scholarly journals Synthesis and Evaluation of the 4-Substituted 2-Hydroxy-5-Iodochalcones and Their 7-Substituted 6-Iodoflavonol Derivatives for Inhibitory Effect on Cholinesterases and β-Secretase

2018 ◽  
Vol 19 (12) ◽  
pp. 4112 ◽  
Author(s):  
Malose Mphahlele ◽  
Emmanuel Agbo ◽  
Samantha Gildenhuys
Keyword(s):  
Kinetic Studies ◽  
Inhibitory Effect ◽  
Docking Studies ◽  
Significant Inhibition ◽  
Strong Interactions ◽  
Protein Residues ◽  
Significant Inhibitory Effect ◽  
Increased Activity ◽  
Bace 1

A series of 2-aryl-3-hydroxy-6-iodo-4H-chromen-4-ones substituted at the 7-position with a halogen atom (X = F, Cl and Br) or methoxy group and their corresponding 4-substituted 2-hydroxy-5-iodochalcone precursors were evaluated in vitro for inhibitory effect against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and β-secretase (BACE1) activities. Although moderate inhibitory effect was observed for the chalcones against AChE, derivatives 2h, 2j and 2n exhibited significant inhibitory effect against BChE and BACE-1. The 2-aryl-7-fluoro-8-iodoflavonols 3b and 3c, on the other hand, exhibited increased activity and selectivity against AChE and reduced effect on BACE-1. The flavonols 3h, 3i, 3k, 3l and 3p exhibited moderate inhibitory effect against AChE, but significant inhibition against BChE. Compounds 2j and 3l exhibited non-competitive mode of inhibition against BACE-1. Molecular docking predicted strong interactions with the protein residues in the active site of BACE-1 implying these compounds bind with the substrate. Similarly docking studies predicted interaction of the most active compounds with both CAS and PAS of either AChE or BChE with mixed type of enzyme inhibition confirmed by kinetic studies.

scholarly journals In Vitro Evaluation and Docking Studies of 5-oxo-5H-furo[3,2-g]chromene-6-carbaldehyde Derivatives as Potential Anti-Alzheimer’s Agents

2019 ◽  
Vol 20 (21) ◽  
pp. 5451
Author(s):  
Malose J. Mphahlele ◽  
Samantha Gildenhuys ◽  
Emmanuel N. Agbo
Keyword(s):  
Breast Cancer ◽  
Biological Activity ◽  
Active Sites ◽  
Kinetic Studies ◽  
Inhibitory Effect ◽  
Docking Studies ◽  
Significant Inhibitory Effect ◽  
Anti Oxidant ◽  
Mcf 7

A series of novel 2-carbo–substituted 5-oxo-5H-furo[3,2-g]chromene-6-carbaldehydes and their 6-(4-trifluoromethyl)phenylhydrazono derivatives have been prepared and evaluated for biological activity against the human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The most active compounds from each series were, in turn, evaluated against the following enzyme targets involved in Alzheimer’s disease, β-secretase (BACE-1) and lipoxygenase-15 (LOX-15), as well as for anti-oxidant potential. Based on the in vitro results of ChE and β-secretase inhibition, the kinetic studies were conducted to determine the mode of inhibition by these compounds. 2-(4-Methoxyphenyl)-5-oxo-5H-furo[3,2-g]chromene-6-carbaldehyde (2f), which exhibited significant inhibitory effect against all these enzymes was also evaluated for activity against the human lipoxygenase-5 (LOX-5). The experimental results were complemented with molecular docking into the active sites of these enzymes. Compound 2f was also found to be cytotoxic against the breast cancer MCF-7 cell line.

