In Vitro and In Silico Kinetic Studies of Patented 1,7-diEthyl and 1,7-diMethyl Aminoalkanol Derivatives as New Inhibitors of Acetylcholinesterase

Two aminoalkanol derivatives of 1,7-diEthyl-8,9-diphenyl-4azatricyclo (5.2.1.02,6) dec-8-ene-3,5,10-trione and two derivatives of 1,7-diMethyl-8,9-diphenyl-4-azatricyclo (5.2.1.02.6) dec-8-ene-3,5,10-trione were evaluated in vitro for their inhibition efficacy of acetylcholinesterase. The Km, Vmax, slope angles of Lineweaver–Burk plots, Ki and IC50 values showed that all four aminoalkanol derivatives are competitive inhibitors of acetylcholinesterase whose inhibitory potency depends, to a varying extent, on the nature of the four different substituents present in the main compound structure. Studies have shown that the most potent acetylcholinesterase inhibitors are derivatives containing isopropylamine and/or methyl substituents in their structure. In contrast, dimethylamine and/or ethyl substituents seem to have a weaker, albeit visible, effect on the inhibitory potency of acetylcholinesterase. Additionally, docking studies suggest that studied compounds binds with the peripheral anionic site and not enter into the catalytic pocket due to the presence of the sterically extended substituent.

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Synthesis, in vitro Acetylcholinesterase Inhibitory Activity Evaluation and Docking Investigation of Some Aromatic Chalcones

MedPharmRes ◽

10.32895/ump.mpr.1.1.15/suffix ◽

2017 ◽

Vol 1 (1) ◽

pp. 15-25

Author(s):

Dao Tran ◽

Son Tran ◽

Vi Nguyen ◽

Tri Le ◽

Minh Thai ◽

...

Keyword(s):

Inhibitory Activity ◽

Condensation Reaction ◽

Acetylcholinesterase Inhibitors ◽

Docking Studies ◽

Acetylcholinesterase Inhibitory Activity ◽

Ic50 Value ◽

Ic50 Values ◽

Inhibitory Activities ◽

Ellman’S Method

In this study, a total of twenty chalcones were synthesized via Claisen-Schmidt condensation reaction and evaluated for their in vitro acetylcholinesterase inhibitory activities using Ellman’s method. Molecular docking studies on acetylcholinesterase were performed to elucidate the interactions between these chalcone derivatives and acetylcholinesterase active site at the molecular level. From the series, six compounds (S1-5 and S17) exhibited strong acetylcholinesterase inhibitory activities with IC50 values below 100 µM compared to the parent unsubstituted chalcone. Compound S17 (4’-amino-2-chlorochalcone) showed the strongest acetylcholinesterase inhibitory activity in the investigated group with IC50 value of 36.10 µM. Molecular modeling studies were consistent with the results of in vitro acetylcholinesterase inhibitory activities, and chalcone S17 could be considered as a potential lead compound for the development of new acetylcholinesterase inhibitors.

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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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Synthesis of Novel 1,2,3-Triazole Derivatives of Isocoumarins and 3,4-Dihydroisocoumarin with Potential Antiplasmodial Activity In Vitro

Medicinal Chemistry ◽

10.2174/1573406416666200602161047 ◽

2020 ◽

Vol 16 ◽

Author(s):

Lucas da Silva Santos ◽

Matheus Fillipe Langanke de Carvalho ◽

Ana Claudia de Souza Pinto ◽

Amanda Luisa da Fonseca ◽

Julio César Dias Lopes ◽

...

Keyword(s):

Triazole Ring ◽

Antiplasmodial Activity ◽

World Health ◽

Dipolar Cycloaddition ◽

Terminal Alkynes ◽

The World ◽

Ic50 Values ◽

Derivatives Of ◽

Active Substances

Background: Malaria greatly affects the world health, having caused more than 228 million cases only in 2018. The emergence of drug resistance is one of the main problems in its treatment, demonstrating the urge for the development of new antimalarial drugs. Objective: Synthesis and in vitro antiplasmodial evaluation of triazole compounds derived from isocoumarins and a 3,4- dihydroisocoumarin. Method: The compounds were synthesized in 4 to 6-step reactions with the formation of the triazole ring via the Copper(I)-catalyzed 1,3-dipolar cycloaddition between isocoumarin or 3,4-dihydroisocoumarin azides and terminal alkynes. This key reaction provided compounds with an unprecedented connection of isocoumarin or 3,4-dihydroisocoumarin and the 1,2,3-triazole ring. The products were tested for their antiplasmodial activity against a Plasmodium falciparum chloroquine resistant and sensitive strains (W2 and 3D7, respectively). Results: Thirty-one substances were efficiently obtained by the proposed routes with an overall yield of 25-53%. The active substances in the antiplasmodial test displayed IC50 values ranging from 0.68-2.89 μM and 0.85-2.07 μM against W2 and 3D7 strains, respectively.

