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Objectives The study aimed to identify nutmeg compounds that indirectly interact with the endocannabinoid system through inhibition of the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) enzymes. Methods Thirteen compounds were screened for FAAH and MAGL inhibition. Compounds demonstrating significant FAAH inhibition were evaluated to determine the halfmaximal inhibitory concentration (IC50). The most potent compound was investigated in the elevated plus maze (EPM) rodent anxiety model. Key findings Three compounds, licarin A (9), 5′-methoxylicarin A (8) and malabaricone C (6) were most active in inhibiting FAAH with IC50 of 7.02 μm ± 2.02, 4.57 μm ± 0.66 and 38.29 μm ± 6.18, respectively. None of the purified compounds showed significant MAGL inhibition. Because of its relative high potency and selectivity, compound 8 was further evaluated in the EPM animal model of anxiety. The compound showed significant increase in number of open arm entries (P < 0.05) when administered at 120 mg/kg dose. No effect was observed on the locomotor activity. Conclusions Results collected introduce active nutmeg compounds as potential leads for further development. Of the three compounds, 8 possesses highest potency and FAAH selectivity as well as anxiolytic activity. Furthermore, in vivo testing in appropriate behavioural animal paradigms is warranted.

Tuberculosis (TB) is one of the deadliest infectious diseases worldwide. The drug discovery process of novel, safe and effective agents to combat TB involves identification of new molecular targets and novel chemical scaffolds. The current anti-TB drug pipeline includes several small molecules with more to follow as new candidates are disclosed. This review highlights the most significant findings described in 78 international, European and US patents for chemically diverse compounds as prospective anti-TB medications. Main points of emphasis include chemical classification, in vitro and in vivo activity, ADME/Tox profile and mycobacterial target as described in each patent. The collective mass of compounds disclosed in the reviewed patents introduces new candidates as potential therapeutic agents for TB infections.

The fruit of the Maclura pomifera tree is a sustainable source for the pharmacologically interesting isoflavones, osajin and pomiferin. A reversed-phase HPLC method was developed to identify osage orange samples with high isoflavone content and to determine the optimum conditions for sample preparation. Analytical run time was 8 min at a flow rate of 1 mL/min using a gradient of acetonitrile in H2O (0.1% formic acid) and UV peak detection at 274 nm. The method was validated for specificity, accuracy, precision, and limits of detection and quantitation (LOD/LOQ). The method was applied to determine the levels of osajin and pomiferin in extracts prepared from different samples of osage orange growing in the Midwest and southern United States. Results demonstrated the effect of different variables, such as sample preparation, geographical location, and growth stage, on the levels of osajin and pomiferin in analyzed samples.

Borututu (Cochlospermum angolensis) is an African tree whose bark has recently emerged as a herbal dietary supplement with claims for antioxidant activity. In order to substantiate the claimed activity of borututu supplements, we performed an activity-guided fractionation of the total extract utilizing a 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging assay. Subsequent flash and centrifugal chromatography resulted in the isolation of gallic acid (1) and protocatechuic acid (2) as the main antioxidant constituents. Two apocarotenoids and one flavonoid were also isolated from the chloroform fraction and were identified as cochloxanthin (3), dihydrocochloxanthin (4), and 7,4′-dimethyltaxifolin (5), respectively. A High-performance liquid chromatography (HPLC) method was also developed for fingerprinting borututu samples, with Compounds 1–4 suggested as chemical markers for quality control purposes.

