Synthesis and Antioxidant Activity of New Norcantharidin Analogs

New norcantharidin analogs were designed and obtained as compounds with biological activity. As a starting material, exo‐7‐oxabicyclo[2.2.1]heptane‐2,3‐dicarboxylic acid anhydride was used. Three groups of compounds: dicarboximides, triazoles and thiazolidines were obtained in multistep reactions. The ¹H‐ and ¹³C‐NMR spectra were used to confirm the structures of all obtained products and they were in agreement with the proposed structure of substances. All derivatives were screened for their antioxidant activity. The most promising group was dicarboximides ( 1 – 4 , 6 ). Derivatives 2–4 displayed antioxidant activity with EC₅₀=7.75–10.89 μg/ml, which may be comparable to strong antioxidant Trolox (EC₅₀=6.13 μg/ml). Excellent activity with EC₅₀=10.75 μg/ml also presented norcantharidin analog with 1,2,4‐triazole system ( 12 ).     

In vitro effects of some herbs used in Egyptian traditional medicine on viability of protoscolices of hydatid cysts

The present work evaluated the effects of alcoholic extracts of salvia (Salvia officinalis), thyme (Thymus vulgaris), and 2 pure compounds (thymol and menthol) on the viability of Echinococcus granulosus protoscolices in vitro. Four different concentrations of each extract (2,500, 1,500, 1,000, and 500 μg/ml) and 3 different concentrations each of thymol and menthol (50, 10, and 1 μg/ml) were used. Concentration of 2,500 μg/ml of both extracts showed a significant protoscolicidal activity on the 6th day. Complete loss of viability of protoscolices occurred with 500 μg/ml concentration of both extracts at day 6 and day 7 post-treatment (PT), respectively. Pure compounds, i.e., menthol and thymol, showed potent effects with 50 μg/ml concentration at day 2 and day 5 PT, respectively. These effects were compared with those of albendazole sulfoxide (800 μg/ml), a commonly used treatment drug for hydatidosis. Krebs-Ringer solution and the hydatid cystic fluid at a ratio of 4:1 was a good preservative solution which kept the protoscolices viable for 15 days.     

Anti-barnacle activity of novel simple alkyl isocyanides derived from citronellol

Twenty novel simple alkyl isocyanides derived from citronellol were synthesized and evaluated for their antifouling activity and toxicity against cypris larvae of the barnacle, Balanus amphitrite. The anti-barnacle activity of the synthesized isocyanides was in the EC(50) range of 0.08-1.49 μg ml(-1). Simple isocyanides containing a benzoate and chloro group showed the most potent anti-barnacle activity. In addition, none of the synthesized compounds showed significant toxicity and LC(50) values were <10 μg ml(-1). The LC(50)/EC(50) ratios of almost all of the synthesized compounds were >10(2). The results indicate that these simple isocyanides are promising low-toxicity antifouling agents.     

Naphthalene Derivatives and Quinones from Ventilago denticulata and Their Nitric Oxide Radical Scavenging,Antioxidant, Cytotoxic,Antibacterial, and Phosphodiesterase Inhibitory Activities

New naphthalene derivatives ( 1 and 2 ) and a new isomer ( 3 ) of ventilagolin, together with known anthraquinones, chrysophanol ( 4 ), physcion or emodin 3‐methyl ether ( 5 ), and emodin ( 6 ), were isolated from vines of Ventilago denticulata. The isolated compounds exhibited cytotoxic activity with IC₅₀ values of 1.15 – 40.54 μg/ml. Compounds 1 – 3 selectively exhibited weak antibacterial activity (MIC values of 200.0 – 400.0 μg/ml), while emodin ( 6 ) displayed moderate antibacterial activity with MIC value of 25.0 μg/ml. The isolated compounds showed nitric oxide and DPPH radical scavenging activities. Compounds 1 – 3 and 6 exhibited weak xanthine oxidase inhibitory activity, while emodin ( 6 ) acted as an aromatase inhibitor with the IC₅₀ value of 10.1 μm . Compounds 1 and 2 exhibited phosphodiesterase 5 inhibitory activity with IC₅₀ values of 8.28 μm and 6.48 μm , respectively.     

