scholarly journals New Tetrahydroacridine Hybrids with Dichlorobenzoic Acid Moiety Demonstrating Multifunctional Potential for the Treatment of Alzheimer’s Disease

2020 ◽  
Vol 21 (11) ◽  
pp. 3765
Author(s):  
Kamila Czarnecka ◽  
Małgorzata Girek ◽  
Przemysław Wójtowicz ◽  
Paweł Kręcisz ◽  
Robert Skibiński ◽  
...  
Keyword(s):  
Active Compound ◽  
Inhibitory Activity ◽  
Docking Study ◽  
Free Radical Scavenger ◽  
Neuroprotective Activity ◽  
Radical Scavenger ◽  
Catalytic Active Site ◽  
Aβ Aggregation ◽  
Ic50 Values

A series of new tetrahydroacridine and 3,5-dichlorobenzoic acid hybrids with different spacers were designed, synthesized, and evaluated for their ability to inhibit both cholinesterase enzymes. Compounds 3a, 3b, 3f, and 3g exhibited selective butyrylcholinesterase (EqBuChE) inhibition with IC50 values ranging from 24 to 607 nM. Among them, compound 3b was the most active (IC50 = 24 nM). Additionally, 3c (IC50 for EeAChE = 25 nM and IC50 for EqBuChE = 123 nM) displayed dual cholinesterase inhibitory activity and was the most active compound against acetylcholinesterase (AChE). Active compound 3c was also tested for the ability to inhibit Aβ aggregation. Theoretical physicochemical properties of the compounds were calculated using ACD Labs Percepta and Chemaxon. A Lineweaver–Burk plot and docking study showed that 3c targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Moreover, 3c appears to possess neuroprotective activity and could be considered a free-radical scavenger. In addition, 3c did not cause DNA damage and was found to be less toxic than tacrine after oral administration; it also demonstrated little inhibitory activity towards hyaluronidase (HYAL), which may indicate that it possesses anti-inflammatory properties. The screening for new in vivo interactions between 3c and known receptors was realized by yeast three-hybrid technology (Y3H).

scholarly journals Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer’s Disease

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2540 ◽  
Author(s):  
Wenhao Wu ◽  
Xintong Liang ◽  
Guoquan Xie ◽  
Langdi Chen ◽  
Weixiong Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Docking Study ◽  
High Concentration ◽  
Molecular Docking Study ◽  
Catalytic Active Site ◽  
Aβ Aggregation ◽  
Ic50 Values ◽  
Targeted Inhibitors ◽  
Further Development

A series of novel ligustrazine derivatives 8a–r were designed, synthesized, and evaluated as multi-targeted inhibitors for anti-Alzheimer’s disease (AD) drug discovery. The results showed that most of them exhibited a potent ability to inhibit both ChEs, with a high selectivity towards AChE. In particular, compounds 8q and 8r had the greatest inhibitory abilities for AChE, with IC50 values of 1.39 and 0.25 nM, respectively, and the highest selectivity towards AChE (for 8q, IC50 BuChE/IC50 AChE = 2.91 × 106; for 8r, IC50 BuChE/IC50 AChE = 1.32 × 107). Of note, 8q and 8r also presented potent inhibitory activities against Aβ aggregation, with IC50 values of 17.36 µM and 49.14 µM, respectively. Further cellular experiments demonstrated that the potent compounds 8q and 8r had no obvious cytotoxicity in either HepG2 cells or SH-SY5Y cells, even at a high concentration of 500 μM. Besides, a combined Lineweaver-Burk plot and molecular docking study revealed that these compounds might act as mixed-type inhibitors to exhibit such effects via selectively targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChEs. Taken together, these results suggested that further development of these compounds should be of great interest.

Anticholinesterase Activity of Cinnamic Acids Derivatives: In Vitro, In Vivo Biological Evaluation, and Docking Study

2020 ◽  
Vol 17 (8) ◽  
pp. 965-982
Author(s):  
Shahrzad Ghafary ◽  
Hamid Nadri ◽  
Mohammad Mahdavi ◽  
Alireza Moradi ◽  
Tahmineh Akbarzadeh ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Kinetic Studies ◽  
Docking Study ◽  
Biological Evaluation ◽  
In Vivo Studies ◽  
Neuroprotective Activity ◽  
Inhibitory Activities ◽  
Ellman’S Method