Nutmeg [Myristica fragrans Houtt. (Myristicaceae)] has a long-standing reputation of psychoactivity. Anecdotal reports of nutmeg use as a cheap marijuana substitute, coupled to previous studies reporting a cannabimimetic-like action, suggest that nutmeg may interact with the endocannabinoid system.The study evaluates nutmeg fractions for binding capacity with various CNS receptors and their potential interaction with the endocannabinoid system.Dichloromethane (DF) and ethyl acetate (EF) fractions were prepared from the methanol extract of powdered whole nutmeg. The HPLC-profiled fractions were assayed by the NIMH Psychoactive Drug Screening Program (PDSP) in a panel of CNS targets at a 10 μg/mL concentration. The fractions were also screened for fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibition, initially at a concentration of 500 μg/mL, then by concentration-dependent inhibition studies.None of the tested fractions showed significant binding to CNS receptors included in the PDSP panel. However, both fractions exerted significant inhibition of the FAAH and MAGL enzymes. The DF fraction inhibited FAAH and MAGL enzymes at ICThe study provides the first piece of evidence that nutmeg interacts with the endocannabinoid system via inhibition of the endocannabinoid catabolizing enzymes. This mechanism provides insight into reported cannabis-like action as well as expands the potential therapeutic utility of nutmeg.

Nutmeg is a valued kitchen spice that has been used for centuries all over the world. In addition to its use in flavoring foods and beverages, nutmeg has been used in traditional remedies for stomach and kidney disorders. The antioxidant, antimicrobial and central nervous system effects of nutmeg have also been reported in literature. Nutmeg is a rich source of fixed and essential oil, triterpenes, and various types of phenolic compounds. Many of the secondary metabolites of nutmeg exhibit biological activities that may support its use in traditional medicine. This article provides an overview of the chemistry of secondary metabolites isolated from nutmeg kernel and mace including common methods for analysis of extracts and pure compounds as well as recent approaches towards total synthesis of some of the major constituents. A summary of the most significant pharmacological investigations of potential drug leads isolated from nutmeg and reported in the last decade is also included.

The aim of this study was to investigate the antimycobacterial activity of the major daucane constituent, ferutinin (jaeschkeandiol p-hydroxybenzoate, 1), four of its natural analogues, its hydrolysis products, as well as methyl p-hydroxybenzoate (methylparaben) against Mycobacterium smegmatis, a rapidly growing surrogate of Mycobacterium tuberculosis. The agar dilution assay was utilised for an antimycobacterial evaluation of single compounds. A modified agar dilution assay, the checkerboard method, was utilised for evaluating the potentiating effect of 1 on different antitubercular drugs, namely isoniazid, ethionamide, rifampin and streptomycin. In the agar dilution assay, 1 exhibited higher potency (minimum inhibitory concentration [MIC] 10 µg mL⁻¹) than streptomycin and rifampin (MIC 20 µg mL⁻¹ for each). Of the natural analogues, 8,9-epoxyjaeschkeandiol p-hydroxybenzoate and 8,9-epoxyjaeschkeandiol benzoate exhibited marginal activity (MIC ≥ 40 and 80 µg mL⁻¹, respectively). The checkerboard method showed that the combination of 1 with each antitubercular drug led to mutual enhancement of the antimycobacterial activity with isoniazid and ethionamide, while no such effect was observed with rifampin or streptomycin. Based on this study and earlier studies with Staphylococcus aureus, the major constituent 1 may be responsible for the major part of the antimicrobial activity of the root of Ferula hermonis.

Nutmeg, the seeds of Myritica fragrans (family Myristicaceae), is a well known kitchen spice with a long-standing reputation as a psychoactive herb. Nutmeg at high doses is considered a cheap substitute to several drugs of abuse. Earlier reports have attributed amphetamine-like activities to nutmeg.To characterize the neuropharmacological effects of different nutmeg extracts, administered orally and intraperitoneally, in comparison to Delta(9)-terahydrocannabinol, amphetamine, and morphine.Methanolic (ME), dichloromethane (DE), and hexane (HE) extracts were obtained from a chromatographically fingerprinted batch of nutmeg. Biological evaluation was conducted in sets of 6-8 mice in the tetrad assay at doses ranging from 100 to 500 and 500 to 1000 mg/kg for i.p. and oral administration, respectively.While oral administration of all the nutmeg extracts at 500 mg/kg caused a significant increase in locomotor activity, the i.p. administration of DE showed significant reduction in rectal temperature along with a significant increase in tail flick latency at 300 mg/kg. A significant decrease in core body temperature was observed with HE at 100 mg/kg, while higher doses caused significant increases in hot plate latency.Different behavioral effects were observed that varied by the type of extract as well as by the route of administration.

