Pure Alkaloids Research Articles

Involvement of the Keap1-Nrf2-ARE pathway in the antioxidant activity of sinomenine

Sinomenine is a pure alkaloid isolated from Sinomenium acutum. This study is aimed to investigate the critical role of the nuclear factor erythroid 2-related factor 2 (Nrf2)-kelch-like ECH-associated protein-1(Keap1)-antioxidant response element (ARE) antioxidative signaling pathway in protecting sinomenine against H2O2-induced oxidative injury. Cytotoxicity and antioxidant experiments to initially determine the protective effects of sinomenine show that sinomenine has no effect on the decreased cell viability and presents similar potency in scavenging all three free radicals. The binding affinity between sinomenine and Keap1 was determined via fluorescence polarization assay, with IC50 of 13.52 μM. Quantum chemical calculation and theoretical simulation illustrated that sinomenine located into the Nrf2-binding site of Keap1 via hydrophobic and hydrogen interactions, showing high stability and binding affinity. On the basis of the stable binding of sinomenine with Keap1, sinomenine efficiently induced nuclear translocation of Nrf2, and increased in ARE activity in a concentration-dependent manner. Quantitative polymerase chain reaction provided further evidences that sinomenine-induced protection upregulated ARE-dependent genes, such as NAD(P)H quinone oxidoreductase 1, hemeoxygenase-1, and glutamate-cysteine ligase modifier subunit. Western blot confirmed that sinomenine increased the expressions of these antioxidative enzymes. Taken together, in vitro and in silico evaluations demonstrate that sinomenine inhibits the binding of Keap1 to Nrf2, promotes the nuclear accumulation of Nrf2 and thus leads to the upregulated expressions of Nrf2-dependent antioxidative genes. Our findings also highlight the use of sinomenine for pharmacological or therapeutic regulation of the Nrf2-Keap1-ARE system, which is a novel strategy to prevent the progression of oxidative injury.

Efficacy of phytochemical-functionalized silver nanoparticles to control Flacherie and Sappe silkworm diseases in Bombyx mori L. larvae

Plant extracts comprise a complex mixture of numerous phytochemicals including important alkaloids and polyphenols that can reduce metal ions, and comprise unsaturated compounds such as α-linolenic and carboxylic acid that acts as stabilizing agents in the greener assembly of nanomaterials. The present study demonstrates the role of phytoconstituents from flowers of Tridax trilobata (T. trilobata) in the synthesis of silver nanoparticles (AgNPs) that investigates their effects on the growth and development of the silkworm Bombyx mori L. besides controlling the occurrence of Flacherie and Sappe microbial diseases. FTIR and 13C NMR spectral studies confirmed the in situ role of phytochemicals from the flower extract responsible for the reduction of silver ions to AgNPs with crystalline structure, which is confirmed by XRD analysis. Compared to pure alkaloids and polyphenols, AgNPs synthesized with crude flower extract displayed synergistic antibacterial activity against Flacherie and Sappe microbial strains such as B. subtilis, S. aureus, E. coli, B. cereus, Aerobactercloacae, and S. typhi. Furthermore, AgNPs prevented the growth of biofilms in a concentration-dependent manner and an increase in inhibition is observed with concentration augmentation from 0 to 50 µg/mL. In addition, the biosynthesized AgNPs increased the feeding efficiency and improved the body weight and shell weight of Bombyx mori L. larvae, pupae, and cocoons. Overall, this integrated study found that AgNPs were effective in reducing Flacherie and Sappe disease caused by the consumption of bacterially contaminated mulberry leaves, thus improving the survival rate of Bombyx mori L. and eventually improving the crop yield through insights into the anti-biofilm activity of phytochemical-adorned AgNPs.

