In Vitro Human Metabolism and Inhibition Potency of Verbascoside for CYP Enzymes

Verbascoside is found in many medicinal plant families such as Verbenaceae. Important biological activities have been ascribed to verbascoside. Investigated in this study is the potential of verbascoside as an adjuvant during tuberculosis treatment. The present study reports on the in vitro metabolism in human hepatic microsomes and cytosol incubations as well as the presence and quantity of verbascoside within Lippia scaberrima. Additionally, studied are the inhibitory properties on human hepatic CYP enzymes together with antioxidant and cytotoxic properties. The results yielded no metabolites in the hydrolysis or cytochrome P450 (CYP) oxidation incubations. However, five different methylated conjugates of verbascoside could be found in S-adenosylmethionine incubation, three different sulphate conjugates with 3′-phosphoadenosine 5′-phosphosulfate (PAPS) incubation with human liver samples, and very low levels of glucuronide metabolites after incubation with recombinant human uridine 5’-diphospho-glucuronosyltransferase (UGT) 1A7, UGT1A8, and UGT1A10. Additionally, verbascoside showed weak inhibitory potency against CYP1A2 and CYP1B1 with IC50 values of 83 µM and 86 µM, respectively. Potent antioxidant and low cytotoxic potential were observed. Based on these data, verbascoside does not possess any clinically relevant CYP-mediated interaction potential, but it has effective biological activity. Therefore, verbascoside could be considered as a lead compound for further drug development and as an adjuvant during tuberculosis treatment.

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In Vitro Anticancer Screening and Preliminary Mechanistic Study of A-Ring Substituted Anthraquinone Derivatives

Cells ◽

10.3390/cells11010168 ◽

2022 ◽

Vol 11 (1) ◽

pp. 168

Author(s):

Ibrahim Morgan ◽

Ludger A. Wessjohann ◽

Goran N. Kaluđerović

Keyword(s):

Cell Lines ◽

Mechanism Of Action ◽

Biological Activities ◽

Mechanistic Study ◽

Redox Active ◽

Anthraquinone Derivatives ◽

M Phase ◽

Ic50 Values ◽

Plant Families

Anthraquinone derivatives exhibit various biological activities, e.g., antifungal, antibacterial and in vitro antiviral activities. They are naturally produced in many fungal and plant families such as Rhamnaceae or Fabaceae. Furthermore, they were found to have anticancer activity, exemplified by mitoxantrone and pixantrone, and many are well known redox-active compounds. In this study, various nature inspired synthetic anthraquinone derivatives were tested against colon, prostate, liver and cervical cancer cell lines. Most of the compounds exhibit anticancer effects against all cell lines, therefore the compounds were further studied to determine their IC50-values. Of these compounds, 1,4-bis(benzyloxy)-2,3-bis(hydroxymethyl)anthracene-9,10-dione (4) exhibited the highest cytotoxicity against PC3 cells and was chosen for a deeper look into its mechanism of action. Based on flow cytometry, the compound was proven to induce apoptosis through the activation of caspases and to demolish the ROS/RNS and NO equilibrium in the PC3 cell line. It trapped cells in the G2/M phase. Western blotting was performed for several proteins related to the effects observed. Compound 4 enhanced the production of PARP and caspase-3. Moreover, it activated the conversion of LC3A/B-I to LC3A/B-II showing that also autophagy plays a role in its mechanism of action, and it caused the phosphorylation of p70 s6 kinase.

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Novel Iodinated Hydrazide-hydrazones and their Analogues as Acetyl- and Butyrylcholinesterase Inhibitors

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200819155503 ◽

2020 ◽

Vol 20 (23) ◽

pp. 2106-2117

Author(s):

Martin Krátký ◽

Šárka Štěpánková ◽

Michaela Brablíková ◽

Katarína Svrčková ◽

Markéta Švarcová ◽

...