New Specific α-Glucosidase Inhibitor Flavonoid from Thymelaea tartonraira Leaves: Structure Elucidation,Biological and Molecular Docking Studies

The phytochemical investigation of Thymelaea tartonraira leaves led to the isolation and characterization of six compounds, including one new flavonoid glycoside identified as hypolaetin 8-O-β-D-galactopyranoside ( 4 ) along with five known compounds, daphnoretin ( 1 ), triumbelletin ( 2 ), genkwanin ( 3 ), tiliroside ( 5 ) and yuankanin ( 6 ). Their structures were established based on spectroscopic methods, such as UV, IR, NMR, and HR-ESI-MS. Triumbelletin ( 2 ) and tiliroside ( 5 ) were isolated for the first time from T. tartonraira leaves. The antioxidant property of all isolated compounds was tested based on DPPH, FRAP and total antioxidant capacity assays. Compound 4 displayed an antioxidant potency more interesting than vitamin C with an IC₅₀=15.00±0.50 μg/ml, followed by compound 5 . Furthermore, the both compounds 4 and 5 were tested for their α-amylase inhibitory activity in-vitro. Compound 4 displayed higher potency to inhibit α-amylase, with an IC₅₀=46.49±2.32 μg/ml, than compound 5 , with an IC₅₀=184.2±9.2 μg/ml, while the reference compound acarbose presented the highest potency to inhibit α-amylase with an IC₅₀=0.44±0.022 μg/ml. Compound 4 displayed a strong inhibitory ability of α-glucosidase activity approximately twice more than the reference compound, acarbose, with IC₅₀ values of 60.00±3.00 and 125.00±6.25 μg/ml, respectively. Thus, compound 4 exhibited a specific inhibitory activity for α-glucosidase. The molecular docking studies have supported our findings and suggested that compound 4 has been involved in various binding interactions within the active site of both enzymes α-amylase and α-glucosidase.     

Seasonal variation in antifouling activity of crude extracts of the brown alga Bifurcaria bifurcata (Cystoseiraceae) against cyprids of Balanus amphitrite and the marine bacteria Cobetia marina and Pseudoalteromonas haloplanktis

Previous studies have demonstrated that macroalgae from Brittany (France) contain products with antifouling activity against marine bacteria, fungi, diatoms, seaweeds and mussels. Little is known regarding the ecological function of these compounds and insufficient attention has been paid to evaluating the possible temporal variation in antifouling activity. Studies of chemical defenses in both terrestrial and marine organisms suggest that organisms vary widely in the production of chemical defenses associated with physical (temperature, light) and biological (e.g. grazing pressure) factors, season and geographical location. The present study aimed to investigate the antifouling activity of crude extracts of monthly collections of the brown alga, Bifurcaria bifurcata, against two marine bacteria, Cobetia marina and Pseudoalteromonas haloplanktis, and cypris larvae of the barnacle, Balanus amphitrite. The toxicity of the extracts was determined with a B. amphitrite nauplius assay.The antimicrobial activity of the extracts was found to be subject to seasonal variation, with the highest level of activity recorded from samples collected between April and September. Results of the anti-settlement experiments showed that the extracts of B. bifurcata (when tested from 0 to 100 μg/ml) can be divided into three groups on the basis of their minimum inhibitory concentrations (MICs): (1) extracts from plants collected from September to March reduced settlement at nontoxic concentrations (50-100 μg/ml); (2) extracts from plants collected from April to July (which were the most active extracts) reduced settlement significantly when tested at >5 μg/ml, but were toxic at 100 μg/ml; (3) the extract prepared from plants harvested in August was inhibitory at >25 μg/ml, but was toxic at 100 μg/ml. Toxicity tests on nauplii showed that LC₅₀ values of samples from the September to March collections were >100 μg/ml, demonstrating that they were nontoxic to nauplii. In contrast, samples obtained from the April to August collections were toxic to nauplii; the most toxic ones being from algae collected in May (LC₅₀=55.6 μg/ml) and in June (LC₅₀=38.3 μg/ml).The antifouling activity of extracts thus reached a peak in summer corresponding to maximal values for water temperature, light intensity and fouling pressure. It remains to be investigated whether this activity has an ecological role in the alga.     

