ECD in cases of 2 and 3. The absolute configuration of ellipeiopsol B (3) was determined for the first time. All these compounds 1-14 were reported from the titled plant for the first time. Most of the isolates were tested for their cytotoxicities against five human cancer cell lines. Four of which, 2, 3, 9, 14 showed moderate bioactivities. Among them, the new compound 2 showed potential cytotoxicity against SMMC-7721, MCF-7, and SW-480 with IC50 values of 9.7, 15.0, and 13.2 μM, respectively.

Psorothatins A-C (1-3), three antibacterial prenylated acylphloroglucinol derivatives, were isolated from the native American plant Psorothamnus fremontii. They feature an unusual α,β-epoxyketone functionality and a β-hydroxy-α,β-unsaturated ketone structural moiety. The latter forms a pseudo-six-membered heterocyclic ring due to strong intramolecular hydrogen bonding, as indicated by the long-range proton-carbon correlations in the NMR experiments. Psorothatin C (3) was the most active compound against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium, with IC50 values in the range 1.4-8.8 μg/mL. The first total synthesis of 3 described herein permits future access to structural analogues with potentially improved antibacterial activities.

The green alga Klebsormidium flaccidum var. zivo is a rich source of proteins, polyphenols, and bioactive small-molecule compounds. An approach involving chromatographic fractionation, anti-inflammatory activity testing, ultrahigh performance liquid chromatography-mass spectrometry profiling, chemometric analysis, and subsequent MS-oriented isolation was employed to rapidly identify its small-molecule anti-inflammatory compounds including hydroxylated fatty acids, chlorophyll-derived pheophorbides, carotenoids, and glycoglycerolipids. Pheophorbide a, which decreased intracellular nitric oxide production by inhibiting inducible nitric oxide synthase, was the most potent compound identified with an IC50 value of 0.24 &micro, M in lipopolysaccharides-induced macrophages. It also inhibited nuclear factor kappaB activation with an IC50 value of 32.1 &micro, M in phorbol 12-myristate 13-acetate-induced chondrocytes. Compared to conventional bioassay-guided fractionation, this approach is more efficient for rapid identification of multiple chemical classes of bioactive compounds from a complex natural product mixture.

Researches focused on soil carbon (C), nitrogen (N), and phosphorus (P) content and the stoichiometry characteristics along elevation gradients are important for effective management of forest ecosystems. Taking the soil of different elevations from 900 to 1700 m on Daiyun Mountain as the object, the elevation distribution of total C, N, and P in soil and their stoichiometry characteristics were studied. Also, the driving factors resulting in the spatial heterogeneity of soil stoichiometry are presented. The results show the following: (1) The average soil C and N content was 53.03 g&middot, kg&minus, 1 and 3.82 g&middot, 1, respectively. The content of C and N at high elevation was higher than that of at low elevation. Soil phosphorus fluctuated with elevation. (2) With increasing elevation, soil C:N ratio increased initially to 17.40 at elevation between 900&ndash, 1000 m, and then decreased to 12.02 at elevation 1600 m. The changing trends of C:P and N:P were similar, and they all fluctuated with elevation. (3) Elevation, soil bulk density, and soil temperature were the main factors influencing the variation of soil C, N, and C:N. Soil pH and slope position were the driving factors for soil P, C:P, and N:P. The soil is rich in C and N, and has less total phosphorus on Daiyun Mountain. Raising the level of phosphate fertilizer appropriately can help to improve soil fertility and promote plant growth as well. In light of this information, in the near future, it will be necessary to conduct separation management of C, N, and P with regular monitoring systems to maintain favorable conditions for soil.

In the screening of natural plant extracts for antifungal activity, assessment of their effects on the growth of cells in suspension or in the wells of microtiter plates is expedient. However, microorganisms, including Candida albicans , grow in nature as biofilms, which are organized cellular communities with a complex architecture capable of conditioning their microenvironment, communicating, and excluding low- and high-molecular-weight molecules and white blood cells. Here, a confocal laser scanning microscopy (CLSM) protocol for testing the effects of large numbers of agents on biofilm development is described. The protocol assessed nine parameters from a single z-stack series of CLSM scans for each individual biofilm analyzed. The parameters included adhesion, thickness, formation of a basal yeast cell polylayer, hypha formation, the vertical orientation of hyphae, the hyphal bend point, pseudohypha formation, calcofluor white staining of the extracellular matrix (ECM), and human white blood cell impenetrability. The protocol was applied first to five plant extracts and derivative compounds and then to a collection of 88 previously untested plant extracts. They were found to cause a variety of phenotypic profiles, as was the case for 64 of the 88 extracts (73%). Half of the 46 extracts that did not affect biofilm thickness affected other biofilm parameters. Correlations between specific effects were revealed. The protocol will be useful not only in the screening of chemical libraries but also in the analysis of compounds with known effects and mutations.

