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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.

Novel therapeutic strategies are needed to address depression, a major neurological disorder affecting hundreds of millions of people worldwide. Cannabinoids and their synthetic derivatives have demonstrated numerous neurological activities and may have the potential to be developed into new treatments for depression. This review highlights cannabinoid (CB) receptors, monoamine oxidase (MAO), N-methyl-D-aspartate (NMDA) receptor, gammaaminobutyric acid (GABA) receptor, and cholecystokinin (CCK) receptor as key molecular targets of cannabinoids that are associated with depression. The anti-depressant activity of cannabinoids and their binding modes with cannabinoid receptors are discussed, providing insights into rational design and discovery of new cannabinoids or cannabimimetic agents with improved druggable properties.

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.

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).

Paenibacillus sp. MS2379 is a highly efficient microbial strain producing fusaricidins, a class of lipopeptides that have demonstrated strong antifungal activities against a broad array of fungal pathogens. An integrated approach combining chromatographic fractionation, UHPLC-QTOF-MS analysis, and NMR spectroscopic interpretation was employed to characterize antifungal metabolites produced by this microbial strain, resulting in the identification of 48 fusaricidins including 30 cyclic and 18 open-chain species. In this regard, UHPLC-QTOF-MS played a vital role in determining structures of 28 new fusaricidins through peptide fragment analysis. The structural determination of the new fusaricidins by the high-resolution mass spectrometry was validated by follow-up isolation and NMR spectroscopic analysis of representative compounds. It is worth noting that novel fusaricidins with amino acid residues of serine and γ-aminobutyric acid were identified, which is of great biosynthetic significance for this biologically important class of compounds. The present study again illustrates the power of UHPLC-QTOF-MS for structural identification of lipopeptides, and the structural diversity of the identified fusaricidins makes this microbial strain unique as a potential biocontrol agent.

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.

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.

A functional metagenomic approach identified novel and diverse soil-derived DNAs encoding inhibitors to methicillin-resistant Staphylococcus aureus (MRSA). A metagenomic DNA soil library containing 19 200 recombinant Escherichia coli BAC clones with 100 Kb average insert size was screened for antibiotic activity. Twenty-seven clones inhibited MRSA, seven of which were found by LC-MS to possess modified chloramphenicol (Cm) derivatives, including three new compounds whose structures were established as 1-acetyl-3-propanoylchloramphenicol, 1-acety1-3-butanoyl-chloramphenicol, and 3-butanoyl-1-propanoylchloramphenicol. Cm was used as the selectable antibiotic for cloning, suggesting that heterologously expressed enzymes resulted in derivatization of Cm into new chemical entities with biological activity. An esterase was found to be responsible for the enzymatic regeneration of Cm, and the gene trfA responsible for plasmid copy induction was found to be responsible for inducing antibacterial activity in some clones. Six additional acylchloramphenicols were synthesized for structure and antibacterial activity relationship studies, with 1-p-nitrobenzoylchloramphenicol the most active against Mycobacterium intracellulare and Mycobacterium tuberculosis, with MICs of 12.5 and 50.0 mu g/mL, respectively. Identification of anti-microbial agents from metagenomic clones

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 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.

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.

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.

Fifteen known compounds including four triterpenoids (1-4), one sterol (5), one diketopiperazine alkaloid (6) and nine phenolics (7-15) were isolated from the stems of Piper wallichii. Their structures were elucidated by means of spectroscopic analysis, and acidic hydrolysis in case of the 2-oxo-3β,19α,23-trihydroxyurs-12-en-28-oic acid β-D-glucopyranosyl ester (1). The structure of compound 1 was fully assigned by 1D and 2D NMR experiments for the first time. All isolates were tested for their antibacterial, antifungal, anti-inflammatory and antiplatelet aggregation bioactivities.

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.

The generation of natural product libraries containing column fractions, each with only a few small molecules, using a high-throughput, automated fractionation system, has made it possible to implement an improved dereplication strategy for selection and prioritization of leads in a natural product discovery program. Analysis of databased UPLC-MS-ELSD-PDA information of three leads from a biological screen employing the ependymoma cell line EphB2-EPD generated details on the possible structures of active compounds present. The procedure allows the rapid identification of known compounds and guides the isolation of unknown compounds of interest. Three previously known flavanone-type compounds, homoeriodictyol (1), hesperetin (2), and sterubin (3), were identified in a selected fraction derived from the leaves of Eriodictyon angustifolium. The lignan compound deoxypodophyllotoxin (8) was confirmed to be an active constituent in two lead fractions derived from the bark and leaves of Thuja occidentalis. In addition, two new but inactive labdane-type diterpenoids with an uncommon triol side chain were also identified as coexisting with deoxypodophyllotoxin in a lead fraction from the bark of T. occidentalis. Both diterpenoids were isolated in acetylated form, and their structures were determined as 14S,15-diacetoxy-13R-hydroxylabd-8(17)-en-19-oic acid (9) and 14R,15-diacetoxy-13S-hydroxylabd-8(17)-en-19-oic acid (10), respectively, by spectroscopic data interpretation and X-ray crystallography. This work demonstrates that a UPLC-MS-ELSD-PDA database produced during fractionation may be used as a powerful dereplication tool to facilitate compound identification from chromatographically tractable small-molecule natural product libraries.

