Synthesis and Biological Evaluation of Thiophene Derivatives as Acetylcholinesterase Inhibitors

Ismail, Mohamed; Kamel, Mona M.; Mohamed, Lamia W.; Faggal, Samar I.; Galal, Mai

doi:10.3390/molecules17067217

Cited by 27 publications

(15 citation statements)

References 17 publications

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“…The benzo[b]-thiophene scaffold plays a crucial rule for many STAT3 inhibitors [14,15]. Additionally, the substituted cycloalkyl[b]thiophene core structure possessed a cytotoxic activity [16], also exhibited biological activities such as the AChE inhibitor [17], I3-AG85 inhibitor (compound VIII) [18], as well as the HCV replication inhibitor (compound IX, Figure 1) [19], antiviral [20], anti-inflammatory [21,22], antibacterial [23,24], and antitumor activities [25][26][27][28][29]. In the proceeding text, we have synthesized a set of compounds based on the cycloalkyl[b]thiophene with different hybrids tethered pharmacophoric/functional groups diversity (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Discovery of New Apoptosis-Inducing Agents for Breast Cancer Based on Ethyl 2-Amino-4,5,6,7-Tetra Hydrobenzo[b]Thiophene-3-Carboxylate: Synthesis, In Vitro, and In Vivo Activity Evaluation

et al. 2020

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A multicomponent synthesis was empolyed for the synthesis of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate 1. An interesting cyclization was obtained when the amino-ester 1 reacted with ethyl isothiocyanate to give the benzo[4,5]thieno[2,3-d][1,3]thiazin-4-one 3. Acylation of the amino-ester 1 with chloroacetyl chloride in DCM and Et3N afforded the acylated ester 4. The amino-ester 1 was cyclized to benzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one 8, which was reacted with some alkylating agents leading to alkylation at nitrogen 9–13. Hydrazide 14 was utilized as a synthon for the synthesis of the derivatives 15–19. Chloro-thieno[2,3-d]pyrimidine 20 was synthesized and reacted with the hydrazine hydrate to afford the hydrazino derivative 21, which was used as a scaffold for getting the derivatives 22–28. Nucleophilic substitution reactions were used for getting the compounds 29–35 from chloro-thieno[2,3-d]pyrimidine 20. In the way of anticancer therapeutics development, the requisite compounds were assessed for their cytotoxicity in vitro against MCF-7 and HepG-2 cancer cell lines. Twelve compounds showed an interesting antiproliferative potential with IC50 from 23.2 to 95.9 µM. The flow cytometric analysis results showed that hit 4 induces the apoptosis in MCF-7 cells with a significant 26.86% reduction in cell viability. The in vivo study revealed a significant decrease in the solid tumor mass (26.6%) upon treatment with compound 4. Moreover, in silico study as an agonist for inhibitors of JAK2 and prediction study determined their binding energies and predicted their physicochemical properties and drug-likeness scores.

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Section: Introductionmentioning

confidence: 99%

Discovery of New Apoptosis-Inducing Agents for Breast Cancer Based on Ethyl 2-Amino-4,5,6,7-Tetra Hydrobenzo[b]Thiophene-3-Carboxylate: Synthesis, In Vitro, and In Vivo Activity Evaluation

et al. 2020

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“…Among the various known thiadiazol derivatives [187][188][189][190] the (1,3,4-thiadiazol-2-yl) benzene-1,3-diol derivative 121 ( Figure 23) was a mixed type and potent AChE inhibitor (IC 50 = 53 nM) with 950 fold selectivity index over BChE (IC 50 = 50200 nM) in electric eel [188]. Figure 24) showed 60% AChE inhibition, which was stronger than donepezil (40% inhibition)in pharmacological studies at 2.6351 mM in adult male albino Wister rats [191]. Molecular modeling revealed that strong one π-π (Trp84) and three H-bond interaction [H-bond (Tyr121), H-bond (Phe331) and H-bond (Phe288)] were responsible for its potency.…”

Section: Novel Heterocyclic Moleculesmentioning

confidence: 99%

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

Saxena¹

2019

AND

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Alzheimer's Disease (AD) is characterized by the loss of memory and learning ability in elderly patients affecting large population worldwide. The enzyme Acetylcholinesterase (AChE), (E.C.3.1.1.7) plays a major role in the hydrolysis of the released neurotransmitter acetylcholine. Most of the clinically used drugs to treat AD are Acetylcholinesterase Inhibitors (AChEIs). These drugs can provide symptomatic benefits only and suffer with loss of therapeutic potential with time. Therefore, there is an urgent need of novel cholinesterase inhibitors with wider therapeutic window for the treatment of AD. The strategies targeting the AChE enzyme along with other target(s) like Butyrylcholinesterase (BChE), amyloid-β (Aβ), β-secretase-1 (BACE), metals (Cu 2+ , Zn 2+ , or Fe 2+), antioxidant properties and free radical scavenging capacity have been mainly focused in the last five years. A number of hybrid molecules incorporating sub-structures with the desired well-established pharmacological profile into a single scaffold have been investigated. The main sub structures used in developing these molecules are derived from diverse chemical classes such as acridine, quinoline, carbamates, huperzine and other heterocyclic analogs. It has been followed by optimization of activity through structural modifications of the prototype molecules for developing the Structure Activity Relationship (SAR). This has led to the development of novel molecules with desired AChE inhibitory activity along with other desirable pharmacological properties. This review summarizes the current therapeutic strategies for the development of these AChEI in the last seven years.

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“…Figure 12) exhibited prominent inhibition (56.67%, 60% for 78 and 79) of AChE which was better than the standard drug donepezil (40%). In molecular docking studies, compound 78 presented strong hydrogen bonding than donepezil, which may be due to the amide group (Ismail et al, 2012b). Omran et al (2005) carried out the synthesis of new indanones and thiaindanones derivatives and evaluated their AChE inhibitory activity.…”

Section: Donepezil Derivatives Having Propargylamine Groupmentioning

confidence: 99%

“…Ismail et al (2012b) carried out the synthesis of donepezil derivatives in which the indanone part of donepezil was substituted by tetrahydrobenzo[b] thiophine ring having carbonyl group at position # 3 of tetrahydrobenzo[b]thiophine. Acetamide group was introduced as a linker between the tetrahydrobenzo[b] thiophine and benzylpiperidine.…”

mentioning

confidence: 99%

Donepezil: A review of the recent structural modifications and their impact on anti-Alzheimer activity

Mohsin

Ahmad

2020

Braz. J. Pharm. Sci.

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Synthesis and Biological Evaluation of Thiophene Derivatives as Acetylcholinesterase Inhibitors

Cited by 27 publications

References 17 publications

Discovery of New Apoptosis-Inducing Agents for Breast Cancer Based on Ethyl 2-Amino-4,5,6,7-Tetra Hydrobenzo[b]Thiophene-3-Carboxylate: Synthesis, In Vitro, and In Vivo Activity Evaluation

Discovery of New Apoptosis-Inducing Agents for Breast Cancer Based on Ethyl 2-Amino-4,5,6,7-Tetra Hydrobenzo[b]Thiophene-3-Carboxylate: Synthesis, In Vitro, and In Vivo Activity Evaluation

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

Donepezil: A review of the recent structural modifications and their impact on anti-Alzheimer activity

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