The enhancing effect of sub-inhibitory concentrations of eugenol and isoeugenol with isoniazid, 6-paradol and 6-shogaol was evaluated in two different strains, Mycobacterium smegmatis and Candida albicans, using the in vitro checkerboard method. With M. smegmatis, isoeugenol (at ½ MIC) was able to lower the MIC (minimum inhibitory concentration) of isoniazid and 6-paradol by 800 percent (10→1.25 μg/mL) and 400 percent (30→7.5 μg/mL), respectively. Against C. albicans, Isoeugenol (at ½ MIC) was also able to lower the MIC of 6-paradol by 1600 percent (60→3.75 μg/mL). Similar synergistic effects were not observed between isoeugenol and 6-shogaol. Eugenol failed to exhibit any of the synergistic effects of isoeugenol under the same experimental conditions. Isoeugenol is a promising enhancing agent for compounds with weak antimycobacterial and anticandidal activities. 6-Paradol may be a potential candidate for further combination studies due to its broader antimicrobial effect against both M. smegmati...

In our ongoing search for anti-inflammatory and neuroprotective agents of natural origin, the total methanolic extract (MPE) of horse apple (Maclura pomifera) and its two major prenylated isoflavones, osajin (OSA) and pomiferin (POM), were evaluated in vitro for their ability to affect four mediators of inflammation and to inhibit tau protein fibrillization. The two isoflavones were effective in enhancing the activity of NSAID activated gene (NAG-1) at 2.5 μg/mL (1.5 – 1.8 fold increase) and inhibiting iNOS and NF-κB activity with IC50 values in the range of 6 – 13 μg/mL. Pomiferin also inhibited intracellular oxidative stress with IC50 of 3.3 μg/mL, while osajin did not show any effect. The extract activated NAG-1 and inhibited iNOS and oxidative stress without affecting NF-κB. As observed by transmission electron microscopy (TEM), MPE, OSA and POM also inhibited arachidonic acid-induced tau fibrillization in a concentration-dependent manner.

The fixed valerian-hops extract combination Ze91019 is used as a sleep aid. Although its exact mechanism of action is not well understood, earlier studies indicate that the CNS effect of valerian might occur through interaction with the GABA, melatonin and/or the adenosine systems in the brain. The use of hops in sleep remedies, however, is mainly based on traditional use and scarce scientific information. In this report, the binding of Ze91019, and the component valerian and hops extracts within, was tested on 14 subtypes of five classes of central receptors (dopamine, serotonin, melatonin, MCH and neuropeptide-Y). Binding affinities could be demonstrated at some of the screened melatonin (ML1 and ML2) and serotonin (5-HT4e, 5-HT6 and 5-HT7) receptor subtypes.

The aim of the study was to demonstrate competition between caffeine and a fixed valerian/hop extract combination (Ze91019) by the central adenosine mechanism. EEG was used to describe the action of caffeine on the central nervous system after oral administration (200 mg) in healthy volunteers. In addition to caffeine, the volunteers (16 in each group) received either placebo or verum (2 and 6 tablets containing the valerian/hop extract). The EEG responses were recorded every 30 min thereafter. The verum medication was capable of reducing (2 tablets) or inhibiting (6 tablets) the arousal induced by caffeine. This pharmacodynamic action was observed 60 minutes after oral administration, indicating not only competition between the antagonist caffeine and the partial agonist, i. e., the valerian/hop extract but also bio-availability of the compound(s) responsible for the agonistic action. In conclusion, the valerian/hop extract acts via a central adenosine mechanism which is possibly the reason for its sleep-inducing and -maintaining activity.