A comparative study of the antibacterial activity of Quercus robur (Ethanolic extract) and Zinc oxide nanoparticles on Salmonella (In vitro)

2018 ◽  
Vol 9 (SPL1) ◽  
Author(s):  
Hams H. H. Alfattli ◽  
Ghufran Zuhair Jiber ◽  
Ghaidaa Gatea Abbass
Keyword(s):  
Zinc Oxide ◽  
Antibacterial Activity ◽  
Zinc Oxide Nanoparticles ◽  
Quercus Robur ◽  
Ethanolic Extract ◽  
Inhibitory Effect ◽  
Significant Inhibition ◽  
Oxide Nanoparticles ◽  
Inhibition Zones

This study which designed to evaluate the inhibitory effect of Ethanolic extract of (Quercusrobur) and Zinc oxide nanoparticles on the growth of one genus of enterobacteriacae (Salmonella). In vitro. For this purpose graduate concentrates for plant extract (50, 100, 200, 400 )mg/ml which prepared and compared with Zinc oxide nanoparticles of different concentration (2, 1, 0.5, 0.25) μg/ml,and examined. The result showed that the studied medicinal plant has antibacterial activity against this bacteria which used. The result showed that the plant has good activity in decrease the growth of this bacteria. The results of the study also showed that the nano-ZnO has very effective antibacterial action against the studied bacteria which was Salmonella,nanoparticles concentrations lead to increasing in the inhibition zones of tested bacterial growth. We also study the effect of three antibiotics Lomefloxacin (LOM), Ciprofloxacin (SIP) and Rifampin (RA) and the result showed,in a comparison within the tested bacteria,Salmonella had a significant inhibition increase in Lomefloxacin ; the ciprofloxacin showed effect on tested bacteria. However,Rifampin does not show any effect on tested bacteria.

Pharmacophore Modeling and Docking Studies to Investigate Potential Leads for the Development of β -Secretase APP Cleavage Enzyme-1 (BACE-1) Inhibitors

2019 ◽  
Vol 16 (7) ◽  
pp. 775-784
Author(s):  
Richa Arya ◽  
Satya Prakash Gupta ◽  
Sarvesh Paliwal ◽  
Swapnil Sharma ◽  
Kirtika Madan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Medical Condition ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Docking Studies ◽  
Pyridine Derivative ◽  
Cleavage Enzyme ◽  
Bace 1

Background: Alzheimer’s disease is a medical condition with detrimental brain health. It is majorly diagnosed in aging individuals plaque in β) characterized by accumulated Amyloidal beta (A 1 BACE) 1 secretase APP cleavage enzyme βneurological areas. The ) is the target of choice that can be exploited to find drugs against Alzheimer’s disease. Methods: A series of BACE-1 inhibitors with reported binding constant were considered for the development of a feature based pharmacophore model. Results: The good correlation coefficient (r=0.91) and RMSD of 0.93 was observed with 30 compounds in training set. The model was validated internally (r2test=0.76) as well as externally by Fischer validation. The pharmacophore based virtual screening retrieved compounds that were docked and biologically evaluated. Conclusion: The three structurally diverse molecules were tested by in-vitro method. The pyridine derivative with highest fit value (6.9) exhibited IC50 value of 2.70 µM and thus was found to be the most promising lead molecule as BACE-1 inhibitor.

scholarly journals A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK and NF-κB pathways

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Ying Liu ◽  
Wenjie Liu ◽  
Ziqiang Yu ◽  
Yan Zhang ◽  
Yinghua Li ◽  
...  
Keyword(s):  
Bone Loss ◽  
Osteoporosis Treatment ◽  
Inhibitory Effect ◽  
Specific Gene ◽  
Actin Ring ◽  
Treatment Target ◽  
Significant Inhibitory Effect ◽  
Promising Treatment

AbstractBromodomain-containing protein 4 (BRD4) has emerged as a promising treatment target for bone-related disorders. (+)-JQ1, a thienotriazolodiazepine compound, has been shown to inhibit pro-osteoclastic activity in a BRD4-dependent approach and impede bone loss caused by ovariectomy (OVX) in vivo. However, clinical trials of (+)-JQ1 are limited because of its poor druggability. In this study, we synthesized a new (+)-JQ1 derivative differing in structure and chirality. One such derivative, (+)-ND, exhibited higher solubility and excellent inhibitory activity against BRD4 compared with its analogue (+)-JQ1. Interestingly, (-)-JQ1 and (-)-ND exhibited low anti-proliferative activity and had no significant inhibitory effect on RANKL-induced osteoclastogenesis as compared with (+)-JQ1 and (+)-ND, suggesting the importance of chirality in the biological activity of compounds. Among these compounds, (+)-ND displayed the most prominent inhibitory effect on RANKL-induced osteoclastogenesis. Moreover, (+)-ND could inhibit osteoclast-specific gene expression, F‐actin ring generation, and bone resorption in vitro and prevent bone loss in OVX mice. Collectively, these findings indicated that (+)-ND represses RANKL‐stimulated osteoclastogenesis and averts OVX-triggered osteoporosis by suppressing MAPK and NF-κB signalling cascades, suggesting that it may be a prospective candidate for osteoporosis treatment.