Antifungal screening of small-molecule natural product libraries showed that a column fraction (CF) derived from the plant extract of Sagittaria latifolia was active against the fungal pathogen Cryptococcus neoformans. Dereplication analysis by liquid chromatography-mass spectrometry (LC-MS) and proton nuclear magnetic resonance spectroscopy ((1)H NMR) indicated the presence of new compounds in this CF. Subsequent fractionation of the plant extract resulted in the identification of two new isopimaradiene-type diterpenoids, 1 and 2. The structures of 1 and 2 were determined by chemical methods and spectroscopic analysis as isopimara-7,15-dien-19-ol 19-O-α-l-arabinofuranoside and isopimara-7,15-dien-19-ol 19-O-α-l-(5'-acetoxy)arabinofuranoside, respectively. Compound 1 exhibited IC50 values of 3.7 and 1.8 μg/mL, respectively, against C. neoformans and C. gattii. Its aglycone, isopimara-7,15-dien-19-ol (3), resulting from acid hydrolysis of 1, was also active against the two fungal pathogens, with IC50 values of 9.2 and 6.8 μg/mL, respectively. This study demonstrates that utilization of the combined LC-MS and (1)H NMR analytical tools is an improved chemical screening approach for hit prioritization in natural product drug discovery.

Bioassay-guided fractionation of the organic extracts of a Bacillus amyloliquefaciens strain (AP183) led to the discovery of a new macrocyclic polyene antibiotic, bacillusin A (1). Its structure was assigned by interpretation of NMR and MS spectroscopic data as a novel macrodiolide composed of dimeric 4-hydroxy-2-methoxy-6-alkenylbenzoic acid lactones with conjugated pentaene-hexahydroxy polyketide chains. Compound 1 showed potent antibacterial activities against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium with minimum inhibitory concentrations in a range of 0.6 to 1.2 μg/mL. The biosynthetic significance of this unique class of antibiotic compounds is briefly discussed.

Piper wallichii (Miq.) Hand.-Mazz. is a medicinal plant used widely for the treatment of rheumatoid arthritis, inflammatory diseases, cerebral infarction and angina in China. Previous study showed that lignans and neolignans from Piper spp. had potential inhibitory activities on platelet aggregation. In the present study, we investigated the chemical constituents of Piper wallichii and their antithrombotic activities, to support its traditional uses.The methanolic extract of the air-dried stems of Piper wallichii was separated and purified using various chromatographic methods, including semi-preparative HPLC. The chemical structures of the isolates were determined by detailed spectroscopic analysis, and acidic hydrolysis in case of the new glycoside 2. Determination of absolute configurations of the new compound 1 was facilitated by calculated electronic circular dichroism using time-dependent density-functional theory. All compounds were tested for their inhibitory effects on platelet aggregation induced by platelet activating factor (PAF) in rabbits׳ blood model, from which the active ones were further evaluated the in vivo antithrombotic activity in zebrafish model.A new neolignan, piperwalliol A (1), and four new aromatic glycosides, piperwalliosides A-D (2-5) were isolated from the stems of Piper wallichii, along with 25 known compounds, including 13 lignans, six aromatic glycosides, two phenylpropyl aldehydes, and four biphenyls. Five known compounds (6-10) showed in vitro antiplatelet aggregation activities. Among them, (-)-syringaresinol (6) was the most active compound with an IC50 value of 0.52 mM. It is noted that in zebrafish model, the known lignan 6 showed good in vivo antithrombotic effect with a value of 37% at a concentration of 30 μM, compared with the positive control aspirin with the inhibitory value of 74% at a concentration of 125μM.This study demonstrated that lignans, phenylpropanoid and biphenyl found in Piper wallichii may be responsible for antithrombotic effect of the titled plant.