Isoquinoline alkaloids isolated from Glaucium corniculatum var. corniculatum and Glaucium grandiflorum subsp. refractum var. torquatum with bioactivity studies

Context The genus Glaucium Mill., one of the important Papaveraceae family plants, is rich in isoquinoline alkaloids and distributed worldwide. Objective Isolation and identification of bioactive alkaloids from Glaucium grandiflorum Boiss. & Huet. subsp. refractum (Nabelek) Mory var. torquatum (Cullen) Mory and G. corniculatum (L.) Rudolph var. corniculatum (Aslan 2012), and investigation of their antioxidant and anticholinesterase activities. Materials and methods The aerial parts of each plant were dried, powdered, and percolated with methanol, then each extract was fractionated between 50% aqueous acetic acid and petroleum. Their aqueous acidic layer was adjusted to pH 7–8 with NH4OH and extracted with chloroform, the extract was subjected to CC separation and isolation. Structures of the isolated alkaloids were elucidated by 1D and 2D-NMR and mass spectral analyses. The alkaloid extracts and their pure alkaloids were tested for anti-cholinesterase (AChE and BuChE) and antioxidant (ABTS, CUPRAC, β-carotene linoleic acid tests) activities in vitro. Results Methanol extracts of Glaucium grandiflorum subsp. refractum var. torquatum and G. corniculatum var. corniculatum afforded a novel compound glauciumoline and seven known isoquinoline alkaloids three of which have an aporphine-type and the other five have a protopine-type skeleton. Among them, trans-protopinium (7) and cis-protopinium (8) were isolated from a Glaucium species for the first time. Tertiary amine extracts (TAEs) of both plants showed very strong acetylcholinesterase inhibitory activity. The TAE of the plants also showed strong antioxidant activity while the isolated alkaloids showed no meaningful activity in the anticholinesterase and antioxidant tests. Discussion and conclusions Glaucium species are considered promising therapeutic agents in the treatment of Alzheimer’s disease.

Modulation of in Vitro SARS-CoV-2 Infection by Stephania tetrandra and Its Alkaloid Constituents.

Botanical natural products have been widely consumed for their purported usefulness against COVID-19. Here, six botanical species from multiple sources and 173 isolated natural product compounds were screened for blockade of wild-type (WT) SARS-CoV-2 infection in human 293T epithelial cells overexpressing ACE-2 and TMPRSS2 protease (293TAT). Antiviral activity was demonstrated by an extract from Stephania tetrandra. Extract fractionation, liquid chromatography-mass spectrometry (LC-MS), antiviral assays, and computational analyses revealed that the alkaloid fraction and purified alkaloids tetrandrine, fangchinoline, and cepharanthine inhibited WT SARS-CoV-2 infection. The alkaloids and alkaloid fraction also inhibited the delta variant of concern but not WT SARS-CoV-2 in VeroAT cells. Membrane permeability assays demonstrate that the alkaloids are biologically available, although fangchinoline showed lower permeability than tetrandrine. At high concentrations, the extract, alkaloid fractions, and pure alkaloids induced phospholipidosis in 293TAT cells and less so in VeroAT cells. Gene expression profiling during virus infection suggested that alkaloid fraction and tetrandrine displayed similar effects on cellular gene expression and pathways, while fangchinoline showed distinct effects on cells. Our study demonstrates a multifaceted approach to systematically investigate the diverse activities conferred by complex botanical mixtures, their cell-context specificity, and their pleiotropic effects on biological systems.

Amaryllidaceae alkaloids in skin cancer management: Photoprotective effect on human keratinocytes and anti-proliferative activity in melanoma cells.

Skin cancer has high rates of mortality and therapeutic failure. In this study, to develop a multi-agent strategy for skin cancer management, the selective cytotoxicity of several alkaloid fractions and pure alkaloids isolated from Amaryllidaceae species was evaluated in melanoma cells. In addition, UVB-stimulated keratinocytes (HaCaT) were exposed to seven alkaloid fractions characterized by GC-MS, and the production of intracellular reactive oxygen species (ROS) and IL-6, were measured to evaluate their photoprotection effects. The Eucharis caucana (bulb) alkaloid fraction (20 μg/ml) had a clear effect on the viability of melanoma cells, reducing it by 45.7% without affecting healthy keratinocytes. This alkaloid fraction and tazettine (both at 2.5 μg/ml) suppressed UVB-induced ROS production by 31.6% and 29.4%, respectively. The highest anti-inflammatory potential was shown by the Zephyranthes carinata (bulb) alkaloid fraction (10 μg/ml), which reduced IL-6 production by 90.8%. According to the chemometric analysis, lycoramine and tazettine had a photoprotective effect on the UVB-exposed HaCaT cells, attenuating the production of ROS and IL-6. These results suggest that Amaryllidaceae alkaloids have photoprotective and therapeutic potential in skin cancer management, especially at low concentrations.