Liposome encapsulation attenuates hemoglobin-induced vasoconstriction in rabbit arterial segments

1997 ◽  
Vol 82 (6) ◽  
pp. 1826-1835 ◽  
Author(s):  
Alan S. Rudolph ◽  
Anthony Sulpizio ◽  
Paul Hieble ◽  
Victor Macdonald ◽  
Mark Chavez ◽  
...  
Keyword(s):  
Kinetic Studies ◽  
Significant Inhibition ◽  
No Donor ◽  
Liposome Encapsulation ◽  
Vasoconstrictor Response ◽  
Ear Artery ◽  
Rabbit Ear ◽  
Before And After ◽  
Potent Vasoconstrictor

Rudolph, Alan S., Anthony Sulpizio, Paul Hieble, Victor Macdonald, Mark Chavez, and Giora Feuerstein. Liposome encapsulation attenuates hemoglobin-induced vasoconstriction in rabbit arterial segments. J. Appl. Physiol.82(6): 1826–1835, 1997.—Free hemoglobin (Hb) induces a potent vasoconstrictor response that may limit its therapeutic application as a red blood cell replacement. We have investigated whether encapsulation of stroma-free Hb (SFHb) or cross-linked Hb (αα-Hb) in liposomes modulates Hb vasoactivity in isolated blood vessels. Relaxation of rabbit thoracic vessels was measured before and after exposure to acellular SFHb, αα-Hb, and liposome-encapsulated SFHb or αα-Hb. SFHb and αα-Hb caused significant inhibition of carbachol-induced relaxation at 0.5 mg/dl, whereas encapsulation inhibited vessel relaxation at 30- to 60-fold higher Hb concentrations. The contractile response of rabbit ear arterial segments to electrical stimulation in the presence of acellular αα-Hb resulted in a 150% increase (EC150) in contractile amplitude at 0.23 mg/dl, whereas the EC150 for encapsulated αα-Hb was 13.7 mg/dl. Mechanistic studies of the vasoconstrictor activity of Hb demonstrated that acellular αα-Hb had no effect on norepinephrine release in the rabbit ear artery. In addition, neither acellular nor encapsulated αα-Hb preparations inhibited endothelial nitric oxide (NO) synthase activity isolated from bovine pulmonary artery. However, inhibition of vessel relaxation by acellular or encapsulated αα-Hb was reversed by the NO donor S-nitrosylpenacillamine, implicating Hb-NO binding as a possible mechanism for the vasoconstrictor response. In vitro stopped-flow kinetic studies of Hb-NO binding showed similar rates of reaction for conversion of oxyhemoglobin to methemoglobin (metHb; <2 ms), followed by rapid conversion of metHb to NO-Hb (300 ms) for both acellular and encapsulated αα-Hb, demonstrating that liposome encapsulation does not retard NO-Hb binding. The attenuated vasoactivity of encapsulated Hb may, therefore, result from the limited access of encapsulated Hb to NO imposed by the physical size of the liposome and reduced penetration of Hb across the vascular endothelium.

scholarly journals Type beta transforming growth factor is a potent inhibitor of murine megakaryocytopoiesis in vitro

Blood ◽  
1987 ◽  
Vol 69 (6) ◽  
pp. 1737-1741 ◽  
Author(s):  
T Ishibashi ◽  
SL Miller ◽  
SA Burstein
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Ache Activity ◽  
Transforming Growth Factor ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Significant Inhibition ◽  
Tgf Beta ◽  
Megakaryocytic Differentiation