Identification of Nor-��-Lapachone Derivatives as Potential Antibacterial Compounds against Enterococcus faecalis Clinical Strain

A broad-spectrum antibiotic therapy has led to medical complications and emergence of multiresistant bacteria including Enterococcus faecalis. In this study, we designed, synthesized, and evaluated the antibacterial activity of 13 nor-β-lapachone derivatives against a drug resistant E. faecalis strain. Two triazole substituted compounds (1e = 8 μg/ml and 1c = 16 μg/ml) and the non-substituted derivative (1a = 8 μg/ml) were promising compared to chloramphenicol (12 μg/ml), an antibiotic currently available in the market. We also performed a structure-activity relationship analysis using a molecular modeling approach that pointed the low HOMO energy values; HOMO density concentrated on the nor-β-lapachone ring, lipophilicity, solubility and number HBA as important stereoelectronic features for the antibacterial profile. In addition the triazole compounds presented low theoretical toxicity profile, and drug-score higher than commercial antibiotics also fulfilling the Lipinski "Rule of Five", which pointed them as promising candidates for further studies in infections caused by multiresistant E. faecalis hospital strains.     

Plant pathotoxins from Alternaria citri: The minor ACRL toxins

Five host-specific pathotoxins, ACRL toxins II, III, III′, IV and IV′, were isolated from the culture broth of Alternaria citri, the fungus causing brown spot disease of rough lemon. These toxins are related structurally to the major ACRL toxin, toxin I, and to its derivative compound A. Chemical and spectral studies indicated that the ACRL minor toxins were a group of analogous compounds of different chain lengths all of which have a α-pyrone group, in contrast to the dihydro-α-pyrone group in toxin I. Toxin II showed a very low biological activity (ED₅₀ greater than 10 μg/ml) whereas the other minor toxins had slightly higher activities ranging from 1 to 10 μg/ml. The dihydropyrone group in ACRL toxin I was correlated with high biological activity (ED₅₀ = 18–30 ng/ml).     

Chemopreventive Effects of Minor Dietary Constituents in Common Foods on Human Cancer Cells

Epidemiological evidence has sugged that vegetables and fruits may have a role in cancer prevention. The aim of the present study was to examine the anti-proliferative activity of ten related pure compounds from common vegetables and fruits. Studies were conducted on a series of carcinoma cells derived from eight human organs. The results show that linalool possessed the strongest activity against nine carcinoma cells, and that baicalein and luteolin also exhibited a broad spectrum of anti-proliferative activities. Among them, linalool showed the strongest activity against carcinoma of the cervix (IC₅₀: 0.37 μg/ml), stomach (IC₅₀: 14.1 μg/ml), skin (IC₅₀: 14.9 μg/ml), lung (IC₅₀: 21.5 μg/ml) and bone (IC₅₀: 21.7 μg/ml). As for the flavonoids, luteolin exhibited the strongest activity against carcinoma of the stomach (IC₅₀: 7.1 μg/ml), cervix (IC₅₀: 7.7 μg/ml), lung (IC₅₀: 11.7 μg/ml) and bladder (IC₅₀: 19.5 μg/ml), whereas baicalein possessed the strongest anti-proliferative activity against carcinoma of the cervix (IC₅₀: 9.8 μg/ml), stomach (IC₅₀: 16.1 μg/ml) and skin (IC₅₀: 19.5 μg/ml). The present study indicates that linalool possessed the strongest activity against a broad spectrum of carcinoma cells, especially cervical carcinoma cells, suggesting that linalool and flavonoids are partially responsible for the cancer prevention of common vegetables and fruits.     

Immunomodulatory compounds from Pestalotiopsis leucothës, an endophytic fungus from Tripterygium wilfordii