Undescribed isoquinolines from Zanthoxylum nitidum and their antiproliferative effects against human cancer cell lines

Eleven previously undescribed alkaloids, including three pairs of enantiomers nitidumalkaloids A–C, a pair of scalemic mixtures nitidumalkaloid D and three optically pure or achiral alkaloids, nitidumalkaloids E–G, along with 20 known alkaloids, were isolated from an ethanolic extract of the whole Zanthoxylum nitidum (Roxb.) DC plant. The chemical structures of the alkaloids were elucidated using a combination of comprehensive nuclear magnetic resonance (NMR) and high-resolution electro-spray ionization mass spectrometry (HR-ESI-MS) analyses. The configuration of the stereogenic centers of all undescribed compounds was precisely established based on single-crystal X-ray diffraction and electronic circular dichroism (ECD) calculations. Racemic mixtures of nitidumalkaloids A–D were purified, and their enantiomers were analyzed via chiral-phase high-performance liquid chromatography with electrochemical detection measurements (HPLC-ECD). Twelve compounds exhibited significant antiproliferative activities against a panel of cancer cell lines. Further studies were designed to investigate the underlying molecular mechanism of (1′S, 6R)-nitidumalkaloid B, which was the most active antiproliferative agent against human cancer A549 cells. G2/M cell cycle arrest, induction of apoptosis, and suppression of the Wnt/β-catenin signaling pathway were in part associated with the antiproliferative activity of (1′S, 6R)-nitidumalkaloid B. Moreover, (1′S, 6R)-nitidumalkaloid B inhibited cell migration by downregulating the epithelial-mesenchymal transition process in A549 cells. These data suggest that the antiproliferation activity of (1′S, 6R)-nitidumalkaloid B was correlated with the stereoselectivity of the stereoisomers, and (1′S, 6R)-nitidumalkaloid B was prioritized as a potential leading compound for the management of aggressive human non-small-cell lung cancer (NSCLC) from natural products.

Computationally assisted structure elucidation of new 2-guanidinoethanesulfonyl sesquiterpenoid alkaloids: Agelasidines G–I from the marine sponge Agelas nakamurai

Three new 2-guanidinoethanesulfonyl sesquiterpene analogues of (−)-agelasidine A, agelasidines G–I (1–3), were isolated from a marine sponge Agelas nakamurai collected in Orchid Island. The absolute configurations of agelasidines G–I (1–3) were established by utilizing the computational NMR data, a statistical DP4+ method, and comparing their experimental optical rotations with the B3LYP calculated data. Moreover, an optical pure bromopyrrole alkaloid, (−)-mukanadin C (4), was discovered for the first time and its absolute configuration was confirmed by a single crystal X-ray diffraction analysis. These marine natural products were evaluated cytotoxic, antimicrobial, and anti-inflammatory activities.

Acute, Sublethal, and Developmental Toxicity of Kratom (Mitragyna speciosa Korth.) Leaf Preparations on Caenorhabditis elegans as an Invertebrate Model for Human Exposure.

Kratom (Mitragyna speciosa Korth.) is a tree native to Southeast Asia with stimulant and opioid-like effects which has seen increased use in Europe and North America in recent years. Its safety and pharmacological effects remain under investigation, especially in regard to developmental and generational toxicity. In the current study, we investigated commercial kratom preparations using the nematode Caenorhabditis elegans as a translational model for toxicity and pharmacological effects. The pure alkaloids mitragynine and 7-hydroxymitragynine as well as aqueous, ethanolic, and methanolic extracts of three commercial kratom products were evaluated using a battery of developmental, genotoxic, and opioid-related experiments. As determined previously, the mitragynine and 7-hydroxymitragynine content in kratom samples was higher in the alcoholic extracts than the aqueous extracts. Above the human consumption range equivalent of 15–70 µg/mL, kratom dose-dependently reduced brood size and health of parent worms and their progeny. 7-hydroxymitragynine, but not mitragynine, presented with toxic and developmental effects at very high concentrations, while the positive control, morphine, displayed toxic effects at 0.5 mM. Kratom and its alkaloids did not affect pumping rate or interpump interval in the same way as morphine, suggesting that kratom is unlikely to act primarily via the opioid-signalling pathway. Only at very high doses did kratom cause developmental and genotoxic effects in nematodes, indicating its relative safety.