Keyword(s):

Biological Activities ◽

Structural Parameters ◽

Covalent Binding ◽

Docking Studies ◽

Potent Inhibition ◽

Brain Barrier Permeability ◽

Electric Eel ◽

Ic50 Values ◽

Ellman’S Method

Background: Hydrazide-hydrazones have been known as scaffold with various biological activities including inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE). Cholinesterase inhibitors are mainstays of dementias’ treatment. Objective: Twenty-five iodinated hydrazide-hydrazones and their analogues were designed as potential central AChE and BuChE inhibitors. Methods: Hydrazide-hydrazones were synthesized from 4-substituted benzohydrazides and 2-/4- hydroxy-3,5-diiodobenzaldehydes. The compounds were investigated in vitro for their potency to inhibit AChE from electric eel and BuChE from equine serum using Ellman’s method. We calculated also physicochemical and structural parameters for CNS delivery. Results: The derivatives exhibited a moderate dual inhibition with IC50 values ranging from 15.1-140.5 and 35.5 to 170.5 μmol.L-1 for AChE and BuChE, respectively. Generally, the compounds produced a balanced or more potent inhibition of AChE. N'-[(E)-(4-Hydroxy-3,5-diiodophenyl)methylidene]-4- nitrobenzohydrazide 2k and 4-fluoro-N'-(2-hydroxy-3,5-diiodobenzyl)benzohydrazide 3a were the most potent inhibitors of AChE and BuChE, respectively. Structure-activity relationships were established, and molecular docking studies confirmed interaction with enzymes. Conclusion: Many novel hydrazide-hydrazones showed lower IC50 values than rivastigmine against AChE and some of them were comparable for BuChE to this drug used for the treatment of dementia. They interact with cholinesterases via non-covalent binding into the active site. Based on the BOILEDEgg approach, the majority of the derivatives met the criteria for blood-brain-barrier permeability.

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In Vitro Study of Multi-Therapeutic Properties of Thymus bovei Benth. Essential Oil and Its Main Component for Promoting Their Use in Clinical Practice

Journal of Clinical Medicine ◽

10.3390/jcm7090283 ◽

2018 ◽

Vol 7 (9) ◽

pp. 283 ◽

Cited By ~ 8

Author(s):

Sherif Hassan ◽

Kateřina Berchová-Bímová ◽

Miroslava Šudomová ◽

Milan Malaník ◽

Karel Šmejkal ◽

...

Keyword(s):

Gas Chromatography ◽

Clinical Practice ◽

Essential Oil ◽

Biological Activities ◽

Structural Parameters ◽

Antihypertensive Agents ◽

Gas Chromatography Mass Spectrometry ◽

Ic50 Values ◽

Main Component

Thymus bovei Benth. (TB) is an important plant in the traditional medicine of the Mediterranean region. This study investigates the health-promoting properties of TB essential oil (TB-EO) for its possible use in clinical practice with regards to its cytotoxic, anti-herpes simplex virus type 2 (HSV-2), and antihypertensive (through inhibition of human angiotensin-converting enzyme; ACE) properties. The phytochemical profile of EO (99.9%) was analyzed by Gas Chromatography with Flame-Ionization Detection (GC-FID) and Gas Chromatography-Mass Spectrometry (GC-MS). In this study, all biological methods were performed at the level of in vitro studies. The results showed that TB-EO exerted remarked cytotoxic properties against human cervical carcinoma cells, colon cancer cells, and lung adenocarcinoma cells with the half-maximal inhibitory concentration (IC50) values of 7.22, 9.30, and 8.62 µg/mL, respectively, in comparison with that of standard anticancer drug cisplatin with IC50 values of 4.24, 5.21, and 5.43 µg/mL, respectively. Fascinatingly, TB-EO showed very weak cytotoxicity on the healthy human fetal lung fibroblast cells with an IC50 value of 118.34 µg/mL compared with that of cisplatin (IC50 = 10.08 µg/mL). TB-EO, its main component geraniol, TB-EO combined with acyclovir (ACV) along with standard ACV, have displayed pronounced inhibitory properties against the replication of HSV-2 with the half-maximal effective concentration (EC50) values of 2.13, 1.92, 0.81 and 1.94 µg/mL, respectively, with corresponding selectivity indices (SI) 98.59, 109.38, 259.26 and 108.25, respectively. TB-EO and geraniol at a concentration of 15 µg/mL showed prominent inhibitory activities against ACE with % of inhibition 95.4% and 92.2%, respectively, compared with that of standard inhibitor captopril (99.8%; 15 µg/mL). Molecular docking studies were performed to unveil the mechanism of action of geraniol as well as structural parameters necessary for anti-HSV-2 activity (through the inhibition of HSV-2 protease) and ACE inhibition. This is the first report on the chemical composition of Egyptian TB-EO along with the above-mentioned biological activities. Our results may be considered as novel findings in the course of a search for new and active anticancer, anti-HSV-2 and antihypertensive agents, and expand the medicinal value of this plant and its phytochemicals in clinical practice.

