scholarly journals Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 329
Author(s):  
Daniel Chavarria ◽  
Ophelie Da Silva ◽  
Sofia Benfeito ◽  
Sandra Barreiro ◽  
Jorge Garrido ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Antioxidant Properties ◽  
Neuroblastoma Cells ◽  
Oxidation Potential ◽  
Fine Tuning ◽  
Mitochondrial Oxidative Stress ◽  
Electric Eel ◽  
Ic50 Values ◽  
System Extension ◽  
Inhibition Potency

Neurotransmitter depletion and mitochondrial dysfunction are among the multiple pathological events that lead to neurodegeneration. Following our previous studies related with the development of multitarget mitochondriotropic antioxidants, this study aims to evaluate whether the π-system extension on the chemical scaffolds of AntiOXCIN2 and AntiOXCIN3 affects their bioactivity and safety profiles. After the synthesis of four triphenylphosphonium (TPP+) conjugates (compounds 2–5), we evaluated their antioxidant properties and their effect on neurotransmitter-metabolizing enzymes. All compounds were potent equine butyrylcholinesterase (eqBChE) and moderate electric eel acetylcholinesterase (eeAChE) inhibitors, with catechols 4 and 5 presenting lower IC50 values than AntiOXCIN2 and AntiOXCIN3, respectively. However, differences in the inhibition potency and selectivity of compounds 2–5 towards non-human and human cholinesterases (ChEs) were observed. Co-crystallization studies with compounds 2–5 in complex with human ChEs (hChEs) showed that these compounds exhibit different binging modes to hAChE and hBChE. Unlike AntiOXCINs, compounds 2–5 displayed moderate human monoamine oxidase (hMAO) inhibitory activity. Moreover, compounds 4 and 5 presented higher ORAC-FL indexes and lower oxidation potential values than the corresponding AntiOXCINs. Catechols 4 and 5 exhibited broader safety windows in differentiated neuroblastoma cells than benzodioxole derivatives 2 and 3. Compound 4 is highlighted as a safe mitochondria-targeted antioxidant with dual ChE/MAO inhibitory activity. Overall, this work is a contribution for the development of dual therapeutic agents addressing both mitochondrial oxidative stress and neurotransmitter depletion.

scholarly journals Novel hybrids of oxoisoaporphine-tryptamine as acetylcholinesterase-induced β-amyloid aggregation inhibitors with improved antioxidant properties

2015 ◽  
Vol 80 (2) ◽  
pp. 127-136 ◽  
Author(s):  
Hai-Tao Zhao ◽  
Shu-Ming Zhong ◽  
Jiang-Ke Qin ◽  
Huang Tang
Keyword(s):  
Inhibitory Activity ◽  
Antioxidant Properties ◽  
Drug Candidates ◽  
Ache Inhibitors ◽  
Ache Inhibitory Activity ◽  
Ic50 Values ◽  
Aggregation Inhibitors ◽  
Β Amyloid ◽  
Micromolar Range

A series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their antioxidant ability and inhibitory potency on AChE and AChE-induced b-amyloid (Ab) aggregation. The new hybrids consist of a unit of 1-azabenzanthrone and a tryptamine or its derivative, connected through a a,w - alkyldiamide bridge. These hybrids exhibit moderate AChE inhibitory activity with IC50 values in the micromolar range and significant in vitro inhibitory activity toward the AChE-induced Ab aggregation. Moreover, six out of the nine hybrids of this series exhibit a higher oxygen radical absorbance capacity than trolox, which makes them promising anti-Alzheimer drug candidates.

Inhibition of Protein Tyrosine Phosphatase 1B by Lutein Derivatives isolated from Mexican Oregano (Lippia graveolens)

2018 ◽  
Vol 17 (3) ◽  
pp. 134-139
Author(s):  
R.M. Perez-Gutierrez
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Inhibitory Activity ◽  
Spectroscopic Data ◽  
Methanol Extract ◽  
Tyrosine Phosphatase ◽  
Positive Control ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Ic50 Value ◽  
Ic50 Values

Methanol extract from Lippia graveolens (Mexican oregano) was studied in order to identify inhibitory bioactives for protein tyrosine phosphatase 1B (PTP1B). Known flavone as lutein (1), and another flavone glycoside such as lutein-7-o-glucoside (2), 6-hydroxy-lutein-7-ohexoside (3) and lutein-7-o-ramnoide (4) were isolated from methanol extract of aerial parts of the Lippia graveolens. All isolates were identified based on extensive spectroscopic data analysis, including UV, IR, NMR, MS and compared with spectroscopic data previously reported. These flavones were evaluated for PTP1B inhibitory activity. Among them, compounds 1 and 3 displayed potential inhibitory activity against PTP1B with IC50 values of 7.01 ± 1.25 μg/ml and 18.4 μg/ml, respectively. In addition, compound 2 and 4 showed moderate inhibitory activity with an IC50 value of 23.8 ± 6.21 and 67.8 ± 5.80 μg/ml respectively. Among the four compounds, luteolin was found to be the most potent PTP1B inhibitor compared to the positive control ursolic acid, with an IC50 value of 8.12 ± 1.06 μg/ml. These results indicate that flavonoids constituents contained in Lippia graveolens can be considered as a natural source for the treatment of type 2 diabetes.