Sub-acute feeding study of a tall fescue endophyte in a perennial ryegrass host using mice

Epichloë endophytes in grass associations express a myriad of secondary metabolites which can affect the health of grazing animals and reduce the impact of insect pests on pasture. The ideal endophyte-grass association must have a favourable chemical profile such that the impact on animal health is minimised while the beneficial, deterrent effect on insect pests is maximised. A number of endophyte-perennial ryegrass associations have been successfully commercialised but research is on-going to further improve production in farming systems. Secondary metabolites expressed by endophyte-infected tall fescue include lolines, an animal-safe class of compound which imparts a potent effect on insects. Since endophyte-infected perennial ryegrass does not express lolines, a tall fescue endophyte, AR501, was inoculated into perennial ryegrass in an attempt to improve the insect resistance of this pasture type. In addition to animal safety, it is imperative that consideration is given to the safety of humans consuming animal products derived from livestock grazing the novel pasture. Although pure loline alkaloids have previously been tested on mice it is essential that the entire AR501 endophyte-infected perennial ryegrass matrix is tested since this will result in the exposure of both known and unknown secondary metabolites to mice. Three treatment groups each containing 6 male and 6 female mice were fed diets containing AR501 endophyte-infected perennial ryegrass seed (30%), perennial ryegrass seed containing no endophyte (30%) or a diet without seed (control) for 3 weeks. Mice fed control diet ate more than either of the treatment groups fed a diet containing seed. Male mice fed diet containing Nil endophyte seed ate more than those eating AR501 endophyte-infected perennial ryegrass seed although there was no difference observed in the food intake of female mice. While a few statistically significant differences were observed in the haematology and serum biochemical data, in every instance the difference was restricted to only one gender so is considered unlikely to be of toxicological significance. Mice fed AR501 endophyte-infected perennial ryegrass seed remained healthy throughout the experimental period despite consuming 62,000 mg/kg lolines and 4600 mg/kg peramine per day as well as the wide array of other unknown secondary metabolites expressed by this endophyte. Although animal products may contain additional metabolites as a result of animal metabolism, this experiment raises no food safety concerns for AR501 endophyte-infected perennial ryegrass.

ATROPA BELLADONNA, DEADLY NIGHTSHADE AND ITS PECULIARITIES

The Deadly Nightshade, Atropa belladonna, is a plant surrounded by myth, fear and awe. In antiquity, the Greeks and the Romans knew that it contained a deadly poison. In medieval times, it was widely used by witches, sorcerors and professional poisoners. Linnaeus later codified its remarkable properties as the genus Atropa, the Fate that slits the thin spun life and the species belladonna because of its power to dilate the pupils. In the 1830s, the pure alkaloid l-atropine was isolated from the plant. This proved to be a significant tool in the study of the autonomic nervous system leading to the identification of acetylcholine as an important neurotransmitter in mammals.

Mesembryanthemum tortuosum L. alkaloids modify anxiety-like behaviour in a zebrafish model