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Effect of Ginkgo biloba extract on rat hepatic microsomal CYP1A activity: role of ginkgolides, bilobalide, and flavonols

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y03-133 ◽

2004 ◽

Vol 82 (1) ◽

pp. 57-64 ◽

Cited By ~ 19

Author(s):

I fan Kuo ◽

Jie Chen ◽

Thomas K.H Chang

Keyword(s):

Ginkgo Biloba ◽

Ginkgo Biloba Extract ◽

Inhibitory Potency ◽

Hepatic Microsomes ◽

Cyp1a Activity ◽

Ginkgo Biloba Extracts ◽

The Individual ◽

Vitro Effect

The present study investigated the in vitro effect of Ginkgo biloba extracts and some of the individual constituents (ginkgolides, bilobalide, and flavonols such as kaempferol, quercetin, isorhamnetin, and their glycosides) on CYP1A-mediated 7-ethoxyresorufin O-dealkylation in hepatic microsomes isolated from rats induced with β-naphthoflavone. G. biloba extract competitively inhibited CYP1A activity, with an apparent Ki value of 1.6 ± 0.4 µg/mL (mean ± SE). At the concentrations present in the G. biloba extracts, ginkgolides A, B, C, and J and bilobalide did not affect CYP1A activity, whereas kaempferol (IC50 = 0.006 ± 0.001 µg/mL, mean ± SE), isorhamnetin (0.007 ± 0.001 µg/mL), and quercetin (0.050 ± 0.003 µg/mL) decreased this activity. The monoglycosides (1 and 10 µg/mL) and diglycosides (10 µg/mL) of kaempferol and quercetin but not those of isorhamnetin also inhibited CYP1A activity. The order of inhibitory potency was kaempferol ~ isorhamnetin > quercetin, and for each of these flavonols the order of potency was aglycone >> monoglycoside > diglycoside. In summary, G. biloba extract competitively inhibited rat hepatic microsomal CYP1A activity, but the effect was not due to ginkgolides A, B, C, or J, bilobalide, kaempferol, quercetin, isorhamnetin, or the respective flavonol monoglycosides or diglycosides.Key words: bilobalide, CYP1A, cytochrome P450, Ginkgo biloba, ginkgolide, flavonol.

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Derivatization of Rosmarinic Acid Enhances its in vitro Antitumor, Antimicrobial and Antiprotozoal Properties

Molecules ◽

10.3390/molecules24061078 ◽

2019 ◽

Vol 24 (6) ◽

pp. 1078 ◽

Cited By ~ 9

Author(s):

Silvia Bittner Fialová ◽

Martin Kello ◽

Matúš Čoma ◽

Lívia Slobodníková ◽

Eva Drobná ◽

...

Keyword(s):