Background: Acetylcholine deficiency in the hippocampus and cortex, aggregation of amyloid-beta, and beta-secretase overactivity have been introduced as the main reasons in the formation of Alzheimer’s disease. Objective: A new series of cinnamic derived acids linked to 1-benzyl-1,2,3-triazole moiety were designed, synthesized, and evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities. Methods: Colorimetric Ellman’s method was used for the determination of IC50% of AchE and BuChE inhibitory activity. The kinetic studies, neuroprotective activity, BACE1 inhibitory activity, evaluation of inhibitory potency on Aβ1-42 self-aggregation induced by AchE, and docking study were performed for studying the mechanism of action. Results: Some of the synthesized compounds, compound 7b-4 ((E)-3-(3,4-dimethoxyphenyl)-N-((1- (4-fluorobenzyl)-1H-1,2,3-triazole-4-yl) methyl) acrylamide) depicted the most potent acetylcholinesterase inhibitory activities ( IC50 = 5.27 μM ) and compound 7a-1 (N- ( (1- benzyl- 1H- 1, 2, 3- triazole - 4-yl) methyl) cinnamamide) demonstrated the most potent butyrylcholinesterase inhibitory activities (IC50 = 1.75 μM). Compound 7b-4 showed neuroprotective and β-secretase (BACE1) inhibitory activitiy. In vivo studies of compound 7b-4 in Scopolamine-induced dysfunction confirmed memory improvement. Conculusion: It should be noted that molecular modeling (compounds 7b-4 and 7a-1) and kinetic studies (compounds 7a-1 and 7b-4) showed that these synthesis compounds interacted simultaneously with both the catalytic site (CS) and peripheral anionic site (PAS) of AChE and BuChE.

OPTIMASI KONDISI EKSTRAKSI SENYAWA AKTIF ANTIOKSIDAN DARI BIJI ANGGUR

2019 ◽  
Vol 3 (2) ◽  
pp. 35
Author(s):  
Kartini Kartini ◽  
Azminah Azminah
Keyword(s):  
Free Radical ◽  
Optimum Condition ◽  
Active Compound ◽  
Grape Seed ◽  
Free Radical Scavenger ◽  
Water Bath ◽  
Radical Scavenger ◽  
Optimum Conditions ◽  
Ethanolic Solution ◽  
Reduced Pressure

In order to prepare standardized extract, optimization of extraction conditions of grape seed has been done. These conditions are type of menstrum (50, 70 and 96% of ethanolic solution), length of extraction (1, 2 and 4 hours) also method of evaporation (reduced pressure and opened air). Activity on free radical scavenger used as parameters to determine optimum conditions. Based on EC50 (concentration which scavenge 50% amount of free radical) can be concluded that optimum condition for extracting antioxidant active compound from grape seed are 70% ethanolic solution as menstrum, length of extraction 1 hour and evaporation on opened air use water bath.

scholarly journals In VitroInhibitory and Cytotoxic Activity of MFM 501, a Novel Codonopsinine Derivative, against Methicillin-ResistantStaphylococcus aureusClinical Isolates

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Saiful Azmi Johari ◽  
Mastura Mohtar ◽  
Sharifah Aminah Syed Mohammad ◽  
Rohana Sahdan ◽  
Zurina Shaameri ◽  
...  
Keyword(s):  
Active Compound ◽  
Inhibitory Activity ◽  
Normal Cell ◽  
Bactericidal Effect ◽  
Selectivity Index ◽  
Cytotoxicity Activity ◽  
A Value ◽  
Value Determination ◽  
Mic Value

28 new pyrrolidine types of compounds as analogues for natural polyhydroxy alkaloids of codonopsinine were evaluated for their anti-MRSA activity using MIC and MBC value determination assay against a panel ofS. aureusisolates. One pyrrolidine compound, MFM 501, exhibited good inhibitory activity with MIC value of 15.6 to 31.3 μg/mL against 55S. aureusisolates (43 MRSA and 12 MSSA isolates). The active compound also displayed MBC values between 250 and 500 μg/mL against 58S. aureusisolates (45 MRSA and 13 MSSA isolates) implying that MFM 501 has a bacteriostatic rather than bactericidal effect against both MRSA and MSSA isolates. In addition, MFM 501 showed no apparent cytotoxicity activity towards three normal cell lines (WRL-68, Vero, and 3T3) with IC50values of >625 µg/mL. Selectivity index (SI) of MFM 501 gave a value of >10 suggesting that MFM 501 is significant and suitable for furtherin vivoinvestigations. These results suggested that synthetically derived intermediate compounds based on natural products may play an important role in the discovery of new anti-infective agents against MRSA.

scholarly journals Discovery of Tricyclic Pyranochromenone as Novel Bruton’s Tyrosine Kinase Inhibitors with In Vivo Antirheumatic Activity

2020 ◽  
Vol 21 (21) ◽  
pp. 7919
Author(s):  
Hyewon Cho ◽  
Eun Lee ◽  
Hye Ah Kwon ◽  
Lee Seul ◽  
Hui-Jeon Jeon ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Docking Study ◽  
Bruton’S Tyrosine Kinase ◽  
Collagen Induced Arthritis ◽  
Bruton's Tyrosine Kinase ◽  
Ic50 Values ◽  
Novel Scaffold ◽  
Btk Inhibitors