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

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.

scholarly journals Inhibitory Effects of Secondary Metabolites from the Lichen Stereocaulon evolutum on Protein Tyrosine Phosphatase 1B

Planta Medica ◽  
2021 ◽  
Author(s):  
Birgit Waltenberger ◽  
Françoise Lohézic-Le Dévéhat ◽  
Thi Huyen Vu ◽  
Olivier Delalande ◽  
Claudia Lalli ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Inhibitory Activity ◽  
Tyrosine Phosphatase ◽  
Inhibitory Effect ◽  
Positive Control ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Ic50 Values ◽  
A Cell

AbstractProtein tyrosine phosphatase 1B plays a significant role in type 2 diabetes mellitus and other diseases and is therefore considered a new drug target. Within this study, an acetone extract from the lichen Stereocaulon evolutum was identified to possess strong protein tyrosine phosphatase 1B inhibition in a cell-free assay (IC50 of 11.8 µg/mL). Fractionation of this bioactive extract led to the isolation of seven known molecules belonging to the depsidones and the related diphenylethers and one new natural product, i.e., 3-butyl-3,7-dihydroxy-5-methoxy-1(3H)-isobenzofurane. The isolated compounds were evaluated for their inhibition of protein tyrosine phosphatase 1B. Two depsidones, lobaric acid and norlobaric acid, and the diphenylether anhydrosakisacaulon A potently inhibited protein tyrosine phosphatase 1B with IC50 values of 12.9, 15.1, and 16.1 µM, respectively, which is in the range of the protein tyrosine phosphatase 1B inhibitory activity of the positive control ursolic acid (IC50 of 14.4 µM). Molecular simulations performed on the eight compounds showed that i) a contact between the molecule and the four main regions of the protein is required for inhibitory activity, ii) the relative rigidity of the depsidones lobaric acid and norlobaric acid and the reactivity related to hydrogen bond donors or acceptors, which interact with protein tyrosine phosphatase 1B key amino acids, are involved in the bioactivity on protein tyrosine phosphatase 1B, iii) the cycle opening observed for diphenylethers decreased the inhibition, except for anhydrosakisacaulon A where its double bond on C-8 offsets this loss of activity, iv) the function present at C-8 is a determinant for the inhibitory effect on protein tyrosine phosphatase 1B, and v) the more hydrogen bonds with Arg221 there are, the more anchorage is favored.

scholarly journals Scale-Up Preparation of Crocins I and II from Gardeniajasminoides by a Two-Step Chromatographic Approach and Their Inhibitory Activity Against ATP Citrate Lyase

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3137
Author(s):  
Shuguang Guan ◽  
Qiaoli Pu ◽  
Yinan Liu ◽  
Honghong Wu ◽  
Wenbo Yu ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
High Speed ◽  
Scale Up ◽  
Cost Effective ◽  
Atp Citrate Lyase ◽  
Gardenia Jasminoides ◽  
Citrate Lyase ◽  
Human Disorders ◽  
Ic50 Values ◽  
Counter Current

Crocins are highly valuable natural compounds for treating human disorders, and they are also high-end spices and colorants in the food industry. Due to the limitation of obtaining this type of highly polar compound, the commercial prices of crocins I and II are expensive. In this study, macroporous resin column chromatography combined with high-speed counter-current chromatography (HSCCC) was used to purify crocins I and II from natural sources. With only two chromatographic steps, both compounds were simultaneously isolated from the dry fruit of Gardenia jasminoides, which is a cheap herbal medicine distributed in a number of countries. In an effort to shorten the isolation time and reduce solvent usage, forward and reverse rotations were successively utilized in the HSCCC isolation procedure. Crocins I and II were simultaneously obtained from a herbal resource with high recoveries of 0.5% and 0.1%, respectively, and high purities of 98.7% and 99.1%, respectively, by HPLC analysis. The optimized preparation method was proven to be highly efficient, convenient, and cost-effective. Crocins I and II exhibited inhibitory activity against ATP citrate lyase, and their IC50 values were determined to be 36.3 ± 6.24 and 29.7 ± 7.41 μM, respectively.