Ethnopharmacological relevanceMesembryanthemum tortuosum L. (previously known as Sceletium tortuosum (L.) N.E. Br.) is indigenous to South Africa and traditionally used to alleviate anxiety, stress and depression. Mesembrine and its alkaloid analogues such as mesembrenone, mesembrenol and mesembranol have been identified as the key compounds responsible for the reported effects on the central nervous system. Aim of the studyTo investigate M. tortuosum alkaloids for possible anxiolytic-like effects in the 5-dpf in vivo zebrafish model by assessing thigmotaxis and locomotor activity. Materials and methodsLocomotor activity and reverse-thigmotaxis, recognised anxiety-related behaviours in 5-days post fertilization zebrafish larvae, were analysed under simulated stressful conditions of alternating light-dark challenges. Cheminformatics screening and molecular docking were also performed to rationalize the inhibitory activity of the alkaloids on the serotonin reuptake transporter, the accepted primary mechanism of action of selective serotonin reuptake inhibitors. Mesembrine has been reported to have inhibitory effects on serotonin reuptake, with consequential anti-depressant and anxiolytic effects. ResultsAll four alkaloids assessed decreased the anxiety-related behaviour of zebrafish larvae exposed to the light-dark challenge. Significant increases in the percentage of time spent in the central arena during the dark phase were also observed when larvae were exposed to the pure alkaloids (mesembrenone, mesembrenol, mesembrine and mesembrenol) compared to the control. However, mesembrenone and mesembranol demonstrated a greater anxiolytic-like effect than the other alkaloids. In addition to favourable pharmacokinetic and physicochemical properties revealed via in silico predictions, high-affinity interactions characterized the binding of the alkaloids with the serotonin transporter. ConclusionsM. tortuosum alkaloids demonstrated an anxiolytic-like effect in zebrafish larvae providing evidence for its traditional and modern day use as an anxiolytic.

Health Benefits of Avicularin in the Medicine Against Cancerous Disorders and other Complications: Biological Importance, Therapeutic Benefit and Analytical Aspects

Background: Herbal drugs and their derived phytochemicals have been used in medicine for the preparation of different types of pharmaceutical products. Pure phytochemicals including flavonoids, alkaloids and terpenoids have been used in medicine for the treatment of different types of human disorders including cancerous disorders. Flavonoids have been well known in medicine for their anti-viral, anti-bacterial, anti-inflammatory, anti-diabetic, anti-cancer, anti-aging and cardioprotective potential. Avicularin, also called quercetin-3-α-l-arabino furanoside, is a pure flavonoid, a class of phytochemicals, found to be present in Lindera erythrocarpa and Lespedeza cuneata. Avicularin has been well known in medicine for its anti-cancer properties. Methods: In the present work, scientific data of avicularin have been collected from different databases such as Google, PubMed, Science Direct, Google Scholar and Scopus and summarized with reference to medicinal importance, pharmacological activities and analytical aspects of avicularin. The present review summarized the health beneficial properties of avicularin in medicine through data analysis of various scientific research works. Further analytical progress in medicine for the qualitative and quantitative analysis of avicularin in medicine has been also discussed in the present work. Results: Scientific data analysis of different literature work revealed the biological importance of flavonoid class of phytochemical ‘avicularin’ in medicine. Scientific data analysis revealed that avicularin was found to be present in the Lindera erythrocarpa, Lespedeza cuneata, Rhododendron schlipenbachii and Psidium guajava. Avicularin has been well known in medicine for its anti-inflammatory, anti-allergic, anti-oxidant, anti-tumor and hepatoprotective activities. Avicularin protects cardiomyocytes and hepatocytes against oxidative stress-induced apoptosis and induces cytotoxicity in cancer lines and tumor tissues. Avicularin has positive influence on human hepatocellular carcinoma and inhibits intracellular lipid accumulation. The role of avicularin in rheumatoid arthritis has been also established with its underlying molecular mechanisms in the scientific work. Recent interest in avicularin has focused on pharmacological investigations for its anti-cancer activity in the medicine. Conclusion: The present work signified the biological importance of avicularin in medicine through its medicinal uses, pharmacological activities and analytical aspects in the biological system.

Sinomenine hydrochloride ameliorates dextran sulfate sodium-induced colitis in mice by modulating the gut microbiota composition whilst suppressing the activation of the NLRP3 inflammasome.