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.

Morusalbanol A (1), a neuro-protective Diels–Alder adduct with a new carbon skeleton, was isolated from the bark of Morus alba. Compound 1 showed evidence of interesting astropisomerism, and resulted in the absence of a number of key proton and carbon signals in the NMR spectra. Its structure was thus elucidated by spectroscopic analysis of its peracetylated derivative (2) and its absolute configuration established as 1S,3S,4R,5S via experimental and calculated ECD spectra of 1. In a neuro-protective assay, morusalbanol A (1) significantly attenuated the H2O2-induced cell damage in a dose-dependent manner.

A new method to open the heterocyclic ring of flavan-3-ols via photolytic cleavage of the ether bond, with stereoselective trapping of the intermediates with phloroglucinol to obtain phloroglucinol grafted derivatives of flavan-3-ols, was developed. Photolysis of catechin and epicatechin, respectively, in the presence of phloroglucinol yielded the enantiomeric (1S,2S)- and (1R,2R)-1,3-di(2,4,6-trihydroxyphenyl)-1-(3,4-dihydroxyphenyl)propan-2-ols, respectively. The absolute configuration at C-1 and C-2 was determined by electronic circular dichroism (experimental and calculated) and these results confirmed that the trapping mechanism is controlled by the C-3 configuration of the flavan-3-ol.

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.

Synthetic analogues of the marine-derived class of natural products phloeodictines have been prepared and exhibited potent in vitro fungicidal activities against a broad array of fungal pathogens including drug resistant strains. The 6-hydroxy-2,3,4,6-tetrahydropyrrolo[1,2-a]pyrimidinium structural moiety with a C12 to C16 aliphatic side chain at C-6 has been shown to be the antifungal pharmacophore and may serve as a new antifungal template for further lead optimization.

Determination of absolute configuration (AC) is one of the most challenging features in the structure elucidation of chiral natural products, especially those with complex structures. With revolutionary advancements in the area of quantum chemical calculations of chiroptical spectroscopy over the past decade, the time dependent density functional theory (TDDFT) calculation of electronic circular dichroism (ECD) spectra has emerged as a very promising tool. The principle is simply based on the comparison of the calculated and experimental ECD spectra: the more closely they match, the more reliable conclusion for the AC assignment can be drawn. This review attempts to use several examples representing monomeric flavonoids, rotationally restricted biflavonoids, complex hexahydroxydiphenoyl-containing flavonoids, conformationally flexible and restrained sesquiterpenoids, cembrane-africanene terpenoids, dihydropyranocoumarins, alkaloids, and dihydroxanthones to illustrate the applicability of this approach in determining the AC of structurally diverse natural products. The findings clearly indicate that the TDDFT calculation of ECD spectra can quantify the contribution of individual conformers and the interaction of multiple chromophores, making it possible to determine the AC of complex chiral molecules. The calculated electronic transitions and molecular orbitals provide new insight into the interpretation of ECD spectra at the molecular level.

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).

The development of an automated, high-throughput fractionation procedure to prepare and analyze natural product libraries for drug discovery screening is described. Natural products obtained from plant materials worldwide were extracted and first prefractionated on polyamide solid-phase extraction cartridges to remove polyphenols, followed by high-throughput automated fractionation, drying, weighing, and reformatting for screening and storage. The analysis of fractions with UPLC coupled with MS, PDA, and ELSD detectors provides information that facilitates characterization of compounds in active fractions. Screening of a portion of fractions yielded multiple assay-specific hits in several high-throughput cellular screening assays. This procedure modernizes the traditional natural product fractionation paradigm by seamlessly integrating automation, informatics, and multimodal analytical interrogation capabilities.

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.

Six new neolignans, casearialignans A–F (1–6, resp.) and one known lignan syringaresinol-β-D-glucoside were isolated from the leaves of Casearia sylvestris. Their structures were determined on the basis of 1D- and 2D-NMR, and HR-ESI-MS analyses. The relative and absolute configurations were determined by the value of the coupling constants and CD spectral analysis, respectively.

Density functional theory/B3LYP has been employed to optimize the conformations of selected 4-arylflavan-3-ols and their phenolic methyl ether 3-O-acetates. The electronic circular dichroism spectra of the major conformers have been calculated using time-dependent density functional theory to validate the empirical aromatic quadrant rule applied to the assignment of the absolute configuration of this class of compounds. The modest 6-31G* basis set was sufficient to produce reasonable spectra. The calculated Cotton effects at 220-240 nm, crucial for the assignment of the C-4 absolute configuration, result from electronic transitions of the molecular orbitals involving the pi-electrons of the spatially close aromatic A-ring and 4-aryl moieties. The sign of this Cotton effect is determined by the orientation of the 4-aryl substituent: the negative and positive Cotton effects are associated with 4alpha- and 4beta-aryl substituents, respectively.

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.

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.

A simple and efficient procedure for the solid-phase synthesis of aryl vinyl ethers using polymer-supported β-bromoethyl selenide with traceless linker strategy is described.

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.