Although the presence of harman alkaloids in the genus Passiflora has been established in a few species, their presence in the medicinally significant P. incarnata (passion flower) is still debatable. Powdered samples from 91 Passiflora species were subjected to accelerated speed extraction and analyzed for their content of five harman alkaloids by reversed-phase HPLC with photodiode array detection. The utilized analytical method was capable of detecting harman alkaloids in more than 50% of the analyzed samples at ppm levels. A library of HPLC chromatograms has also been generated as a tool for fingerprinting and authentication of the studied Passiflora species.

Clutia richardiana L. is a traditional medicinal herb with demonstrated hypoglycemic effects. An HPLC method (Luna((R)) C(18) column, gradient elution, UV detection at 220 nm) has been utilized to determine the levels of the major diterpenes of C. richardiana in extracts obtained by using three different solvents. Extraction with the organic solvents methanol and acetonitrile was more efficient than aqueous extraction with hot water, but nine markers could be detected equally in all extracts. The aqueous extract was non-toxic against a number of human cell lines, which is a promising indication for its use as a safe and effective antidiabetic herbal preparation.

Phytopharmaceuticals and dietary supplements containing valerian are used as mild sleep-inducing agents. An in vitro radioligand binding assay at A(1) and A(2A) adenosine receptors (ARs) was conducted with a fixed extract combination of valerian and hop (Ze 91019) to investigate a possible mechanism for the pharmacological activity of the extract. Component extracts of valerian and hop were also individually investigated. The fixed combination Ze 91019 as well as the valerian extracts therein exhibited selective affinity to A(1)ARs (K(i) = 0.15-0.37 mg/mL vs [(3)H]CCPA). The same extracts exhibited partial agonist activity at the A(1) adenosine receptor as indicated by a lower degree of stimulation of [35S]GTP gamma S binding in membrane preparations of CHO-hA(1) cells as compared to the full A(1) AR agonist N(6)-cyclopentyladenosine (CPA). In addition valerian extract inhibited cAMP accumulation in CHO-hA(1) cell membranes. The partial agonistic activity at A(1)ARs may thus play a role in the sleep inducing effect of Ze 91019 and the valerian extract therein.

An approach comprising accelerated solvent extraction followed by quantitative HPLC analysis has been adopted in fingerprinting 115 samples of different species of the genus Passiflora. The C-flavonoid glycosides schaftoside (1), isoschaftoside (2), isoorientin (3), orientin (4), isovitexin (5) and vitexin (6) were chosen as analytical standards and their overall prevalence in all samples was determined. The developed HPLC method utilizes gradient elution on an analytical Phenomenex Hypersil ODS column and UV detection at 280 nm. The availability of unique fingerprints, as well as quantitative data, for each species can provide a number of benefits including, but not limited to (a) authentication of samples, (b) determination of chemotaxonomic markers, (c) identification of constituent patterns related to specific geographical locations, (d) supportive data in genetic studies, (e) identifying possible substitutes for Passiflora incarnata, (f) differentiating between closely related species, and (g) relati...

Lotaustralin was isolated as a mixture of two diastereoisomeric forms from the methanol extract of Rhodiola rosea roots, together with the known compounds rosavin, rosarin, rosin, rosiridin, salidroside, and beta-sitosterol. The structure of lotaustralin was established by 1D and 2D-NMR spectroscopy, including 1H-1H COSY, NOESY, HMQC, and HMBC, and FAB and HR MS.