Abstract To investigate the potential role of platelets in the inhibition of megakaryocytopoiesis, freeze-thawed extracts of human platelets were added to serumless liquid cultures of murine marrow. When acetylcholinesterase (AchE), a marker of megakaryocytic differentiation in mice, was assayed, a significant inhibition of enzymatic activity was noted in cultures containing the equivalent of greater than 5 X 10(6) solubilized platelets per milliliter. Freeze-thawed extracts of granulocytes had significantly less inhibitory effect than did platelets. Transforming growth factor beta (TGF-beta), a growth factor known to be inhibitory to some cell lineages and to be found at relatively high concentrations in platelets, was then added to liquid marrow cultures. A similar inhibition of AchE activity was detected when cultures were stimulated with mitogen-stimulated conditioned medium. The effect was potent with 50% inhibition of AchE activity observed at 4 pmol TGF-beta/L. To determine if TGF-beta inhibited specifically one aspect of megakaryocytic differentiation, the factor was added to isolated single megakaryocytes in serumless culture induced by interleukin 3 (IL3) to increase in size. The number of megakaryocytes increasing in size in response to IL 3 exposure was reduced from 68% to 20% when both factors were simultaneously added to cultures. Colony assays showed that megakaryocytic and granulocyte- macrophage colony detection was inhibited at picomolar concentrations of the factor. These data suggest that TGF-beta is a potent in vitro inhibitor of the murine megakaryocytic lineage, although its effects are not limited to this lineage.

scholarly journals Garlic Extract: Inhibition of Biochemical and Biophysical Changes in Glycated HSA

2021 ◽  
Vol 11 (22) ◽  
pp. 11028
Author(s):  
Mohd W. A. Khan ◽  
Ahmed A. Otaibi ◽  
Arwa F. M. Alhumaid ◽  
Abdulmohsen K. D. Alsukaibi ◽  
Asma K. Alshamari ◽  
...  
Keyword(s):  
Structural Changes ◽  
Therapeutic Potential ◽  
Inhibitory Effect ◽  
Significant Inhibition ◽  
Garlic Extract ◽  
Diabetic Patients ◽  
Age Related ◽  
Health Complications ◽  
Biophysical Changes

Glycation of various biomolecules contributes to structural changes and formation of several high molecular weight fluorescent and non-fluorescent, advanced glycation end products (AGEs). AGEs and glycation are involved in various health complications. Synthetic medicines, including metformin, have several adverse effects. Natural products and their derivatives are used in the treatment of various diseases due to their significant therapeutic qualities. Allium sativum (garlic) is used in traditional medicines because of its antioxidant, anti-inflammatory, and anti-diabetic properties. This study aimed to determine the anti-glycating and AGEs inhibitory activities of garlic. Biochemical and biophysical analyses were performed for in vitro incubated human serum albumin (HSA) with 0.05 M of glucose for 1, 5, and 10 weeks. Anti-glycating and AGEs inhibitory effect of garlic was investigated in glycated samples. Increased biochemical and biophysical changes were observed in glycated HSA incubated for 10 weeks (G-HSA-10W) as compared to native HSA (N-HSA) as well as glycated HSA incubated for 1 (G-HSA-1W) and 5 weeks (G-HSA-5W). Garlic extract with a concentration of ≥6.25 µg/mL exhibited significant inhibition in biophysical and biochemical changes of G-HSA-10W. Our findings demonstrated that garlic extract has the ability to inhibit biochemical and biophysical changes in HSA that occurred due to glycation. Thus, garlic extract can be used against glycation and AGE-related health complications linked with chronic diseases in diabetic patients due to its broad therapeutic potential.

Granulocyte Adherence is Inhibited by Radiographic Contrast Media in Vitro

1992 ◽  
Vol 33 (4) ◽  
pp. 379-383 ◽  
Author(s):  
F. Rasmussen ◽  
S. Antonsen ◽  
J. Georgsen
Keyword(s):  
Contrast Media ◽  
Whole Blood ◽  
Inhibitory Effect ◽  
Significant Inhibition ◽  
Autologous Plasma ◽  
Radiographic Contrast ◽  
Radiographic Contrast Media ◽  
Meglumine Diatrizoate ◽  
High Concentrations