The immunomodulatory effects of three compounds designated BS, GS, and YS produced by Pestalotiopsis leucothës, an endophytic fungus isolated from Tripterygium wilfordii, were evaluated. The 50% inhibition concentration (IC₅₀) value of BS in the proliferative assay with various stimulating agents such as phytohemagglutinin-M (PHA-M), phorbol myristate acetate (PMA)/ionomycin, mixed lymphocyte reaction (MLR) and poke weed mitogen (PWM) was 0.35, 1.6, 0.8 and 5.4 μg/ml, respectively. In addition, BS significantly inhibited the production of cytokines such as interleukin (IL)-1β, IL-2, interferon (IFN)-γ and tumor necrosis factor (TNF)-α, by peripheral blood mononuclear cells (PBMNC) and soluble IL-2 receptor expression at concentrations greater than 1 μg/ml. Inhibition of PHA stimulated PBMNC proliferation and IL-2 and sIL-2R production by BS indicates that it is a T-cell specific immunosuppressant. However, BS also moderately inhibited immunoglobulin (Ig) G and M at concentrations greater than 1 μg/ml suggesting that it also has B cell immunosuppressive effects. YS was 10% less active than BS in all assay systems. In contrast, GS exhibited both suppression and enhancement of PBMNC proliferation in the presence of various stimulants. However, GS inhibited PWM stimulated PBMNC proliferation and IL-4 and IgG and IgM production at concentrations above 1 μg/ml. All three fungal compounds altered the percentage of T-lymphocyte subpopulations only at high concentrations. Cell viability was not affected at the immunosuppressive concentrations of these compounds. In conclusion, work from our laboratory has identified three potentially potent immunomodulatory compounds from P. leucothës. These compounds have variable effects on T- and B-cells and monocytes. They may partially explain the immunosuppressive activity of T. wilfordii. In addition, they may represent a new source of immunomodulatory compounds for the treatment of human immune mediated diseases.     

A newly isolated Streptomyces sp. CS392 producing three antimicrobial compounds

With the aim of isolating new microbes capable of producing strong antimicrobial substances, strain CS392 was screened from 700 soil isolates preserved in our laboratory. The strain was related to genus Streptomyces based on various characteristics. Three highly active antimicrobial compounds, C1, C2 and C3, produced by the strain were purified by solvent extraction followed by silica gel column chromatography. These compounds were highly active against various Gram-positive resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA), and vancomycin-resistant Enterococcus (VRE). Among three, C3 was the most active against MRSA and VRSA with minimal inhibitory concentration (MIC) of 2 μg/ml while C2 and C3 had MIC values of 4 μg/ml for the strains. In case of Bacillus subtilis ATCC6633, C1 and C3 were more effective with MIC values of 0.5 μg/ml than C2 with MIC of 2 μg/ml. Those antibiotics were variably active (MIC of 4-32 μg/ml) against Micrococcus luteus ATCC 9341, Enterococcus faecalis ATCC 29212, Mycobacterium smegmatis ATCC 9341 and VRE.     

Chloroform Extract of Underground Parts of Ferula heuffelii: Secondary Metabolites and Spasmolytic Activity

Plants from the genus Ferula L. (Apiaceae) were used for various purposes in traditional medicine of different nations throughout the history. Ferula heuffelii Griseb . ex Heuffel is a perennial species endemic for Balkan peninsula. Ten compounds which belong to classes of prenyl‐furocoumarin‐, prenyl‐dihydrofurochromone‐, prenyl‐benzoyl‐ and prenyl‐benzoylfuranone‐type sesquiterpenoids, as well as sesquiterpene coumarins and phenylpropanoids, were, for the first time, isolated from the CHCl₃ extract of the underground parts of this plant and identified. Furthermore, extract and three isolated compounds, i.e., latifolone ( 1 ), dshamirone ( 4 ), and (2S*,3R*)‐2‐[(3E)‐4,8‐dimethylnona‐3,7‐dien‐1‐yl]‐2,3‐dihydro‐7‐hydroxy‐2,3‐dimethylfuro[3,2‐c]coumarin ( 6 ) were, for the first time, evaluated for their in vitro antispasmodic activities in three experimental models: spontaneous contraction, and ACh‐ and KCl‐induced contraction of an isolated rat ileum. The extract (0.1–1.3 mg/ml) and compound 6 (1–10 μg/ml) exhibited dose‐dependent effect in all three models. Compound 1 (1–6 μg/ml) affected spontaneous contractions and those induced by KCl, while compound 4 (8 μg/ml) displayed only moderate activity with ACh‐induced contractions. It can be concluded that tested compounds contribute to exhibited antispasmodic activity of crude extract. Additionally, extract (0.1–1.3 mg/ml) was tested for in vitro relaxant activity on an isolated rat trachea, and relaxed the KCl‐induced contractions in a dose‐dependent manner.     