A novel one-pot protocol for the synthesis of symmetrical dinucleoside tri-, tetra-, and pentaphosphates, and their phosphonate analogs simply from nucleoside 5′-phosphoropiperidates has been developed by utilizing 4,5-dicyanoimidazole-promoted tandem P–O coupling reactions.

Two new phloroglucinol-coupled sesquiterpenoids, eucalmaidials A and B (1 and 2), were isolated from the juvenile leaves of Eucalyptus maideni, along with eight known macrocarpals (3–10), eucalyptone (11), and three known triterpenoids (12–14). Eucalmaidials A and B represent a new skeleton of phloroglucinol-coupled iphionane. Their structures were elucidated by extensive NMR spectroscopic analysis and theoretical calculation of the 13C NMR chemical shifts. The biosynthetic pathway of 1 and 2 was also postulated. Compounds 1, 3, 5, 7, 8, and 10–14 were evaluated for their antifungal and antibacterial activities. Compound 1 exhibited antifungal activity against Candida glabrata with an IC50 value of 0.75 μg mL−1.

Thirty-three natural-product-based acylphloroglucinol derivatives were synthesized to identify antifungal compounds against Cryptococcus spp. that cause the life-threatening disseminated cryptococcosis. In vitro antifungal testing showed that 17 compounds were active against C. neoformans ATCC 90113, C. neoformans H99, and C. gattii ATCC 32609, with minimum inhibitory concentrations (MICs) in the range 1.0-16.7 μg/mL. Analysis of the structure and antifungal activity of these compounds indicated that the 2,4-diacyl- and 2-acyl-4-alkylphloroglucinols were more active than O-alkyl-acylphloroglucinols. The most promising compound found was 2-methyl-1-(2,4,6-trihydroxy-3-(4-isopropylbenzyl)phenyl)propan-1-one (11j), which exhibited potent antifungal activity (MICs, 1.5-2.1 μg/mL) and low cytotoxicity against the mammalian Vero and LLC-PK1 cell lines (IC50 values50 μg/mL). This compound may serve as a template for further synthesis of new analogues with improved antifungal activity. The findings of the present work may contribute to future antifungal discovery toward pharmaceutical development of new treatments for cryptococcosis.

Fourteen compounds including vanicoside B (1), vanicoside F (2), vanicoside E (3) and 5,6-dehydrokawain (4), aniba-dimer-A (5), 6,6′-((1α,2α,3β,4β)-2,4-diphenylcyclobutane-1,3-diyl)bis(4-methoxy-2H-pyran-2-one) (6), (+)-ketopinoresinol (7), isorhamnetin (8), 3,7-dihydroxy-5,6-dimethoxy-flavone (9), isalpinin (10), cardamomin (11), pinosylvin (12), 2-desoxy-4-epi-pulchellin (13) and β-sitosterol (14) were isolated from dichloromethane-soluble portion of Polygonum hydropiper. By using Alamar blue assay, compounds 2, 7, 8, 11 and 12 were found to be active against Trypanosoma brucei with IC50 values in the range of 0.49–7.77 μg/mL. Cardamomin (11) had most significant activity against T. brucei with IC50/IC90 values of 0.49/0.81 μg/mL compared to the positive control DFMO (IC50/IC90: 3.02/8.05 μg/mL). Furthermore, in antimalarial, antimicrobial, anti-inflammatory, PPAR and cytotoxic assays, some compounds have demonstrated moderate inhibitory potentials.