scholarly journals In Vitro Antimicrobial, Antioxidant and Anticancer Activities of Egyptian Citrus Beebread

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2433
Author(s):  
Nesren Elsayed ◽  
Hatem Sharaf El-Din ◽  
Ammar B. Altemimi ◽  
Hanaa Y. Ahmed ◽  
Anubhav Pratap-Singh ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Inhibitory Activity ◽  
Nutritive Value ◽  
Antioxidant Properties ◽  
Antitumor Agent ◽  
Monounsaturated Fatty Acids ◽  
Free Sugar ◽  
Natural Food ◽  
Anticancer Activities

In this study, Egyptian beebread (EBB) was investigated for its nutritive value, chemical composition, antioxidant properties, antimicrobial and antitumor activities. Results indicated that EBB was a good source of protein (23.58 ± 0.183 g/100 g BB), total free sugar (20.266 ± 0.930) and potassium (290.202 ± 2.645 mg/100 g). Additionally, 14 fatty acids were identified in EBB, wherein polyunsaturated and monounsaturated fatty acids represented 51.06% ± 0.09% and 9.86% ± 0.01%, respectively. The EBB extract exhibited almost 400% better antiradical activity than BHT, with IC50 of EBB extract being 10.7 µg/mL compared to 39.5 µg/mL for BHT. EBB exhibited higher inhibitory activity than the reference compound against Staphylococcus aureus and Escherichia coli, followed by Bacillus subtilis. No inhibitory activity was observed against Aspergillus Niger. Additionally, the highest inhibitory activity was recorded against Caco-2 cells, followed by PC3 and HepG-2 cancer cell lines with IC50 values 262, 314 and 386 μg/mL, respectively. These findings establish the potential of EBB as an antioxidant, antimicrobial and antitumor agent, with possible applications as natural food supplements and natural preservatives.

scholarly journals Mammalian Arginase Inhibitory Activity of Methanolic Extracts and Isolated Compounds from Cyperus Species

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1694
Author(s):  
Kamel Arraki ◽  
Perle Totoson ◽  
Alain Decendit ◽  
Andy Zedet ◽  
Justine Maroilley ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Methanolic Extract ◽  
Significant Inhibition ◽  
Isolation And Identification ◽  
Vasorelaxant Effect ◽  
Methanolic Extracts ◽  
Phytochemical Investigation ◽  
Ic50 Values ◽  
First Time

Polyphenolic enriched extracts from two species of Cyperus, Cyperus glomeratus and Cyperus thunbergii, possess mammalian arginase inhibitory capacities, with the percentage inhibition ranging from 80% to 95% at 100 µg/mL and 40% to 64% at 10 µg/mL. Phytochemical investigation of these species led to the isolation and identification of two new natural stilbene oligomers named thunbergin A-B (1–2), together with three other stilbenes, trans-resveratrol (3), trans-scirpusin A (4), trans-cyperusphenol A (6), and two flavonoids, aureusidin (5) and luteolin (7), which were isolated for the first time from C.thunbergii and C. glomeratus. Structures were established on the basis of the spectroscopic data from MS and NMR experiments. The arginase inhibitory activity of compounds 1–7 was evaluated through an in vitro arginase inhibitory assay using purified liver bovine arginase. As a result, five compounds (1, 4–7) showed significant inhibition of arginase, with IC50 values between 17.6 and 60.6 µM, in the range of those of the natural arginase inhibitor piceatannol (12.6 µM). In addition, methanolic extract from Cyperus thunbergii exhibited an endothelium and NO-dependent vasorelaxant effect on thoracic aortic rings from rats and improved endothelial dysfunction in an adjuvant-induced arthritis rat model.

Novel photochromic inhibitor for mitotic kinesin Eg5 which forms multiple isomerization states

2021 ◽  
Author(s):  
Islam Md Alrazi ◽  
Kei Sadakane ◽  
Shinsaku Maruta
Keyword(s):  
Inhibitory Activity ◽  
Molecular Motor ◽  
The Novel ◽  
Precise Control ◽  
Atpase Assay ◽  
Ic50 Value ◽  
Motor Activities ◽  
Ic50 Values ◽  
Kinesin Eg5 ◽  
Mitotic Kinesin Eg5