Effect of cyclic analogues of valproic acid on glutamic acid decarboxylase activity as determined by different methods

In order to study the anticonvulsant activity of cyclic analogues of valproic acid, the effects of sodium valproate, sodium spiro (4:6) undecane-2-carboxylate, and sodium spiro (4:6) undecane-2-acetate were observed on the L-glutamic acid decarboxylase (GAD) activity of E. coli and C. welchii by radioisotopic, volumetric, and gravimetric methods. The results indicated that these compounds potentiated enzyme activity at low concentrations but higher concentrations exhibited an inhibitory effect. Fifty percent enzyme inhibition (ID_5O) ranges were 200–250 μg/ml, 50–75 μg/ml, and 150–200 μg/ml, for the three compounds respectively as determined by the radioisotopic method. While the radioisotopic was used as a conventional method, the microvolumetric and microgravimetric methods were developed for the first time and found to be applicable in determining the effect of the compounds on enzyme activity. The advantages of the latter two methods are that they are simple, safe, and inexpensive as compared to the radioisotopic method. The results by these methods indicated that the second compound was the strongest inhibitor of GAD activity.     

Simultaneous determination of a new anticancer agent (NB-506) and its active metabolite in human plasma and urine by high-performance liquid chromatography with ultraviolet detection

A high-performance liquid chromatographic method with ultraviolet detection has been developed to quantify NB-506 and its active metabolite in human plasma and urine. This method is based on solid-phase extraction, thereby allowing the simultaneous measurement of the drug and metabolite with the limit of quantification of 0.01 μg/ml in plasma and 0.1 μg/ml in urine. Standard curves for the compounds were linear in the concentration ranges investigated. The range for the drug in plasma was 0.01–2.5 μg/ml, and for the metabolite 0.01–1 μg/ml. In urine, the range for both compounds was 0.1–10 μg/ml. The method was validated and applied to the assay of plasma and urinary samples from phase I studies.     

Fluorinated Carbaacyclonucleosides: Synthesis and Evaluation of Antiviral Activity

Abstract

Two series of fluoroacyclic nucleosides were synthesised by condensation of nucleic acid bases with substituted fluoropentanes. 1-(5′-Fluoro-4′-hydroxypentyl)-cytosine showed a modest activity against cytomegalovirus (MIC₅₀: 12–15 μg/ml). All the other compounds were inactive against all the viruses tested.     

Toxicity of Thiophenes from Echinops transiliensis (Asteraceae) against Aedes aegypti (Diptera: Culicidae) Larvae

Structure? activity relationships of nine thiophenes, 2,2′: 5′,2″‐terthiophene ( 1 ), 2‐chloro‐4‐[5‐(penta‐1,3‐diyn‐1‐yl)thiophen‐2‐yl]but‐3‐yn‐1‐yl acetate ( 2 ), 4‐(2,2′‐bithiophen‐5‐yl)but‐3‐yne‐1,2‐diyl diacetate ( 3 ), 4‐[5‐(penta‐1,3‐diyn‐1‐yl)thiophen‐2‐yl]but‐3‐yne‐1,2‐diyl diacetate ( 4 ), 4‐(2,2′‐bithiophen‐5‐yl)‐2‐hydroxybut‐3‐yn‐1‐yl acetate ( 5 ), 2‐hydroxy‐4‐[5‐(penta‐1,3‐diyn‐1‐yl)thiophen‐2‐yl]but‐3‐yn‐1‐yl acetate ( 6 ), 1‐hydroxy‐4‐[5‐(penta‐1,3‐diyn‐1‐yl)thiophen‐2‐yl]but‐3‐yn‐2‐yl acetate ( 7 ), 4‐(2,2′‐bithiophen‐5‐yl)but‐3‐yne‐1,2‐diol ( 8 ), and 4‐[5‐(penta‐1,3‐diyn‐1‐yl)thiophen‐2‐yl]but‐3‐yne‐1,2‐diol ( 9 ), isolated from the roots of Echinops transiliensis, were studied as larvicides against Aedes aegypti. Structural differences among compounds 3, 5 , and 8 consisted in differing AcO and OH groups attached to C(3″) and C(4″), and resulted in variations in efficacy. Terthiophene 1 showed the highest activity (LC₅₀, 0.16 μg/ml) among compounds 1 – 9 , followed by bithiophene compounds 3 (LC₅₀, 4.22 μg/ml), 5 (LC₅₀, 7.45 μg/ml), and 8 (LC₅₀, 9.89 μg/ml), and monothiophene compounds 9 (LC₅₀, 12.45 μg/ml), 2 (LC₅₀, 14.71 μg/ml), 4 (LC₅₀, 17.95 μg/ml), 6 (LC₅₀, 18.55 μg/ml), and 7 (LC₅₀, 19.97 μg/ml). These data indicated that A. aegypti larvicidal activities of thiophenes increase with increasing number of thiophene rings, and the most important active site in the structure of thiophenes could be the tetrahydro‐thiophene moiety. In bithiophenes, 3, 5 , and 8 , A. aegypti larvicidal activity increased with increasing number of AcO groups attached to C(3″) or C(4″), indicating that AcO groups may play an important role in the larvicidal activity.     