6-Nonadecynoic acid (6-NDA), a plant-derived acetylenic acid, exhibits strong inhibitory activity against the human fungal pathogens Candida albicans , Aspergillus fumigatus , and Trichophyton mentagrophytes . In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model yeast Saccharomyces cerevisiae to investigate its mechanism of action. 6-NDA elicited a transcriptome response indicative of fatty acid stress, altering the expression of genes that are required for yeast growth in the presence of oleate. Mutants of S. cerevisiae lacking transcription factors that regulate fatty acid β-oxidation showed increased sensitivity to 6-NDA. Fatty acid profile analysis indicated that 6-NDA inhibited the formation of fatty acids longer than 14 carbons in length. In addition, the growth inhibitory effect of 6-NDA was rescued in the presence of exogenously supplied oleate. To investigate the response of a pathogenic fungal species to 6-NDA, transcriptional profiling and biochemical analyses were also conducted in C. albicans . The transcriptional response and fatty acid profile of C. albicans were comparable to those obtained in S. cerevisiae , and the rescue of growth inhibition with exogenous oleate was also observed in C. albicans . In a fluconazole-resistant clinical isolate of C. albicans , a fungicidal effect was produced when fluconazole was combined with 6-NDA. In hyphal growth assays, 6-NDA inhibited the formation of long hyphal filaments in C. albicans . Collectively, our results indicate that the antifungal activity of 6-NDA is mediated by a disruption in fatty acid homeostasis and that 6-NDA has potential utility in the treatment of superficial Candida infections.

This review documents chemical structures and antifungal activities of 68 compounds isolated from 22 Piper species of the plant family Piperaceae. These compounds include amides, flavonoids, prenylated benzoic acid derivatives, lignans, phenylpropanoids, butenolides, and cyclopentendiones. Some of them may serve as leads for potential pharmaceutical or agricultural fungicide development.

Seven 6-alkyl-2,3,4,5-tetrahydropyridines (5a–5g) that mimic the natural piperideines that were recently identified in the fire ant venom have been synthesized. Compounds 5c–5g with the C-6 alkyl chain lengths from C14 to C18 showed varying degrees of antifungal activities, with 5e (6-hexadecyl-2,3,4,5-tetrahydropyridine) and 5f (6-heptadecyl-2,3,4,5-tetrahydropyridine) being the most active. Compound 5e exhibited minimum fungicidal concentrations (MFCs) of 3.8, 15.0, 7.5, and 7.5 μg/mL against Cryptococcus neoformans, Candida albicans, Candida glabrata, and Candida krusei, respectively. The antifungal activities of these compounds appear to be associated with the C-6 side chain length. This study represents the first effort to evaluate antifungal activities of synthetic analogs of the newly identified fire ant venom alkaloids.

Five ursane type triterpene glucosyl esters including a new one, 2alpha,3beta-dihydroxyurs-12,18-dien-28-oic acid 28-O-beta-D-glucopyranosyl ester (1) were isolated from the bark of Terminalia arjuna, along with two known phenolic compounds. It is the first report of ursane type triterpenoids from this species.

Six new steroidal saponins (1-6), angudracanosides A-F, were isolated from fresh stems of Dracaena angustifolia (Agavaceae), together with eight known compounds. The structures of compounds 1-6 were determined by detailed spectroscopic analyses and chemical methods. Antifungal testing of all compounds showed that 6 and 7 were active against Cryptococcus neoformans with IC50s of 9.5 and 20.0 μg/mL, respectively.

A new biflavonoid (1), a new xanthone enantiomer (2), five new caged xanthones (3-7), and several known compounds were isolated from the stem bark of Garcinia lateriflora, collected in Indonesia. The structures of the new compounds were determined by analysis of spectroscopic data, and the absolute configuration of the caged xanthones was shown for the first time at carbons 5, 7, 8, 8a, 10a, and 27, by analysis of COSY and NOESY NMR and ECD spectra. The biflavonoids exhibited proteasome inhibitory activity, and the known compound, morelloflavone (8) was found to have the greatest potency (IC(50) = 1.3 muM). The caged xanthones were cytotoxic towards HT-29 cells, with the known compound, morellic acid (10) being the most active (ED(50) = 0.36 muM). However, when tested in an in vivo hollow fiber assay, it was inactive at the highest dose tested (20 mg/kg).

Three new alpha-tetralone galloylghlcosides, 1-3, were isolated from the fresh pericarps of Juglans sigillata (Juglandaceae), together with six known compounds. The structures of the new compounds were determined as 1,2,3,4-tetrahydro-7-hydroxy-4-oxonaphthalen-1-yl 6-O-[(3,4,5-trihydroxyphenyl)carbonyl]-beta-D-glucopyranoside (1), (IS)-1,2,3,4-tetrahydro-8-hydroxy-4-oxonaphthalen-1-yl 6-O-[(3,4,5-trihydroxyphenyl)carbonyl]-beta-D-glycopyranoside (2), and 1,2,3,4-tetrahydro-7,8-dihydroxy-4-oxonaphthalen-1-yl 6-O-[(3,4,5-trihydroxphenyl)carbonyl]-beta-D-glucopyranoside (3), respectively, on the basis of detailed spectroscopic analyses, and acidic and enzymatic hydrolysis. The antimicrobial activities of the isolated compounds 2, 4, and 7-9 were evaluated.