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Exploring Diverse-Ring Analogues on Combretastatin A4 (CA-4) Olefin as Microtubule-Targeting Agents

International Journal of Molecular Sciences ◽

10.3390/ijms21051817 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1817 ◽

Cited By ~ 1

Author(s):

Ming-Yu Song ◽

Qiu-Rui He ◽

Yi-Lin Wang ◽

Hao-Ran Wang ◽

Tian-Cheng Jiang ◽

...

Keyword(s):

Hepg2 Cells ◽

Annexin V ◽

Docking Studies ◽

Cytotoxic Agents ◽

Tubulin Polymerization ◽

Microtubule Network ◽

Microtubule Targeting Agents ◽

Ic50 Values ◽

Tubulin Polymerization Inhibitor

Combretastatin-4 (CA-4) as a tubulin polymerization inhibitor draws extensive attentions. However, due to its weak stability of cis-olefin and poor metabolic stability, structure modifications on cis-configuration are being performed. In this work, we constructed a series of novel CA-4 analogues with linkers on olefin containing diphenylethanone, cis-locked dihydrofuran, α-substituted diphenylethanone, cyclobutane and cyclohexane on its cis-olefin. Cytotoxic activity of all analogues was measured by an SRB assay. Among them, compound 6b, a by-product in the preparation of diphenylethanone analogues, was found to be the most potent cytotoxic agents against HepG2 cells with IC50 values of less than 0.5 μM. The two isomers of 6b induced cellular apoptosis tested by Annexin V-FITC and propidium iodide (PI) double staining, arrested cells in the G2/M phase by PI staining analysis, and disrupted microtubule network by immunohistochemistry study in HepG2 cells. Moreover, 6b-(E) displayed a dose-dependent inhibition effect for tubulin assembly in in vitro tubulin polymerization assay. In addition, molecular docking studies showed that two isomers of 6b could bind efficiently at colchicine binding site of tubulin similar to CA-4.

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Zinc(II) Terpyridine Complexes: Substituent Effect on Photoluminescence, Antiproliferative Activity, and DNA Interaction

Molecules ◽

10.3390/molecules24244519 ◽

2019 ◽

Vol 24 (24) ◽

pp. 4519 ◽

Cited By ~ 7

Author(s):

Jiahe Li ◽

Rongping Liu ◽

Jinzhang Jiang ◽

Xing Liang ◽

Ling Huang ◽

...

Keyword(s):

Tumor Cells ◽

Antiproliferative Activity ◽

Conformational Transition ◽

Dna Interaction ◽

Docking Studies ◽

In Vitro Cytotoxicity ◽

Human Carcinoma ◽

Ic50 Values ◽

The Difference

A series of ZnCl2 complexes (compounds 1–10) with 4′-(substituted-phenyl)-2,2′:6′,2′′-terpyridine that bears hydrogen (L1), p-methyl (L2), p-methoxy (L3), p-phenyl (L4), p-tolyl (L5), p-hydroxyl (L6), m-hydroxyl (L7), o-hydroxyl (L8), p-carboxyl (L9), or p-methylsulfonyl (L10) were prepared and then characterized by 1H NMR, electrospray mass-spectra (ESI-MS), IR, elemental analysis, and single crystal X-ray diffraction. In vitro cytotoxicity assay was used to monitor the antiproliferative activities against tumor cells. Absorption spectroscopy, fluorescence titration, circular dichroism spectroscopy, and molecular modeling studied the DNA interactions. All of the compounds display interesting photoluminescent properties and different maximal emission peaks due to the difference of the substituent groups. The cell viability studies indicate that the compounds have excellent antiproliferative activity against four human carcinoma cell lines, A549, Bel-7402, MCF-7, and Eca-109, with the lowest IC50 values of 0.33 (10), 0.66 (6), 0.37 (7), and 1.05 (7) μM, respectively. The spectrophotometric results reveal that the compounds have strong affinity binding with DNA as intercalator and induce DNA conformational transition. Molecular docking studies indicate that the binding is contributed by the π…π stacking and hydrogen bonds, providing an order of nucleotide sequence binding selectivity as ATGC > ATAT > GCGC. These compounds intercalate into the base pairs of the DNA of the tumor cells to affect their replication and transcription, and the process is supposed to play an important role in the anticancer mechanism.

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α-Glucosidase Inhibition and Molecular Docking Studies of Natural Brominated Metabolites from Marine Macro Brown Alga Dictyopteris hoytii

Marine Drugs ◽

10.3390/md17120666 ◽

2019 ◽

Vol 17 (12) ◽

pp. 666 ◽

Cited By ~ 8

Author(s):

Najeeb Ur Rehman ◽

Kashif Rafiq ◽

Ajmal Khan ◽

Sobia Ahsan Halim ◽

Liaqat Ali ◽

...

