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Design, Synthesis, and Structure-Activity Relationships of Thiazole Analogs as Anticholinesterase Agents for Alzheimer's Disease.
Molecules. 2020 Sep 20; 25(18)M

Abstract

Dementia is a neurological condition commonly correlated with Alzheimer's disease (AD), and it is seen with many other central nervous system (CNS) disorders. The restricted number of medications is not appropriate to offer enough relief to enhance the quality of life of patients suffering from this symptom; thus, all therapeutic choices should be carefully assessed. In this study, new thiazolylhydrazone derivatives (2a-2l) were designed and synthesized based on the cholinergic hypothesis. Their chemical structures were confirmed by 1H NMR, 13C NMR, and HRMS spectrometric techniques. The ADME (absorption, distribution, metabolism, elimination) parameters of the synthesized compounds were predicted by using QikProp 4.8 software. It was concluded that all compounds presented satisfactory drug-like characteristics. Furthermore, their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro were also tested by modified the Ellman spectrophotometric method. According to the results, all compounds showed a weak inhibitory effect on BChE. On the other hand, most of the compounds (2a, 2b, 2d, 2e, 2g, 2i, and 2j) had a certain AChE inhibitory activity, and the IC50 values of them were calculated as 0.063 ± 0.003, 0.056 ± 0.002, 0.147 ± 0.006, 0.040 ± 0.001, 0.031 ± 0.001, 0.028 ± 0.001, and 0.138 ± 0.005 µM, respectively. Among these derivatives, compound 2i was found to be the most active agent in the series with an IC50 value of 0.028 ± 0.001 µM, which indicated an inhibition profile at a similar rate as the reference drug, donepezil. The potential binding modes of compounds 2a, 2b, 2e, 2g, and 2i with AChE were investigated and compared with each other by the molecular docking studies. The results showed that these compounds were strongly bound up with the AChE enzyme active site with the optimal conformations.

Authors+Show Affiliations

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey. Doping and Narcotic Compounds Analysis Laboratory, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey.Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey. Doping and Narcotic Compounds Analysis Laboratory, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey.Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey. Doping and Narcotic Compounds Analysis Laboratory, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey.Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey. Doping and Narcotic Compounds Analysis Laboratory, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey.Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Zonguldak Bülent Ecevit University, 67600 Zonguldak, Turkey.Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey. Doping and Narcotic Compounds Analysis Laboratory, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey.Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32962239

Citation

Sağlık, Begüm Nurpelin, et al. "Design, Synthesis, and Structure-Activity Relationships of Thiazole Analogs as Anticholinesterase Agents for Alzheimer's Disease." Molecules (Basel, Switzerland), vol. 25, no. 18, 2020.
Sağlık BN, Osmaniye D, Acar Çevik U, et al. Design, Synthesis, and Structure-Activity Relationships of Thiazole Analogs as Anticholinesterase Agents for Alzheimer's Disease. Molecules. 2020;25(18).
Sağlık, B. N., Osmaniye, D., Acar Çevik, U., Levent, S., Kaya Çavuşoğlu, B., Özkay, Y., & Kaplancıklı, Z. A. (2020). Design, Synthesis, and Structure-Activity Relationships of Thiazole Analogs as Anticholinesterase Agents for Alzheimer's Disease. Molecules (Basel, Switzerland), 25(18). https://doi.org/10.3390/molecules25184312
Sağlık BN, et al. Design, Synthesis, and Structure-Activity Relationships of Thiazole Analogs as Anticholinesterase Agents for Alzheimer's Disease. Molecules. 2020 Sep 20;25(18) PubMed PMID: 32962239.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, Synthesis, and Structure-Activity Relationships of Thiazole Analogs as Anticholinesterase Agents for Alzheimer's Disease. AU - Sağlık,Begüm Nurpelin, AU - Osmaniye,Derya, AU - Acar Çevik,Ulviye, AU - Levent,Serkan, AU - Kaya Çavuşoğlu,Betül, AU - Özkay,Yusuf, AU - Kaplancıklı,Zafer Asım, Y1 - 2020/09/20/ PY - 2020/08/12/received PY - 2020/09/10/revised PY - 2020/09/18/accepted PY - 2020/9/23/entrez PY - 2020/9/24/pubmed PY - 2020/9/24/medline KW - ADME parameters KW - Alzheimer’s disease KW - anticholinesterase enzyme activity KW - molecular docking KW - thiazole JF - Molecules (Basel, Switzerland) JO - Molecules VL - 25 IS - 18 N2 - Dementia is a neurological condition commonly correlated with Alzheimer's disease (AD), and it is seen with many other central nervous system (CNS) disorders. The restricted number of medications is not appropriate to offer enough relief to enhance the quality of life of patients suffering from this symptom; thus, all therapeutic choices should be carefully assessed. In this study, new thiazolylhydrazone derivatives (2a-2l) were designed and synthesized based on the cholinergic hypothesis. Their chemical structures were confirmed by 1H NMR, 13C NMR, and HRMS spectrometric techniques. The ADME (absorption, distribution, metabolism, elimination) parameters of the synthesized compounds were predicted by using QikProp 4.8 software. It was concluded that all compounds presented satisfactory drug-like characteristics. Furthermore, their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro were also tested by modified the Ellman spectrophotometric method. According to the results, all compounds showed a weak inhibitory effect on BChE. On the other hand, most of the compounds (2a, 2b, 2d, 2e, 2g, 2i, and 2j) had a certain AChE inhibitory activity, and the IC50 values of them were calculated as 0.063 ± 0.003, 0.056 ± 0.002, 0.147 ± 0.006, 0.040 ± 0.001, 0.031 ± 0.001, 0.028 ± 0.001, and 0.138 ± 0.005 µM, respectively. Among these derivatives, compound 2i was found to be the most active agent in the series with an IC50 value of 0.028 ± 0.001 µM, which indicated an inhibition profile at a similar rate as the reference drug, donepezil. The potential binding modes of compounds 2a, 2b, 2e, 2g, and 2i with AChE were investigated and compared with each other by the molecular docking studies. The results showed that these compounds were strongly bound up with the AChE enzyme active site with the optimal conformations. SN - 1420-3049 UR - https://www.unboundmedicine.com/medline/citation/32962239/Design_Synthesis_and_Structure_Activity_Relationships_of_Thiazole_Analogs_as_Anticholinesterase_Agents_for_Alzheimer's_Disease_ L2 - https://www.mdpi.com/resolver?pii=molecules25184312 DB - PRIME DP - Unbound Medicine ER -
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