Effect of nitrogen nutrition on Fusarium wilt of tomato plants

The role of nitrate-nitrogen (NO₃-N) in relation to the development of tomato wilt caused by Fusarium oxysporum f. sp. lycopersici R1 was studied. Plants receiving 284 μg/ml nitrogen in the nutrient solution exhibited the same severe wilt symptoms as the control plants in soil. Disease decreased with increasing nitrogen levels (420, 630 and 1050 μg/ml). Apparently, the plants were also less susceptible to the disease when the concentration of nitrogen was 70 μg/ml, i. e. below the optimal level (284 μg/ml). Protein content in tissues of plants grown with different amounts of nitrogen was also determined. High nitrogen levels, which decreased disease severity, increased the protein content in leaf tissues. Of 17 amino acids only proline content increased with increasing nitrogen supply. High doses of NO₃–N decreased the phenol content and the activity of peroxidase in stem and leaf tissues of tomato plants. It is suggested that phenolic compounds and the activity of peroxidase are not significant in the resistance of tomato to Fusarlum wilt associated with high nitrogen supply.     

In vitro activities of antimicrobials against Brucella abortus isolates from cattle in Korea during 1998-2006

In vitro activities of 13 antibiotics were assessed against 85 Brucella abortus isolates from naturally infected cattle in the Republic of Korea during 1998-2006, using broth microdilution test. Tetracyclines showed the most excellent activity against B. abortus, displaying MIC values of 0.5 μg/ml or below. In particular, minocycline showed the lowest MIC??/?? values (0.125/0.125 μg/ml) in this study. Among four fluoroquinolones tested, ciprofloxacin (MIC??/??, 0.5/1 μg/ml) and norfloxacin (MIC??/??, 8/8 μg/ml) had the most and the least activities, respectively. Gentamicin (MIC??/??, 1/1 μg/ml) was more effective than streptomycin, erythromycin, rifampin, and chloramphenicol (MIC??/??, 2/2 μg/ml).     

Antioxidant and antimicrobial activities of rosemary extracts linked to their polyphenol composition

Rosmarinus officinalis extracts were investigated by a combination of bioassays and biochemical analysis to identify bioactive compounds. The 2,2-diphenyl-2-picrylhydracyl hydrate (DPPH) radical scavenging method, Folin–Ciocaulteau method and HPLC chromatography were used to study the distribution and levels of antioxidants (AOXs). Antimicrobial activity analysis was carried out using the disk diffusion and broth dilution techniques. A good correlation between the AOX activities and total phenol content in the extracts was found. Although all rosemary extracts showed a high radical scavenging activity, a different efficacy as antimicrobial agent was observed. Methanol extract containing 30% of carnosic acid, 16% of carnosol and 5% of rosmarinic acid was the most effective antimicrobial against Gram positive bacteria (minimal inhibition concentration, MIC, between 2 and 15 μg/ml), Gram negative bacteria (MIC between 2 and 60 μg/ml) and yeast (MIC of 4 μg/ml). By contrast, water extract containing only 15% of rosmarinic acid showed a narrow activity. MIC value of the methanol and water extracts is in a good correlation with the values obtained with pure carnosic acid and rosmarinic acid, respectively. Therefore, our results suggested that the antimicrobial rosemary extracts efficacy was associated with their specific phenolic composition. Carnosic acid and rosmarinic acid may be the main bioactive antimicrobial compounds present in rosemary extracts. From a practical point of view, rosemary extract may be a good candidate for functional foods as well as for pharmaceutical plant-based products.