Keyword(s):

Molecular Docking ◽

Brown Alga ◽

Docking Studies ◽

Spectroscopic Techniques ◽

Molecular Docking Studies ◽

Ethyl Methyl ◽

2D Noesy ◽

Ic50 Value ◽

Ic50 Values

Bioassay guided isolation of the methanolic extract of marine macro brown alga Dictyopteris hoytii afforded one new metabolite (ethyl methyl 2-bromobenzene 1,4-dioate, 1), one new natural metabolite (diethyl-2-bromobenzene 1,4-dioate, 2) along with six known metabolites (3–8) reported for the first time from this source. The structure elucidation of all these compounds was achieved by extensive spectroscopic techniques including 1D (1H and 13C) and 2D (NOESY, COSY, HMBC and HSQC) NMR and mass spectrometry and comparison of the spectral data of known compounds with those reported in literature. The in vitro α-glucosidase inhibition studies confirmed compound 7 to be the most active against α-glucosidase enzyme with IC50 value of 30.5 ± 0.41 μM. Compounds 2 and 3 demonstrated good inhibition with IC50 values of 234.2 ± 4.18 and 289.4 ± 4.91 μM, respectively, while compounds 1, 5, and 6 showed moderate to low inhibition. Furthermore, the molecular docking studies of the active compounds were performed to examine their mode of inhibition in the binding site of the α-glucosidase enzyme.

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O-Aminoalkyl-O-Trimethyl-2,3-Dehydrosilybins: Synthesis and In Vitro Effects Towards Prostate Cancer Cells

Molecules ◽

10.3390/molecules23123142 ◽

2018 ◽

Vol 23 (12) ◽

pp. 3142 ◽

Cited By ~ 3

Author(s):

Bao Vue ◽

Sheng Zhang ◽

Andre Vignau ◽

Guanglin Chen ◽

Xiaojie Zhang ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Apoptosis ◽

Prostate Cancer Cell ◽

Synthetic Methods ◽

Step Procedure ◽

Ic50 Values ◽

In Vitro Effects ◽

Synthetic Approaches ◽

Derivatives Of

As part of our ongoing silybin project, this study aims to introduce a basic nitrogen-containing group to 7-OH of 3,5,20-O-trimethyl-2,3-dehydrosilybin or 3-OH of 5,7,20-O-trimethyl-2,3-dehydrosilybin via an appropriate linker for in vitro evaluation as potential anti-prostate cancer agents. The synthetic approaches to 7-O-substituted-3,5,20-O-trimethyl-2,3-dehydrosilybins through a five-step procedure and to 3-O-substituted-5,7,20-O-trimethyl-2,3- dehydrosilybins via a four-step transformation have been developed. Thirty-two nitrogen-containing derivatives of silybin have been achieved through these synthetic methods for the evaluation of their antiproliferative activities towards both androgen-sensitive (LNCaP) and androgen-insensitive prostate cancer cell lines (PC-3 and DU145) using the WST-1 cell proliferation assay. These derivatives exhibited greater in vitro antiproliferative potency than silibinin. Among them, 11, 29, 31, 37, and 40 were identified as five optimal derivatives with IC50 values in the range of 1.40–3.06 µM, representing a 17- to 52-fold improvement in potency compared to silibinin. All these five optimal derivatives can arrest the PC-3 cell cycle in the G0/G1 phase and promote PC-3 cell apoptosis. Derivatives 11, 37, and 40 are more effective than 29 and 31 in activating PC-3 cell apoptosis.

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Inhibitors of Acetylcholinesterase Derived from 7-Methoxytacrine and Their Effects on the Choline Transporter CHT1

Dementia and Geriatric Cognitive Disorders ◽

10.1159/000453256 ◽

2016 ◽

Vol 43 (1-2) ◽

pp. 45-58 ◽

Cited By ~ 4

Author(s):

Zdenka Kristofikova ◽

Jan Ricny ◽

Ondrej Soukup ◽

Jan Korabecny ◽

Eugenie Nepovimova ◽

...