Five novel 18,19-secooleanane-type triterpene glycosyl esters, namely arjunasides A-E, were isolated from the MeOH extract of the bark of Terminalia arjuna along with nine known oleanane triterpenoids. The structures of the new compounds were determined by spectroscopic analyses including 2D NMR, HRESIMS, and CD spectra.

Tricalysiosides V and W, two new ent-kaurane glycosides with an acylated disaccharide moiety at the C-3 position, were isolated from the roots of Tricalysia okelensis and their structures established by spectroscopic and chemical methods as ent-kauran-3alpha,16alpha,17-triol-19-al 3-O-[5-O-vanilloyl-beta-D-apiopyranosyl(1--6)]-beta-D-glucopyranoside (1) and ent-kauran-3alpha,16alpha,17-triol-19-al 3-O-[5-O-E-sinapoyl-beta-D-apiopyranosyl(1--6)]-beta-D-glucopyranoside (2).

Phytochemical investigation of the leaves of Sutherlandia frutescens led to the isolation of four new 3-hydroxy-3-methylglutaroyl-containing flavonol glycosides, sutherlandins A-D ( 1- 4). Their structures were elucidated by chemical and spectroscopic methods as quercetin 3- O- beta- D-xylopyranosyl(1 --> 2)-[6- O-(3-hydroxy-3-methylglutaroyl)]- beta- D-glucopyranoside ( 1), quercetin 3- O- beta- D-apiofuranosyl(1 --> 2)-[6- O-(3-hydroxy-3-methylglutaroyl)]- beta- D-glucopyranoside ( 2), kaempferol 3- O- beta- D-xylopyranosyl(1 --> 2)-[6- O-(3-hydroxy-3-methylglutaroyl)]- beta- D-glucopyranoside ( 3), and kaempferol 3- O- beta- D-apiofuranosyl(1 --> 2)-[6- O-(3-hydroxy-3-methylglutaroyl)]- beta- D-glucopyranoside ( 4).

Bioassay-guided fractionation of the extract of Topsentia sp. led to the identification of two new sulfated sterols, geodisterol-3-O-sulfite (1) and 29-demethylgeodisterol-3-O-sulfite (2), the active constituents reversing efflux pump-mediated fluconazole resistance. Both compounds enhanced the activity of fluconazole in a Saccharomyces cerevisiae strain overexpressing the Candida albicans efflux pump MDR1, as well as in a fluconazole-resistant Candida albicans clinical isolate known to overexpress MDR1. These results provide insight into the clinical utility of combining efflux pump inhibitors with current antifungals to combat the resistance associated with opportunistic fungal infections caused by C. albicans.

Verbesinosides A-F (1-6), six new 15,27-cyclooleanane-type triterpenoid saponins carrying different aromatic acyl moieties on the aglycon, were isolated from the leaves and flowers of Verbesina virginica. Their structures were established by interpretation of spectroscopic data and chemical methods. The representative major saponin, verbesinoside A (1), has the structure 21-trimethoxybenzoyl 15alpha,27-cycloolean-12-en-3beta,21beta-diol-28-oic acid 3-O-beta-D-xylopyranosyl(1--4)-beta-D-xylopyranosyl(1--2)-beta-D-glucopyranoside. This is the first report of triterpenoid saponins possessing the unique 15,27-cyclooleanane skeleton. The anisotropic effects of the aromatic acyl moieties on the triterpenoid skeleton are discussed.

The effects of natural hybridization on secondary metabolite production and diversification have only recently been studied in plants and have essentially been overlooked in marine organisms. Chemical investigation of the hybrid soft coral Sinularia maxima x S. polydactyla resulted in the isolation of five new terpenoids, 7E-polymaxenolide (1), 7E-5-epipolymaxenolide (2), and polymaxenolides A-C (3-5), possessing a cembrane-africanane skeleton. Their structures were established by detailed analysis of NMR and MS data. The contentious issue of defining the absolute configuration at the stereogenic centers of the conformationally mobile cembrane macrocyclic ring was addressed by joint application of electronic circular dichroism and X-ray diffraction analyses.