Many studies on the biological activities of nutmeg continue to appear in the literature. The most common targets include GIT, CNS, oxidative stress and inflammation. However, results obtained from most studies are often inconsistent due to the variability of utilized samples, lack of standardized nutmeg products or insufficient amounts of pure compounds for comprehensive follow-up investigation. To address the consistency and supply issue we utilized available technology to develop a reproducible procedure for preparation of specific extracts and isolation of the major phenolic constituents present in nutmeg kernel. A well-defined and reproducible sequence of extraction, fractionation and chromatographic purification was adopted and was guided by HPLC fingerprinting. Spectroscopic methods, mainly NMR, and mass spectrometry were utilized to identify each compound. Thirteen compounds were isolated in a pure form and identified as: elemicin (1), isoelemicin (2), myristicin (4), surinamensin (5), malabaricone C (6), 2-(3′-allyl-2′,6′-dimethoxy-phenyloxy)-1-acetoxy-(3,4-dimethoxyphenyl)-propyl ester (7), methoxylicarin A (8), licarin A (9), malabaricone B (10), licarin C (11), 5′-methoxylicarin B (12), licarin B (13), and 2-(3′-allyl-2′,6′-dimethoxy-phenyloxy)-1-methyl-5-methoxy-1,2-dihydrobenzofuran (3, a new compound). With repeated isolation runs, these pure compounds can be prepared in quantities sufficient for biological evaluation as needed. The availability of purified compounds will also allow the development of specific, accurate, and sensitive analytical procedures for pharmacokinetic studies and for quality control of nutmeg products. Both aspects are essential for nutmeg-focused drug discovery. The same approach can also be adapted to other medicinal plants of potential interest.

Microbial transformation of silybin ( 1 ), the major flavonolignan of milk thistle ( Silybum marianum , Asteraceae), resulted in the isolation of four metabolites. The structures of the isolated metabolites were determined by spectroscopic methods. One phase I metabolite was produced by Beauveria bassiana and was characterized as 8-hydroxysilybin ( 2 ). Three phase II metabolites were produced by two Cunninghamella species and were identified as 2,3-dehydrosilybin-3- O -β- d -glucoside ( 3 ), obtained from Cunninghamella species; and silybin-7-sulfate ( 4 ) and 2,3-dehydrosilybin-7-sulfate ( 5 ), obtained from Cunninghamella blakesleana . Compared to 1 (IC 50 284 μg/mL), the generated metabolites displayed varying levels of antioxidant activities in the DPPH free-radical scavenging assay.

Phytochemical investigation of the leaves of Paullinia pinnata L. (Sapindaceae) resulted in the isolation of the two new flavone glycosides characterized as diosmetin-7-O-(2' '-O-beta-D-apiofuranosyl-6' '-acetyl-beta-D-glucopyranoside) (1) and tricetin-4'-O-methyl-7-O-(2' '-O-beta-D-apiofuranosyl-6' '-acetyl-beta-D-glucopyranoside) (2).

The chemical composition of three essential oil samples (stored aerial parts, fresh aerial parts, and fresh flowering tops) of Commiphora opobalsamum L., obtained by hydrodistillation, was determined using GC-MS analysis. The identified constituents represented 69.5 to 84.4 percent of the total chemical compounds of the three samples. The major components were α-cadinol in the stored aerial parts, α-calacorene in the fresh aerial parts, and terpinen-4-ol in the fresh flowering tops. The essential oil from the fresh aerial parts exhibited antimicrobial activity against Bacillus subtilis, Staphylococcus aureus, Candida glabrata, C. krusei, Cryptococcus neoformans, and Mycobacterium intracellulare. The same oil sample was non-selectively cytotoxic to four tumor cell lines: SK-MEL, KB, BT549 and SK-OV3. Weak antioxidant activity of the oil from the fresh aerial sample was demonstrated in a DPPH free-radical scavenging assay.

