Design, synthesis, biological evaluation, and molecular dynamics of novel cholinesterase inhibitors as anti‐Alzheimer's agents

Shamsimeymandi, Reza; Pourshojaei, Yaghoub; Eskandari, Khalil; Mohammadi‐Khanaposhtani, Maryam; Abiri, Ardavan; Khodadadi, Arash; Langarizadeh, Mohammad Amin; Sharififar, Fariba; Amirheidari, Bagher; Akbarzadeh, Tahmineh; Lotfian, Hania; Foroumadi, Alireza; Asadipour, Ali

doi:10.1002/ardp.201800352

Cited by 16 publications

(10 citation statements)

References 58 publications

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“…The particle‐mesh‐based Ewald pattern was utilized for summation of long‐range electrostatic forces. A cutoff radius range of 9.0 Å was set for computation of Columbic forces [34, 49, 50].…”

Section: Methodsmentioning

confidence: 99%

Phlorotannins as HIV Vpu inhibitors, an in silico virtual screening study of marine natural products

Langarizadeh

Abiri

Ghasemshirazi

et al. 2020

Biotech and App Biochem

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The importance of new effective treatment methodologies for human immunodeficiency virus (HIV) is undeniable for the medical society. Viral protein U (Vpu), one of the disparaged accessory proteins of HIV, is responsible for the dissemination of viral particles, and HIV mutants lacking Vpu protein have remarkably reduced pathogenicity. Here, we explored the marine natural products to find the leading structures which can potentially inhibit the activity of Vpu in silico. To fulfill this goal, we set up a virtual screening based on molecular docking to evaluate the binding capacity of different marine products to Vpu. For validation, we used molecular dynamics simulation and monitored the root mean square deviation value and binding interactions. The results were intriguing when we realized that the hit compounds (phlorotannins) had previously been identified as reverse transcriptase and HIV protease inhibitors. This research inaugurates a new road to combat HIV by multifaceted mode of action of these marine natural products without putting the normal cells in jeopardy (with their safe toxicological profile).

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Section: Methodsmentioning

confidence: 99%

Phlorotannins as HIV Vpu inhibitors, an in silico virtual screening study of marine natural products

Langarizadeh

Abiri

Ghasemshirazi

et al. 2020

Biotech and App Biochem

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“…All the synthesized compounds were screened for their cholinesterase activity by Ellman’s spectrophotometric method with a slight modification 24 . All chemicals, reagents and reference drug, AChE (E.C.3.1.1.7, from electric eel), acetylthiocholine iodide (ATCI), BuChE (E.C.3.1.1.8, from equine serum), butyrylthiocholine iodide (BTCI), 5,5′-dithiobis-(2-nitrobenzoic acid) (DTNB) and donepezil hydrochloride) used in the procedure were supplied from Sigma-Aldrich and Fluka.…”

Section: Methodsmentioning

confidence: 99%

“…It is unraveled that an amine (usually in the form of piperidine) interacts with the anionic site of CAS and substituting the benzyl piperidine part of donepezil with phenoxyethyl piperidine or morpholine is one of the recent approaches toward stronger cholinesterase inhibitors 20,21 . In the other side of the molecule, nitrile groups, ketones and also etheric linkages are often observed 22–24 . These two parts are usually linked together by a phenyl or indanone scaffold 25 (Fig.…”

Section: Introductionmentioning

confidence: 99%

Phenoxyethyl Piperidine/Morpholine Derivatives as PAS and CAS Inhibitors of Cholinesterases: Insights for Future Drug Design