Bruton’s tyrosine kinase (BTK) is an attractive target for treating patients with B cell malignancies and autoimmune diseases. Many BTK inhibitors have been identified; however, like other kinase inhibitors, they lack diversity in their core structures. Therefore, it is important to secure a novel scaffold that occupies the adenine-binding site of BTK. We screened an in-house library of natural products and their analogs via a biochemical assay to identify a novel scaffold for targeting BTK. A pyranochromenone scaffold, derived from a natural active component decursin, was found to be effective at targeting BTK and was selected for further optimization. A series of pyranochromenone analogs was synthesized through the modification of pyranochromenone at the C7 position. Pyranochromenone compounds with an electrophilic warhead exhibited promising BTK inhibitory activity, with IC50 values in the range of 0.5–0.9 µM. A docking study of the representative compound 8 provided a reasonable explanation for compound activity. Compound 8 demonstrated good selectivity over other associated kinases and decreased the production of proinflammatory cytokines in THP cells. Moreover, compound 8 presented significant in vivo efficacy in a murine model of collagen-induced arthritis.

scholarly journals A New Tyrosinase Inhibitor from the Red Alga Symphyocladia latiuscula (Harvey) Yamada (Rhodomelaceae)

Marine Drugs ◽  
2019 ◽  
Vol 17 (5) ◽  
pp. 295 ◽  
Author(s):  
Pradeep Paudel ◽  
Aditi Wagle ◽  
Su Hui Seong ◽  
Hye Jin Park ◽  
Hyun Ah Jung ◽  
...  
Keyword(s):  
Methyl Ether ◽  
Inhibitory Activity ◽  
Biological Activities ◽  
Docking Study ◽  
Red Alga ◽  
Moderate Activity ◽  
Molecular Docking Study ◽  
Tyrosinase Inhibitory Activity ◽  
Ic50 Values ◽  
Catalytic Hydrogen

A marine red alga, Symphyocladia latiuscula (Harvey) Yamada (Rhodomelaceae), is a rich source of bromophenols with a wide array of biological activities. This study investigates the anti-tyrosinase activity of the alga. Moderate activity was demonstrated by the methanol extract of S. latiuscula, and subsequent column chromatography identified three bromophenols: 2,3,6-tribromo-4,5-dihydroxybenzyl methyl alcohol (1), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (2), and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether) (3). Bromophenols 1 and 3 exhibited potent competitive tyrosinase inhibitory activity against l-tyrosine substrates, with IC50 values of 10.78 ± 0.19 and 2.92 ± 0.04 μM, respectively. Against substrate l-3,4-dihydroxyphenylalanine (l-DOPA), compounds 1 and 3 demonstrated moderate activity, while 2 showed no observable effect. The experimental data were verified by a molecular docking study that found catalytic hydrogen and halogen interactions were responsible for the activity. In addition, compounds 1 and 3 exhibited dose-dependent inhibitory effects in melanin and intracellular tyrosinase levels in α-melanocyte-stimulating hormone (α-MSH)-induced B16F10 melanoma cells. Compounds 3 and 1 were the most effective tyrosinase inhibitors. In addition, increasing the bromine group number increased the mushroom tyrosinase inhibitory activity.

scholarly journals Exploring Aurone Derivatives as Potential Human Pancreatic Lipase Inhibitors through Molecular Docking and Molecular Dynamics Simulations

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4657
Author(s):  
Phuong Thuy Viet Nguyen ◽  
Han Ai Huynh ◽  
Dat Van Truong ◽  
Thanh-Dao Tran ◽  
Cam-Van Thi Vo
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Pancreatic Lipase ◽  
Inhibitory Activity ◽  
Dynamics Simulation ◽  
Stable Complex ◽  
Catalytic Active Site ◽  
Dynamics Simulations

Inhibition of human pancreatic lipase, a crucial enzyme in dietary fat digestion and absorption, is a potent therapeutic approach for obesity treatment. In this study, human pancreatic lipase inhibitory activity of aurone derivatives was explored by molecular modeling approaches. The target protein was human pancreatic lipase (PDB ID: 1LPB). The 3D structures of 82 published bioactive aurone derivatives were docked successfully into the protein catalytic active site, using AutoDock Vina 1.5.7.rc1. Of them, 62 compounds interacted with the key residues of catalytic trial Ser152-Asp176-His263. The top hit compound (A14), with a docking score of −10.6 kcal⋅mol−1, was subsequently submitted to molecular dynamics simulations, using GROMACS 2018.01. Molecular dynamics simulation results showed that A14 formed a stable complex with 1LPB protein via hydrogen bonds with important residues in regulating enzyme activity (Ser152 and Phe77). Compound A14 showed high potency for further studies, such as the synthesis, in vitro and in vivo tests for pancreatic lipase inhibitory activity.

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