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Design, synthesis and biological activity of novel tacrine-isatin Schiff base hybrid derivatives.
Bioorg Chem. 2019 08; 89:103006.BC

Abstract

A series of novel tacrine-isatin Schiff base hybrid derivatives (7a-p) were designed, synthesized and evaluated as multi-target candidates against Alzheimer's disease (AD). The biological assays indicated that most of these compounds displayed potent inhibitory activity toward acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) and specific selectivity for AChE over BuChE. It was also found that they act as excellent metal chelators. The compounds 7k and 7m were found to be good inhibitors of AChE-induced amyloid-beta (Aβ) aggregation. Most of the compounds inhibited AChE with the IC50 values, ranging from 0.42 nM to 79.66 nM. Amongst them, 7k, 7m and 7p, all with a 6 carbon linker between tacrine and isatin Schiff base exhibited the strongest inhibitory activity against AChE with IC50 values of 0.42 nM, 0.62 nM and 0.95 nM, respectively. They were 92-, 62- and 41-fold more active than tacrine (IC50 = 38.72 nM) toward AChE. Most of the compounds also showed a potent BuChE inhibition among which 7d with an IC50 value of 0.11 nM for BuChE is the most potent one (56-fold more potent than that of tacrine (IC50 = 6.21 nM)). In addition, most compounds exhibited the highest metal chelating property. Kinetic and molecular modeling studies revealed that 7k is a mixed-type inhibitor, capable of binding to catalytic and peripheral site of AChE. Our findings make this hybrid scaffold an excellent candidate to modify current drugs in treating Alzheimer's disease (AD).

Authors+Show Affiliations

Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address: sadeghpurh@sums.ac.ir.Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address: asakhteman@sums.ac.ir.Hacettepe University, Faculty of Pharmacy, Department of Biochemistry, Sihhiye-Ankara, Turkey.Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31158577

Citation

Riazimontazer, E, et al. "Design, Synthesis and Biological Activity of Novel Tacrine-isatin Schiff Base Hybrid Derivatives." Bioorganic Chemistry, vol. 89, 2019, p. 103006.
Riazimontazer E, Sadeghpour H, Nadri H, et al. Design, synthesis and biological activity of novel tacrine-isatin Schiff base hybrid derivatives. Bioorg Chem. 2019;89:103006.
Riazimontazer, E., Sadeghpour, H., Nadri, H., Sakhteman, A., Tüylü Küçükkılınç, T., Miri, R., & Edraki, N. (2019). Design, synthesis and biological activity of novel tacrine-isatin Schiff base hybrid derivatives. Bioorganic Chemistry, 89, 103006. https://doi.org/10.1016/j.bioorg.2019.103006
Riazimontazer E, et al. Design, Synthesis and Biological Activity of Novel Tacrine-isatin Schiff Base Hybrid Derivatives. Bioorg Chem. 2019;89:103006. PubMed PMID: 31158577.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis and biological activity of novel tacrine-isatin Schiff base hybrid derivatives. AU - Riazimontazer,E, AU - Sadeghpour,H, AU - Nadri,H, AU - Sakhteman,A, AU - Tüylü Küçükkılınç,T, AU - Miri,R, AU - Edraki,N, Y1 - 2019/05/21/ PY - 2018/12/08/received PY - 2019/03/10/revised PY - 2019/05/19/accepted PY - 2019/6/4/pubmed PY - 2020/9/23/medline PY - 2019/6/4/entrez KW - Acetylcholinesterase KW - Alzheimer’s disease KW - Amyloid-beta aggregation KW - Butyrylcholinesterase KW - Cholinesterase inhibitors KW - Isatin Schiff base KW - Metal chelation KW - Tacrine SP - 103006 EP - 103006 JF - Bioorganic chemistry JO - Bioorg. Chem. VL - 89 N2 - A series of novel tacrine-isatin Schiff base hybrid derivatives (7a-p) were designed, synthesized and evaluated as multi-target candidates against Alzheimer's disease (AD). The biological assays indicated that most of these compounds displayed potent inhibitory activity toward acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) and specific selectivity for AChE over BuChE. It was also found that they act as excellent metal chelators. The compounds 7k and 7m were found to be good inhibitors of AChE-induced amyloid-beta (Aβ) aggregation. Most of the compounds inhibited AChE with the IC50 values, ranging from 0.42 nM to 79.66 nM. Amongst them, 7k, 7m and 7p, all with a 6 carbon linker between tacrine and isatin Schiff base exhibited the strongest inhibitory activity against AChE with IC50 values of 0.42 nM, 0.62 nM and 0.95 nM, respectively. They were 92-, 62- and 41-fold more active than tacrine (IC50 = 38.72 nM) toward AChE. Most of the compounds also showed a potent BuChE inhibition among which 7d with an IC50 value of 0.11 nM for BuChE is the most potent one (56-fold more potent than that of tacrine (IC50 = 6.21 nM)). In addition, most compounds exhibited the highest metal chelating property. Kinetic and molecular modeling studies revealed that 7k is a mixed-type inhibitor, capable of binding to catalytic and peripheral site of AChE. Our findings make this hybrid scaffold an excellent candidate to modify current drugs in treating Alzheimer's disease (AD). SN - 1090-2120 UR - https://www.unboundmedicine.com/medline/citation/31158577/Design_synthesis_and_biological_activity_of_novel_tacrine_isatin_Schiff_base_hybrid_derivatives_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0045-2068(18)31416-0 DB - PRIME DP - Unbound Medicine ER -