Keyword(s):

Side Effects ◽

Amyloid Β ◽

Acetylcholinesterase Inhibitors ◽

Side Chain ◽

Choline Transporter ◽

Disease Therapy ◽

Cortical Membranes ◽

Derivatives Of

Background: Reversible acetylcholinesterase inhibitors are used in Alzheimer disease therapy. However, tacrine and its derivatives have severe side effects. Derivatives of the tacrine analogue 7-methoxytacrine (MEOTA) are less toxic. Methods: We evaluated new derivatives of 7-MEOTA (2 homodimers linked by 2 C4-C5 chains and 5 N-alkylated C4-C8 side chain derivatives) in vitro, using the rat hippocampal choline transporter CHT1. Results: Some derivatives were effective inhibitors of rat acetylcholinesterase and comparable with 7-MEOTA. All derivatives were able to inhibit CHT1, probably via quaternary ammonium, and this interaction could be involved in the enhancement of their detrimental side effects and/or in the attenuation of their promising effects. Under conditions of disrupted lipid rafts, the unfavorable effects of some derivatives were weakened. Only tacrine was probably able to stereospecifically interact with the naturally occurring amyloid-β isoform and to simultaneously stimulate CHT1. Some derivatives, when coincubated with amyloid β, did not influence CHT1. All derivatives also increased the fluidity of the cortical membranes. Conclusion: The N-alkylated derivative of 7-MEOTA bearing from C4 side chains appears to be the most promising compound and should be evaluated in future in vivo research.

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Synthesis and evaluation of some novel derivatives of 2-propoxybenzylidene isonicotinohydrazide for their potential antimicrobial activity

Journal of the Serbian Chemical Society ◽

10.2298/jsc110310170m ◽

2012 ◽

Vol 77 (5) ◽

pp. 589-597 ◽

Cited By ~ 5

Author(s):

Manav Malhotra ◽

Manu Arora ◽

Abdul Samad ◽

Kapendra Sahu ◽

Priyanka Phogat ◽

...

Keyword(s):

Antimicrobial Activity ◽

Mannich Bases ◽

Dependent Manner ◽

Lung Adenocarcinoma Cell Line ◽

Ic50 Values ◽

Nmr Methods ◽

Human Lung Adenocarcinoma Cell ◽

Dose Dependent ◽

Derivatives Of

A novel series of Mannich which contained isoniaside were prepared. First by the reaction of 2-propoxybenzaldehyde with isoniazid corresponding hydrazone (2a) was obtained. After that, product 2a after mannich reaction of aminomethylation with formaldehyde and secondary give amines (2b-2k). The inhibitory potencies of the synthesized compounds were assayed in vitro against a panel of microorganisms and against A549 human lung adenocarcinoma cell line. Compounds 2c and 2k displayed moderate to potent antimicrobial activity against all the tested strains and they also exhibited significant cytotoxicity in a dose-dependent manner with an IC50 values ranging from 2.84 to 8.55 (?g) and 0.007-0.030 (?M). The structures of newly synthesized compounds were evaluated by elemental and spectral (IR, 1HNMR, 13C-NMR) methods. The result demonstrates the potential and importance of developing new mannich bases which would be effective against resistant microbial strain and they may be useful leads for anticancer drug development in the future.

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Selected Derivatives of Erythromycin B-In Silico and Anti-Malarial Studies

Materials ◽

10.3390/ma14226980 ◽

2021 ◽

Vol 14 (22) ◽

pp. 6980

Author(s):

Pranab K. Bhadra ◽

Rachael N. Magwaza ◽

Niroshini Nirmalan ◽

Sally Freeman ◽

Jill Barber ◽

...

Keyword(s):

Molecular Docking ◽

In Silico ◽

Bacterial Agent ◽

Ic50 Values ◽

Exit Tunnel ◽

Erythromycin A ◽

Erythronolide B ◽

In Silico Molecular Docking ◽

Derivatives Of

Erythromycin A is an established anti-bacterial agent against Gram-positive bacteria, but it is unstable to acid. This led to an evaluation of erythromycin B and its derivatives because these have improved acid stability. These compounds were investigated for their anti-malarial activities, by their in silico molecular docking into segments of the exit tunnel of the apicoplast ribosome from Plasmodium falciparum. This is believed to be the target of the erythromycin A derivative, azithromycin, which has mild anti-malarial activity. The erythromycin B derivatives were evaluated on the multi-drug (chloroquine, pyrimethamine, and sulfadoxine)-resistant strain K1 of P. falciparum for asexual growth inhibition on asynchronous culture. The erythromycin B derivatives were identified as active in vitro inhibitors of asexual growth of P. falciparum with low micro-molar IC50 values after a 72 h cycle. 5-Desosaminyl erythronolide B ethyl succinate showed low IC50 of 68.6 µM, d-erythromycin B 86.8 µM, and erythromycin B 9-oxime 146.0 µM on the multi-drug-resistant K1 of P. falciparum. Based on the molecular docking, it seems that a small number of favourable interactions or the presence of unfavourable interactions of investigated derivatives of erythromycin B with in silico constructed segment from the exit tunnel from the apicoplast of P. falciparum is the reason for their weak in vitro anti-malarial activities.

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