Different amounts of diatrizoate, ioxaglate, iohexol, iodixanol, NaCl 1000 mOsm/kg, mannitol 1098 mOsm/kg, and meglumine (meglumine concentrations corresponding to the content in the diatrizoate solutions) were added to either whole blood or a suspension of granulocytes in autologous plasma, and the adherence to nylon fibers was determined. At high concentrations all the investigated contrast media (CM) inhibited granulocyte adherence. The degree of inhibition was significantly greater when the ionic CM diatrizoate and ioxaglate were used, as compared with the nonionic media. Meglumine solutions at high concentrations also inhibited adherence but significantly less than diatrizoate solutions containing the same amount of meglumine. Diatrizoate showed the greatest inhibitory effect on granulocyte adherence, and significant inhibition could be detected even with a 1.25% solution.

scholarly journals Synthesis and In Vitro Screening of Novel Heterocyclic β-d-Gluco- and β-d-Galactoconjugates as Butyrylcholinesterase Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2833
Author(s):  
Krešimir Baumann ◽  
Lorena Kordić ◽  
Marko Močibob ◽  
Goran Šinko ◽  
Srđanka Tomić
Keyword(s):  
Active Site ◽  
Kinetic Studies ◽  
Inhibitory Effect ◽  
In Vitro Screening ◽  
Sugar Moiety ◽  
Brain Barrier Permeability ◽  
The Central Nervous System ◽  
Key Residues ◽  
Micromolar Range

The development of selective butyrylcholinesterase (BChE) inhibitors may improve the treatment of Alzheimer’s disease by increasing lower synaptic levels of the neurotransmitter acetylcholine, which is hydrolysed by acetylcholinesterase, as well as by overexpressed BChE. An increase in the synaptic levels of acetylcholine leads to normal cholinergic neurotransmission and improved cognitive functions. A series of 14 novel heterocyclic β-d-gluco- and β-d-galactoconjugates were designed and screened for inhibitory activity against BChE. In the kinetic studies, 4 out of 14 compounds showed an inhibitory effect towards BChE, with benzimidazolium and 1-benzylbenzimidazolium substituted β-d-gluco- and β-d-galacto-derivatives in a 10–50 micromolar range. The analysis performed by molecular modelling indicated key residues of the BChE active site, which contributed to a higher affinity toward the selected compounds. Sugar moiety in the inhibitor should enable better blood–brain barrier permeability, and thus increase bioavailability in the central nervous system of these compounds.

Beta-1 adrenergic inhibition of kallikrein release from rat kidney cortical slices

1990 ◽  
Vol 258 (5) ◽  
pp. F1425-F1431
Author(s):  
J. P. Girolami ◽  
J. L. Bascands ◽  
P. Valet ◽  
C. Pecher ◽  
G. Cabos
Keyword(s):  
De Novo ◽  
Rat Kidney ◽  
Inhibitory Effect ◽  
Significant Inhibition ◽  
Sodium Diet ◽  
Kidney Slices ◽  
Low Sodium Diet ◽  
Rat Cortical Slices ◽  
Cortical Slices

Renal storage; release, and biosynthesis of kallikrein were studied using rat cortical slices. This model permitted the study of the direct effect of norepinephrine on the renal kallikrein system in the absence of changes in perfusion pressure. Kallikrein was measured by its kininogenase activity and its direct immunoreactive concentration. Under basal conditions, rat kidney cortical slices synthesize and release glandular kallikrein in vitro at a linear rate for up to 40 min. Kidney slices obtained from rats fed with a low-sodium diet (LS) released more kallikrein into the incubation medium than slices from rats under a normal-sodium diet (NS). Cycloheximide and incubation at 4 degrees C inhibited the release and the biosynthesis of kallikrein independently of the sodium diet. Addition of norepinephrine (NE, 10(-8)-10(-5) M) induced a similar dose-dependent inhibition of kallikrein secretion, which reached -27 +/- 8% in NS rats and -29 +/- 9% in LS rats with 10(-7) M NE. This inhibition of the secretion was associated with an increase in tissue kallikrein concentration in kidney slices from rats on both sodium diets. However, a significant inhibition of the calculated net de novo synthesis was only observed in LS rats. In both groups of animals the ratio of active to total kallikrein was unchanged. The inhibitory effect of kallikrein secretion by NE was never modified in the presence of the alpha-antagonist phentolamine (10(-6) M). In contrast the beta-antagonist propranolol (10(-6) M) prevented the inhibitory effect of 10(-7) M NE.(ABSTRACT TRUNCATED AT 250 WORDS)

Sign in / Sign up

Export Citation Format

Share Document