Abstract The mitotic kinesin Eg5 is a plus-end directed homotetrameric molecular motor essential for the formation of bipolar spindles during cell division. Kinesin Eg5 is overexpressed in cancer cells and hence considered as a target for cancer therapy; the inhibitors specific for Eg5 have been developed as anticancer drugs. In this study, we synthesized a novel functional photoresponsive inhibitor composed of spiropyran and azobenzene derivatives to control Eg5 function with multistage inhibitory activity accompanied by the formation of different isomerization states. The photochromic inhibitor spiropyran-sulfo-azobenzene (SPSAB) exhibited three isomerization states: spiro (SP)-trans, merocyanine (MC)-cis and MC-trans, upon exposure to visible light, ultraviolet and in the dark, respectively. SPSAB-induced reversible changes in the inhibitory activity of ATPase and motor activities correlating with photoisomerization among the three states. Among the three isomerization states of SPSAB, the SP-trans isomer showed potent inhibitory activity at an IC50 value of 30 µM in the basal ATPase assay. MC-trans and MC-cis exhibited less inhibitory activity at IC50 values of 38 and 86 µM, respectively. The results demonstrated that the novel photochromic inhibitor enabled precise control of Eg5 function at three different levels using light irradiation.

scholarly journals ANTIDIABETIC AND ANTIOXIDANT ACTIVITIES OF ETHANOLIC EXTRACT OF PIPER BETLE L. LEAVES IN CATFISH, CLARIAS GARIEPINUS

2018 ◽  
Vol 11 (3) ◽  
pp. 194 ◽  
Author(s):  
Kavitha S ◽  
Parthasarathi Perumal
Keyword(s):  
Antioxidant Activities ◽  
Clarias Gariepinus ◽  
Antioxidant Properties ◽  
Radical Scavenging ◽  
Metformin Hydrochloride ◽  
Piper Betle ◽  
Phytochemical Analysis ◽  
Standard Drug ◽  
Antioxidant Agents ◽  
Ic50 Values

 Objective: The present study was undertaken to assess the α-amylase inhibitory activity and antidiabetic experimental catfish model and antioxidant properties of Piper betle L. ethanolic (PBE) extract.Methods: The phytochemical analysis of PBE extract was performed. The PBE extract was tested for their inhibitory effect on the α-amylase assay, which compared to the control, acarbose. The absorbance was read at 540 nm using a spectrophotometer, and IC50 values were calculated. In this present investigation, diabetes mellitus was induced in catfish, Clarias gariepinus by epaxial musculature injection to glucose and standard drug, Metformin hydrochloride. After 24-h incubation, the treated fishes were dissected, and the blood, liver, tissue samples, and epaxial musculature regions were collected. In addition, the antioxidant properties of PBE were determined by 2,2-diphenyl-l-picrylhydrazyl (DPPH) radical scavenging and 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging (ABTS) assays.Results: The phytochemical screening of PBE revealed the presence of alkaloid, flavonoids, tannins, phenol, glycosides, sterols, saponins, and quinines. Furthermore, the values of (μg/ml) 3.038 and 7.672 α-amylase enzyme inhibition were excellent activity when compared to the acarbose. Moreover, elevated the glucose level (mg/dl) was estimated in blood 1.9±0.35, liver 0.5±0.25, tissue 0.2±0.25, and epaxial musculature 0.8±0.2 after 24-h incubation. The antioxidant effect of maximum activity was found in PBE; IC50 values (μg/ml) of DPPH and ABTS were 9.362 and 6.606, respectively.Conclusions: These studies might be responsible for the P. betle L. that was used as the new source of antidiabetic and antioxidant agents. 

Inhibitory Activity of Extracts from Mycelia Materials of Several Mushrooms on the Angiotensin I-Converting Enzyme

2012 ◽  
Vol 610-613 ◽  
pp. 3541-3544
Author(s):  
Pei Sheng Yan ◽  
Xiu Jun Gao
Keyword(s):  
Liquid Medium ◽  
Inhibitory Activity ◽  
Water Extract ◽  
Angiotensin I ◽  
Water Extracts ◽  
Angiotensin I Converting Enzyme ◽  
Ic50 Value ◽  
Ic50 Values ◽  
The Difference ◽  
Ace Inhibitory

ACE inhibitory activities of water extracts from mycelia of 6 kinds of mushrooms in liquid fermentation were investigated. All strains cultivated in shaking flask containing liquid medium, and yield of mycelia ranged from 0.051 to 1.392 g mycelia/day/L liquid medium in average. Resulting mycelia were extracted with distilled water at 50°Cfor 200 min, and the yield of water extracts from mycelia ranged from 287.475 to 490.088 mg/g dried mycelia. These water extracts were used to assay their ACE inhibitory activity. Results showed that their IC50 values ranged from 1.277 to 5.250 mg/ml. The difference among IC50 values of these water extracts were significant (p<0.05 or p<0.001). Lactarius camphorates (IC50: 1.646±0.061mg/mL) was the specie which had relatively lower IC50 value than others, as well as relatively higher water extract yield. The results highlighted the potential for making antihypertensive functional foods or drugs from liquid cultured mycelia of Lactarius camphorates.

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