Rosmarinic Acid ◽

Antimicrobial Agents ◽

Biological Activities ◽

Fold Increase ◽

Inhibitory Effect ◽

Phosphonium Salts ◽

Ros Scavenging ◽

Ic50 Values ◽

Quaternary Phosphonium Salts

On its own, rosmarinic acid possesses multiple biological activities such as anti-inflammatory, antimicrobial, cardioprotective and antitumor properties, and these are the consequence of its ROS scavenging and inhibitory effect on inflammation. In this study, two quaternary phosphonium salts of rosmarinic acid were prepared for the purpose of increasing its penetration into biological systems with the aim of improving its antimicrobial, antifungal, antiprotozoal and antitumor activity. The synthetized molecules, the triphenylphosphonium and tricyclohexylphosphonium salts of rosmarinic acid, exhibited significantly stronger inhibitory effects on the growth of HCT116 cells with IC50 values of 7.28 or 8.13 μM in comparison to the initial substance, rosmarinic acid (>300 μM). For the synthesized derivatives, we detected a greater than three-fold increase of activity against Acanthamoeba quina, and a greater than eight-fold increase of activity against A. lugdunensis in comparison to rosmarinic acid. Furthermore, we recorded significantly higher antimicrobial activity of the synthetized derivatives when compared to rosmarinic acid itself. Both synthetized quaternary phosphonium salts of rosmarinic acid appear to be promising antitumor and antimicrobial agents, as well as impressive molecules for further research.

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Momilactones A, B, and Tricin in Rice Grain and By-Products are Potential Skin Aging Inhibitors

Foods ◽

10.3390/foods8120602 ◽

2019 ◽

Vol 8 (12) ◽

pp. 602 ◽

Cited By ~ 3

Author(s):

Nguyen Van Quan ◽

Dam Duy Thien ◽

Tran Dang Khanh ◽

Hoang-Dung Tran ◽

Tran Dang Xuan

Keyword(s):

Liquid Chromatography ◽

High Performance ◽

Biological Activities ◽

Ultra Performance Liquid Chromatography ◽

Skin Aging ◽

Ionization Mass ◽

Rice Grain ◽

Synergistic Activity ◽

Ic50 Values

We previously reported the inhibitory potentials of momilactones A (MA) and B (MB) against key enzymes related to type 2 diabetes and obesity. In this study, antioxidant and anti-skin-aging activities of MA and MB were investigated and compared with tricin, a well-known antioxidant and antiaging flavonoid in rice. MA, MB, and tricin were purified from rice husk by column chromatography and their biological activities were subsequently assayed by in vitro trials. The contents of MA, MB, and tricin of different commercial rice cultivars in Japan were quantified and confirmed by ultra-performance liquid chromatography-electrospray ionization-mass spectrometry (UPLC-ESI-MS) and high-performance liquid chromatography (HPLC) analyses. The antioxidant assays revealed a synergistic activity of the mixture MA and MB (MAB, 1:1, v/v). In addition, in 2,2’-azino-bis (ABTS) assay, IC50 values of MAB (0.3 mg/mL) and tricin (0.3 mg/mL) was 4-fold and 9-fold greater than that of individual MB (1.3 mg/mL) or MA (2.8 mg/mL), respectively. The in vitro enzymatic assays on pancreatic elastase and tyrosinase indicated that MA and MB were potential to relief skin wrinkles and freckles. In detail, MA exerted higher inhibition on both enzymatic activities (30.9 and 37.6% for elastase and tyrosinase inhibition, respectively) than MB (18.5 and 12.6%) and MAB (32.0 and 19.7%) at a concentration of 2.0 mg/mL. Notably, MA and the mixture MAB exhibited stronger inhibitions on elastase and tyrosinase in comparison with tricin and vanillin. MA, MB, and tricin in rice are potential to develop cosmetics as well as supplements for skin aging treatments.

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Synthesis, Antimicrobial Activity and Molecular Docking of Novel Thiourea Derivatives Tagged with Thiadiazole, Imidazole and Triazine Moieties as Potential DNA Gyrase and Topoisomerase IV Inhibitors

Molecules ◽

10.3390/molecules25122766 ◽

2020 ◽

Vol 25 (12) ◽

pp. 2766 ◽

Cited By ~ 1

Author(s):

Heba E. Hashem ◽

Abd El-Galil E. Amr ◽

Eman S. Nossier ◽

Elsayed A. Elsayed ◽

Eman M. Azmy

Keyword(s):