Sinomenine is a pure alkaloid that can be isolated from the root of Sinomenium acutum and has been found to exert anti-inflammatory and immunosuppressive effects. The present study investigated the effects of sinomenine hydrochloride (SIN) on inflammation and the gut microbiota composition in the colon of mouse models of dextran sulfate sodium (DSS)-induced colitis. DSS-induced mice colitis was established by treating the mice with drinking water containing 3% (w/v) DSS for 7 days. The disease activity index of each mouse was calculated on a daily basis. All mice were sacrificed on day 11, then the weight of their spleen and length of their colons were measured. The histological analysis was measured by hematoxylin-eosin staining. Oral administration of SIN (100 mg/kg/day) attenuated the DSS-induced increases in the disease activity indices and spleen indices, DSS-induced shortening of the colon length and histological damage. In addition, reverse transcription-quantitative PCR data showed that SIN treatment effectively regulated the expression of inflammatory mediators, specifically by suppressing the expression of proinflammatory gene (TNF-α, IL-6 and inducible nitric oxide synthase) whilst increasing those associated with inhibiting inflammation (IL-10 and arginine 1). Gut microbiota analysis was conducted using 16S ribosomal DNA sequencing. The results revealed that SIN improved bacterial community homeostasis and diversity, which were damaged by DSS. Furthermore, western blotting showed that the activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome was markedly suppressed by SIN treatment. In conclusion, these results indicated that SIN may ameliorate experimental colitis by modulating the gut microbiota composition and suppressing the activation of the NLRP3 inflammasome in mice. Overall, these findings suggested a broad protective effect of SIN in treating inflammatory gut diseases, including ulcerative colitis.

Repercussion of piperine on pharmacokinetics parameters of eletriptan in albino rats: Involvement of CYP3A and P-GP inhibition

Eletriptan is at the type of triptan medication suggested for the management of episodes of severe headache with or without aura. Piperine (1-piperoylpiperidine) is a pure alkaloid as well as the basic tanginess material from the pipli and peppercorn. There are signs that piperine inhibits Cytochrome P-450 enzymes and P-glycoprotein, rather than arouses, drug metabolism generally, thus increasing the bioavailability and effect of several medications. The analysis was undertaken to assess the results of Piperine on the pharmacokinetics of Eletriptan. Samples of blood were taken at different time points for example 0 (predose), 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 6.0, 8.0, 12, 24 hours post-treatment. The plasma concentration of Eletriptan was estimated with the HPLC procedure. In our study Cmax, Tmax, AUC0-24 , AUC0-8, AUC%, AUMC0-24, AUMC0-8, t1/2, MRT0-24, MRT0-8 and Volume of distribution were increased by approximately 51.76%, 7.55%, 72.93%, 84.42%, 42.72%, 93.56%, 128.82%, 19.97%, 11.74%, 23.96% and 3% respectively, where as clearance decreased by 42.10% when eletriptan co-administered with piperine. In summary, the results obtained herein imply that Piperine is improving the bioavailability of Eletriptan by strengthening the exposure (AUC) of their Eletriptan when concomitantly administered by the oral route. The Piperine improved the oral bioavailability of eletriptan by inhibiting CYP3A and P-GP in rats. This observation indicates the possibility that the combo of piperine along with other CYP3A and P-GP double substrates can also enhance bioavailability.

In vitro cytotoxicity and neurotoxicity assessment of the alkaloidal constituents derived from Asimina triloba twigs

This study was aimed to evaluate the efficacy and safety of Asimina triloba extracts and its alkaloidal constituents in terms of their cytotoxicity and neurotoxicity towards different cell lines. Six alkaloids (anolobine-9-O-β-d-glucopyranoside, anolobine, norushinsunine, liriodenine, squamolone and coclaurine) were evaluated for their cytotoxic potential in four human solid tumor cell lines (SK-MEL, KB, BT-549, and SK-OV-3). The potential for neurotoxicity was determined using rat cortical neurons. Three extracts, namely a crude methanolic extract, an alkaloid-rich extract, and an acetogenin-rich extract, were also included in the study. The acetogenin-rich extract was the most potent, among all tested extracts, towards SK-MEL, KB, and BT-549 cells with IC50 values in the range of 0.09–0.11 µg/mL. Also, the same extract was found to be significantly toxic to the neurons at 10 µg/mL. The alkaloid-rich extract also showed cytotoxicity, albeit with lower potency, towards SK-MEL, KB, and BT-549 cell lines with IC50 values in the range of 1.7–2.6 µg/mL. Out of the six isolated alkaloids, three alkaloids (anolobine-9-O-β-D-glucopyranoside, norushinsunine, and liriodenine) demonstrated cytotoxic activity. Although the alkaloidal extract did not show any toxicity to neurons up to 10 µg/mL, the pure alkaloids were toxic to the neurons in a concentration-dependent manner. In conclusion, this study underlines the contribution of the alkaloidal constituents in the neurotoxicity and cytotoxicity of A. triloba.