Pourshojaei

Abiri

Eskandari

et al. 2019

Sci Rep

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Acetylcholinesterase (AChE) catalyzes the conversion of Aβ peptide to its aggregated form and the peripheral anionic site (PAS) of AChE is mainly involved in this phenomenon. Also catalytic active site (CAS) of donepezil stimulates the break-down of acetylcholine (ACh) and depletion of ACh in cholinergic synapses are well established in brains of patients with AD. In this study, a set of compounds bearing phenoxyethyl amines were synthesized and their inhibitory activity toward electric eel AChE (eeAChE) and equine butyrylcholinesterase (eqBuChE) were evaluated. Molecular dynamics (MD) was employed to record the binding interactions of best compounds against human cholinesterases (hAChE and hBuChE) as well as donepezil as reference drug. In vitro results revealed that compound 5c is capable of inhibiting eeAChE activity at IC50 of 0.50 µM while no inhibitory activity was found for eqBuChE for up to 100 µM concentrations. Compound 5c, also due to its facile synthesis, small structure and high selectivity for eeAChE would be very interesting candidate in forthcoming studies. The main interacting parts of compound 5c and compound 7c (most potent eeAChE and eqBuChE inhibitors respectively) with receptors which confer selectivity for AChE and BuChE inhibition were identified, discussed, and compared with donepezil’s interactions. Also during MD simulation it was discovered for the first time that binding of substrates like donepezil to dual CAS and PAS or solely CAS region might have a suppressive impact on 4-α-helical bundles near the tryptophan amphiphilic tetramerization (WAT) domain of AChE and residues which are far away from AChE active site. The results proposed that residues involved in donepezil interactions (Trp86 and Phe295) which are located in CAS and mid-gorge are the mediator of conformational changes in whole protein structure.

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“…As search algorithms, Lamarckian Genetic Algorithm (LGA) was applied and performed by AutoDock 4.2. [17,[19][20][21]. Finally, the PDBQT file of the receptors was obtained using MGLTOOLS 1.5.6.…”

Section: Docking Proceduresmentioning

confidence: 99%

Imidazole and carbazole derivatives as potential anticancer agents: molecular docking studies and cytotoxic activity evaluation

Taheri¹,

Taghavi²,

Zarei³

et al. 2020

Bull. Chem. Soc. Eth.

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Carbazoles and imidazole represent two important classes of heterocycles which exhibit diverse biological activities such as antitumor properties. In this study, imidazole (C1-C3) and carbazole (C4 and C5) derivatives were evaluated for their cytotoxic activity against three human cancer cell lines namely, MCF7 (human breast cancer), HT29 (human colon cancer), and HeLa (human cervical cancer). Carbazole derivatives (C4 and C5) with IC50 < 10 µM showed greater cytotoxic effect than imidazole derivatives (C1-C3). Furthermore, all compounds exhibited better anticancer activity against MCF-7 than other two cell lines (HT-29, HeLa) and compound C4 was the most potent compound with the IC50 values of 2.5, 5.4 and 4.0 µM, against MCF-7, Hela and HT-29 cell lines, respectively. Physicochemical properties of compounds were calculated and their correlation with the IC50 values on MCF-7 cell line investigated. Surface area and polarizability of compounds showed good correlation by R2 = 0.8396 and R2 = 0.834, respectively. Docking studies of these compounds were also performed on the DNA as proposed target to comprehend their binding interactions and binding energies. The docking energy of compounds ranged from - 11.32 to -13.48 kcal/mol. Compound C3 with energy of -13.48 kcal/mol had the highest docking energy. Docking results indicated that these compounds (C1-C5) had strong affinity in binding to the DNA. KEY WORDS: Imidazole, Carbazole, Molecular docking, Cancer, MTT assay Bull. Chem. Soc. Ethiop. 2020, 34(2), 377-384 DOI: https://dx.doi.org/10.4314/bcse.v34i2.14

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Design, synthesis, biological evaluation, and molecular dynamics of novel cholinesterase inhibitors as anti‐Alzheimer's agents

Cited by 16 publications

References 58 publications

Phlorotannins as HIV Vpu inhibitors, an in silico virtual screening study of marine natural products

Phlorotannins as HIV Vpu inhibitors, an in silico virtual screening study of marine natural products

Phenoxyethyl Piperidine/Morpholine Derivatives as PAS and CAS Inhibitors of Cholinesterases: Insights for Future Drug Design

Imidazole and carbazole derivatives as potential anticancer agents: molecular docking studies and cytotoxic activity evaluation

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