Antimicrobial Activity ◽

Molecular Docking ◽

Antimicrobial Agents ◽

Biological Activities ◽

Topoisomerase Iv ◽

Thiourea Derivatives ◽

E Coli ◽

Cytotoxicity Studies ◽

Ic50 Values

To develop new antimicrobial agents, a series of novel thiourea derivatives incorporated with different moieties 2–13 was designed and synthesized and their biological activities were evaluated. Compounds 7a, 7b and 8 exhibited excellent antimicrobial activity against all Gram-positive and Gram-negative bacteria, and the fungal Aspergillus flavus with minimum inhibitory concentration (MIC) values ranged from 0.95 ± 0.22 to 3.25 ± 1.00 μg/mL. Furthermore, cytotoxicity studies against MCF-7 cells revealed that compounds 7a and 7b were the most potent with IC50 values of 10.17 ± 0.65 and 11.59 ± 0.59 μM, respectively. On the other hand, the tested compounds were less toxic against normal kidney epithelial cell lines (Vero cells). The in vitro enzyme inhibition assay of 8 displayed excellent inhibitory activity against Escherichia coli DNA B gyrase and moderate one against E. coli Topoisomerase IV (IC50 = 0.33 ± 1.25 and 19.72 ± 1.00 µM, respectively) in comparison with novobiocin (IC50 values 0.28 ± 1.45 and 10.65 ± 1.02 µM, respectively). Finally, the molecular docking was done to position compound 8 into the E. coli DNA B and Topoisomerase IV active pockets to explore the probable binding conformation. In summary, compound 8 may serve as a potential dual E. coli DNA B and Topoisomerase IV inhibitor.

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Synthesis of Novel 2-(Pyridin-2-yl) Pyrimidine Derivatives and Study of Their Anti-Fibrosis Activity

Molecules ◽

10.3390/molecules25225226 ◽

2020 ◽

Vol 25 (22) ◽

pp. 5226

Author(s):

Yi-Fei Gu ◽

Yue Zhang ◽

Feng-li Yue ◽

Shao-tong Li ◽

Zhuo-qi Zhang ◽

...

Keyword(s):

Biological Activities ◽

Collagen Type I ◽

Type I ◽

The Novel ◽

Pyrimidine Derivatives ◽

Wide Range ◽

Ic50 Values ◽

Privileged Structures ◽

Pyrimidine Moiety

A pyrimidine moiety exhibiting a wide range of pharmacological activities has been employed in the design of privileged structures in medicinal chemistry. To prepare libraries of novel heterocyclic compounds with potential biological activities, a series of novel 2-(pyridin-2-yl) pyrimidine derivatives were designed, synthesized and their biological activities were evaluated against immortalized rat hepatic stellate cells (HSC-T6). Fourteen compounds were found to present better anti-fibrotic activities than Pirfenidone and Bipy55′DC. Among them, compounds ethyl 6-(5-(p-tolylcarbamoyl)pyrimidin-2-yl)nicotinate (12m) and ethyl 6-(5-((3,4-difluorophenyl)carbamoyl)pyrimidin-2-yl)nicotinate (12q) show the best activities with IC50 values of 45.69 μM and 45.81 μM, respectively. Furthermore, the study of anti-fibrosis activity was evaluated by Picro-Sirius red staining, hydroxyproline assay and ELISA detection of Collagen type I alpha 1 (COL1A1) protein expression. Our study showed that compounds 12m and 12q effectively inhibited the expression of collagen, and the content of hydroxyproline in cell culture medium in vitro, indicating that compounds 12m and 12q might be developed the novel anti-fibrotic drugs.

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Chemical Composition and Enzymatic Screening of Micromeria fruticosa serpyllifolia Volatile Oils Collected from Three Different Regions of West Bank, Palestine

BioMed Research International ◽

10.1155/2018/6536919 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Nihaya Salameh ◽

Naser Shraim ◽

Nidal Jaradat

Keyword(s):