Repercussion of piperine on pharmacokinetics parameters of eletriptan in albino rats: Involvement of CYP3A and P-GP inhibition

Eletriptan is at the type of triptan medication suggested for the management of episodes of severe headache with or without aura. Piperine (1-piperoylpiperidine) is a pure alkaloid as well as the basic tanginess material from the pipli and peppercorn. There are signs that piperine inhibits Cytochrome P-450 enzymes and P-glycoprotein, rather than arouses, drug metabolism generally, thus increasing the bioavailability and effect of several medications. The analysis was undertaken to assess the results of Piperine on the pharmacokinetics of Eletriptan. Samples of blood were taken at different time points for example 0 (predose), 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 6.0, 8.0, 12, 24 hours post-treatment. The plasma concentration of Eletriptan was estimated with the HPLC procedure. In our study Cmax, Tmax, AUC0-24 , AUC0-8, AUC%, AUMC0-24, AUMC0-8, t1/2, MRT0-24, MRT0-8 and Volume of distribution were increased by approximately 51.76%, 7.55%, 72.93%, 84.42%, 42.72%, 93.56%, 128.82%, 19.97%, 11.74%, 23.96% and 3% respectively, where as clearance decreased by 42.10% when eletriptan co-administered with piperine. In summary, the results obtained herein imply that Piperine is improving the bioavailability of Eletriptan by strengthening the exposure (AUC) of their Eletriptan when concomitantly administered by the oral route. The Piperine improved the oral bioavailability of eletriptan by inhibiting CYP3A and P-GP in rats. This observation indicates the possibility that the combo of piperine along with other CYP3A and P-GP double substrates can also enhance bioavailability.

Target-Guided Isolation of O-tigloylcyclovirobuxeine -B from Buxus sempervirens L. by Centrifugal Partition Chromatography.

The increasing drug resistance of malaria parasites challenges the treatment of this life-threatening disease. Consequently, the development of innovative and effective antimalarial drugs is inevitable. O-tigloylcyclovirobuxeine-B, a nor-cycloartane alkaloid from Buxus sempervirens L., has shown promising and selective in vitro activity in previous studies against Plasmodium falciparum (Pf), causative agent of Malaria tropica. For further investigations, it is indispensable to develop an advanced and efficient isolation procedure of this valuable natural product. Accordingly, we used liquid–liquid chromatography including centrifugal partition chromatography (CPC) to obtain the pure alkaloid on a semi-preparative scale. Identification and characterization of the target compound was accomplished by UHPLC/+ESI-QqTOF-MS/MS, 1H NMR and 13C NMR. In conclusion, this work provides a new and efficient method to obtain O-tigloylcyclovirobuxeine-B, a valuable natural product, as a promising antiplasmodial lead structure for the development of innovative and safe medicinal agents.

Isolation of Three Lycorine Type Alkaloids from Rhodolirium speciosum (Herb.) Ravenna Using pH-Zone-Refinement Centrifugal Partition Chromatography and Their Acetylcholinesterase Inhibitory Activities.