Hoodia gordonii is a ‘weight loss’ herb, which has gained popularity in the western countries as an appetite suppressant dietary supplement. Phytochemical study of its aerial parts led to isolation of seven pregnane glycosides (hoodigosides W–Z, hoodistanalosides A–B). Their structures were elucidated by chemical degradation studies and spectroscopic methods, including 1D and 2D NMR and CD spectroscopic methods.

Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C 16 to C 20 : 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides . Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes , and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus , with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 μM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 μmol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.

Ten steroidal saponins with cis-fused A/B ring, including a smilagenin glycoside, elephanoside A (4), and the five furostanol bisdesmosides, elephanosides B-F (6-10), were isolated from the stems of Yucca elephantipes Regel. (Agavaceae). Their structures were determined by detailed chemical and spectroscopic analysis. All the isolated compounds were tested for their in vitro antifungal and antibacterial activities. Only the two known spirostanol glycosides Ys-II (1) and Ys-IV (2) showed moderate inhibitory activity against the growth of Candida albicans and Cryptococcus neoformans.

As part of our search for new antifungal agents from natural resources, 22 C-27 steroidal saponins and 6 steroidal sapogenins isolated from several monocotyledonous plants were tested for their antifungal activity against the opportunistic pathogens Candida albicans , Candida glabrata , Candida krusei , Cryptococcus neoformans , and Aspergillus fumigatus . The results showed that the antifungal activity of the steroidal saponins was associated with their aglycone moieties and the number and structure of monosaccharide units in their sugar chains. Within the 10 active saponins, four tigogenin saponins (compounds 1 to 4) with a sugar moiety of four or five monosaccharide units exhibited significant activity against C. neoformans and A. fumigatus , comparable to the positive control amphotericin B. The antifungal potency of these compounds was not associated with cytotoxicity to mammalian cells. This suggests that the C-27 steroidal saponins may be considered potential antifungal leads for further preclinical study.

A whole-cell-based assay using Saccharomyces cerevisiae strains that overexpress Candida albicans CDR1 and MDR1 efflux pumps has been employed to screen natural product extracts for reversal of fluconazole resistance. The tropical green alga Penicillus capitatus was selected for bioassay-guided isolation, leading to the identification of capisterones A and B (1 and 2), which were recently isolated from this alga and shown to possess antifungal activity against the marine pathogen Lindra thallasiae. Current work has assigned their absolute configurations using electronic circular dichroism and determined their preferred conformations in solution based on detailed NOE analysis. Compounds 1 and 2 significantly enhanced fluconazole activity in S. cerevisiae, but did not show inherent antifungal activity when tested against several opportunistic pathogens or cytotoxicity to several human cancer and noncancerous cell lines (up to 35 microM). These compounds may have a potential for combination therapy of fungal infections caused by clinically relevant azole-resistant strains.

Two new phloroglucinol-coupled sesquiterpenoids, eucalmaidials A and B (1 and 2), were isolated from the juvenile leaves of Eucalyptus maideni, along with eight known macrocarpals (3–10), eucalyptone (11), and three known triterpenoids (12–14). Eucalmaidials A and B represent a new skeleton of phloroglucinol-coupled iphionane. Their structures were elucidated by extensive NMR spectroscopic analysis and theoretical calculation of the 13C NMR chemical shifts. The biosynthetic pathway of 1 and 2 was also postulated. Compounds 1, 3, 5, 7, 8, and 10–14 were evaluated for their antifungal and antibacterial activities. Compound 1 exhibited antifungal activity against Candida glabrata with an IC50 value of 0.75 μg mL−1.

Antifungal bioassay-guided isolation of the ethanol extract of the roots of Pentagonia gigantifolia yielded 6-octadecynoic acid (1) and the new 6-nonadecynoic acid (2). Compounds 1 and 2 inhibited the growth of fluconazole-susceptible and -resistant Candida albicans strains. Their antifungal potencies were comparable to those of amphotericin B and fluconazole. Of particular significance is the low cytotoxicity and specific activity of 1 and 2 against C. albicans.