Plant Extracts ◽

Biological Activities ◽

West Bank ◽

Chemical Components ◽

Chemical Compositions ◽

Therapeutic Effects ◽

Volatile Oils ◽

Ic50 Values ◽

Micromeria Fruticosa

Introduction. Volatile oils (VOs) have been commonly used in cosmetics and food as fragrances, flavoring, and preservative agents or in alternative medicine for their therapeutic effects. This necessitates investigating those plants and their VOs. This study was conducted to investigate the chemical compositions of the VOs of Micromeria fruticosa serpyllifolia growing widely in three regions in Palestine (i.e., Hebron, Ramallah, and Nablus districts representing south, middle, and north of West Bank). Afterwards, VOs were subjected to in vitro screening and their enzymatic properties were compared. Methods. The analysis of chemical components of VOs was performed by gas chromatography coupled with mass spectrometry (GC-MS). The antilipase activity was evaluated using porcine pancreatic lipase and p-nitrophenyl butyrate. The antiamylase activity was assessed using porcine pancreatic α-amylase, starch, and 3,5-dinitrosalicylic. Results. Plant extracts yield range was 0.67 to 0.99 w/w%. GC-MS analysis showed the high percentages of oxygenated components in the range of 86.1-89.88% and nonoxygenated components in the range of 4.38-4.71%. Seven components were observed, pulegone was the most abundant component in the three samples in the range of 74.43-86.04%, and isomenthone was the second most abundant component with the range of 3.16-14.41%. The sample collected from Nablus showed the most potent antilipase and antiamylase activity with IC50 values of 39.81 μg/mL and 3.31 μg/mL, respectively. Conclusions. The study showed that Micromeria fruticosa serpyllifolia volatile oils samples from different regions in Palestine contained different proportions of phytochemicals which provided different potential biological activities such as antiobesity and antidiabetes activities that were in line with traditional uses of the plant extracts. The plant extracts showed higher antilipase and antiamylase potency than that of the relative references and there were significant differences in these activities compared to each other.

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Design, Synthesis, Antibacterial, Antifungal and Anticancer Evaluations of Novel β-Pinene Quaternary Ammonium Salts

International Journal of Molecular Sciences ◽

10.3390/ijms222011299 ◽

2021 ◽

Vol 22 (20) ◽

pp. 11299

Author(s):

Li Zhang ◽

Xue-Zhen Feng ◽

Zhuan-Quan Xiao ◽

Guo-Rong Fan ◽

Shang-Xing Chen ◽

...

Keyword(s):

Cell Lines ◽

Anticancer Agents ◽

Quaternary Ammonium ◽

Biological Activities ◽

Cell Membrane Permeability ◽

Vitro Assay ◽

Ic50 Values ◽

Hct 116 ◽

Mcf 7

β-pinene is a monoterpene isolated from turpentine oil and numerous other plants’ essential oils, which has a broad spectrum of biological activities. In the current work, six novel β-pinene quaternary ammonium (β-PQA) salts were synthesized and evaluated in vitro for their antifungal, antibacterial and anticancer activities. The in vitro assay results revealed that compounds 4a and 4b presented remarkable antimicrobial activity against the tested fungi and bacteria. In particular, compound 4a showed excellent activities against F. oxysporum f.sp. niveum, P. nicotianae var.nicotianae, R. solani, D. pinea and Fusicoccumaesculi, with EC50 values of 4.50, 10.92, 9.45, 10.82 and 6.34 μg/mL, respectively. Moreover, compound 4a showed the best antibacterial action against E. coli, P. aeruginosa, S. aureus and B. subtilis, with MIC at 2.5, 0.625, 1.25 and 1.25 μg/mL, respectively. The anticancer activity results demonstrated that compounds 4a, 4b, 4c and 4f exhibited remarkable activity against HCT-116 and MCF-7 cell lines, with IC50 values ranged from 1.10 to 25.54 μM. Notably, the compound 4c displayed the strongest cytotoxicity against HCT-116 and MCF-7 cell lines, with the IC50 values of 1.10 and 2.46 μM, respectively. Furthermore, preliminary antimicrobial mechanistic studies revealed that compound 4a might cause mycelium abnormalities of microbial, cell membrane permeability changes and inhibition of the activity of ATP. Altogether, these findings open interesting perspectives to the application of β-PQA salts as a novel leading structure for the development of effective antimicrobial and anticancer agents.

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