The aerial part of Commiphora opobalsamum L. (Burseraceae) growing in Saudi Arabia was subjected to a phytopharmacological investigation in order to identify its major chemical constituents and to evaluate its extracts and isolated compounds in preliminary in vitro assays for antimicrobial, antimalarial, antitumor, anti-inflammatory (COX-2 inhibition), antioxidant and estrogenic activity. Six compounds were isolated and identified as the triterpenes friedelin, canophyllal, and oleanonic acid; the flavonols mearnsetin and quercetin; and syringic acid. The ethyl acetate extract was moderately active against Staphylococcus aureus, Pseudomonas aeruginosa, and Plasmodium falciparum; while the petroleum ether and chloroform extracts inhibited COX-2 at 5 and 10 microg mL(-1), respectively. Of the isolated compounds, syringic acid showed moderate antimalarial, anticandidal, and antimycobacterial activity; while mearnsetin and quercetin exhibited antioxidant activity comparable to ascorbic acid and trolox. This is the first detailed phytochemical investigation of C. opobalsamum L. growing in Saudi Arabia and elsewhere. The isolated compounds are reported from this plant for the first time and their full (1)H and (13)C NMR assignments are included.

Microbial transformation of the semisynthetic sesquiterpene artemether, using Cunninghamella elegans and Streptomyces lavendulae, resulted in the isolation of five microbial metabolites that were c...

Although the traditional use of Ephedra 'ma huang' has been established for thousands of years, its resurgence in the US as a herbal dietary supplement is currently a matter of national controversy. At the heart of the debate are three important questions: (1) the identity and composition of Ephedra products with regard to ephedrine and related alkaloids; (2) the potential therapeutic utility of Ephedra supplements for weight loss or performance enhancement; and (3) potential health risks associated with such uses of Ephedra, particularly in sensitive individuals or in cases of intentional abuse for its stimulant properties. This review surveys the literature on Ephedra with regard to traditional uses, botany, chemistry, analytics, pharmacological effects and health risks. A brief discussion of the central issues in the current debate on the regulation of Ephedra in the United States is included as this is where most of the problems have occurred to date.

Goldenseal ( Hydrastis canadensis L., Ranunculaceae) is an ingredient of various dietary supplements intended for enhancing general body immunity. Many goldenseal products are currently available in the United States, either alone or in combination with echinacea. In most products, the content of the main active alkaloids of goldenseal, hydrastine and berberine, is not indicated on the label. A high‐performance liquid chromatography (HPLC) method has been developed for the detection and quantification of hydrastine and berberine in a number of products obtained from the United States market. The method uses a Phenomenex® Luna C 18 column, a mobile phase consisting of solvent A (100 mM sodium acetate/acetic acid, pH 4.0) and solvent B (acetonitrile/methanol; 90/10, v/v). Elution was run at a flow rate of 1.0 mL/min, with a linear gradient of 80– 40% A in B over 20 min and ultraviolet detection at 290 nm. A wide range of content variation was observed for both alkaloids in the tested samples. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:817–822, 2001

Maesanin (1) is a naturally occurring bioactive benzoquinone isolated from the fruits of Maesa lanceolata (Myrsinaceae). Three carboxylic acid metabolites of maesanin were isolated in the course of a prospective microbial transformation study. The first metabolite, 2, was produced by Lipomyces lipofer ATCC 10742 and was characterized as (Z)-15-(2'-hydroxy-5'-methoxy-3', 6'-dioxocyclohexa-1',4'-dienyl)pentadec-5-enoic acid. Metabolites 3 and 4 were produced by Rhodotorula rubra ATCC 20129 and were characterized as 6-(2'-hydroxy-5'-methoxy-3',6'-dioxocyclohexa-1', 4'-dienyl)hexanoic acid and 4-(2'-hydroxy-5'-methoxy-3', 6'-dioxocyclohexa-1',4'-dienyl)butanoic acid, respectively.

The substituted 1,4-benzoquinone, maesanin (1), is a potent 5-lipoxygenase (5-LO) inhibitor present in the fruit of Maesa lanceolata Forssk. Thirteen natural, synthetic, semisynthetic, and microbially transformed analogs of 1 were tested for their in vitro inhibition of 5-lipoxygenase (5-LO) and cyclooxygenase-1 (COX-1). Maesanin was the most active 5-LO inhibitor. All other analogs were inactive or less active than the natural products as 5-LO inhibitors. None of the tested compounds was strongly active in the COX-1 inhibition assay.