Preparative separation of three lycorine type alkaloids from Rhodolirum speciosum (Amaryllidaceae) was successfully carried out using pH-zone-refinement centrifugal partition chromatography (CPC) using the solvent system methyl-tert-butyl ether/acetonitrile/water (4:1:5, v/v/v) in descending mode. Using this system, Alkaloid 1 (165.7 mg, 88.2%, purity), 2 (60.1 mg, 97.7% purity) and 3 (12.3 mg, 84.4% purity) were obtained in one step. For structure elucidation, the pure alkaloids were subjected to spectroscopy analysis using nuclear magnetic resonance experiments (1H-NMR, 13C-NMR) and gas chromatography coupled with mass spectrometry (GC-MS). Alkaloids 1, 2, and 3 were identified as 1-O-acetyl-5,6-dehydrolycorine, 1-O-acetyl-lycorine, and 1,2-O-diacetyl-5,6-dehydrolycorine, respectively. The acetylcholinesterase inhibitory activity of these alkaloids was IC50 151.1 μg/mL, IC50 203.5 μg/mL, IC50 470.0 μg/mL, and IC50 17.1 μg/mL, respectively.

Erratum: Antimycobacterial Activity of Alkaloids and Extracts from Tabernaemontana alba and T. arborea.

Tuberculosis is the main cause of death from a single infectious agent. Globally, according to the World Health Organization, in 2018, there were an estimated 1.2 million tuberculosis deaths. Moreover, there is a continuous appearance of drug-resistant strains. Thus, development of new antituberculosis medicines should receive high priority. Plant-derived natural products are promising candidates for this purpose. We therefore screened alkaloid extracts obtained from the root and stem barks of the Mexican Apocynaceae species Tabernaemontana alba and Tabernaemontana arborea, as well as the pure alkaloids ibogaine, voacangine, and voacamine, tested for activity against Mycobacterium tuberculosis H37Rv and cytotoxicity to mammalian Vero cells using the resazurin microtiter and the MTT assays, respectively. The extracts were analyzed by GC-MS and HPLC-UV. T. arborea root bark alkaloid extract showed the highest activity against M. tuberculosis (MIC100 = 7.8 µg/mL) of the four extracts tested. HPLC suggested that voacangine and voacamine were the major components. The latter was isolated by column chromatography, and its chemical structure was elucidated by 1H and 13C NMR, and MS. Unambiguous assignation was performed by HSQC, HMBC, and NOESY experiments. Voacamine is a dimeric bis-indole-type alkaloid and is 15 times more potent than the monomeric ibogan-type alkaloids ibogaine and voacangine (MIC100 = 15.6, 250.0, and 250.0 µg/mL, respectively). However, all of these compounds showed cytotoxicity to Vero cells, with a poor selectivity index of 1.00, 0.16, and 1.42, respectively. This is the first report of voacamine activity against M. tuberculosis.

Antimycobacterial Activity of Alkaloids and Extracts from Tabernaemontana alba and T. arborea.

Tuberculosis is the main cause of death from a single infectious agent. Globally, according to the World Health Organization, in 2018, there were an estimated 1.2 million tuberculosis deaths. Moreover, there is a continuous appearance of drug-resistant strains. Thus, development of new antituberculosis medicines should receive high priority. Plant-derived natural products are promising candidates for this purpose. We therefore screened alkaloid extracts obtained from the root and stem barks of the Mexican Apocynaceae species Tabernaemontana alba and Tabernaemontana arborea, as well as the pure alkaloids ibogaine, voacangine, and voacamine, tested for activity against Mycobacterium tuberculosis H37Rv and cytotoxicity to mammalian Vero cells using the resazurin microtiter and the MTT assays, respectively. The extracts were analyzed by GC-MS and HPLC-UV. T. arborea root bark alkaloid extract showed the highest activity against M.tuberculosis (MIC100 = 7.8 µg/mL) of the four extracts tested. HPLC suggested that voacangine and voacamine were the major components. The latter was isolated by column chromatography, and its chemical structure was elucidated by 1H and 13C NMR, and MS. Unambiguous assignation was performed by HSQC, HMBC, and NOESY experiments. Voacamine is a dimeric bis-indole-type alkaloid and is 15 times more potent than the monomeric ibogan-type alkaloids ibogaine and voacangine (MIC100 = 15.6, 250.0, and 250.0 µg/mL, respectively). However, all of these compounds showed cytotoxicity to Vero cells, with a poor selectivity index of 1.00, 0.16, and 1.42, respectively. This is the first report of voacamine activity against M.tuberculosis.