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Novel tetrahydroacridine derivatives with iodobenzoic acid moiety as multifunctional acetylcholinesterase inhibitors.
Chem Biol Drug Des. 2018 02; 91(2):505-518.CB

Abstract

New synthesized series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with iodobenzoic acid moiety were studied for their inhibitory activity toward cholinesterase and against β-amyloid aggregation. All novel molecules 3a-3i interacted with both cholinesterases-acetylcholinesterase and butyrylcholinesterase-delivered nanomolar IC50 values. The structure-activity relationship showed that N-butyl moiety derivatives are stronger inhibitors toward AChE and BuChE than N-ethyl and N-propyl moieties compounds. The most potent compound toward acetylcholinesterase was inhibitor 3f (IC50 = 31.2 nm), and it was more active than reference drug, tacrine (IC50 = 100.2 nm). Compound 3f showed strong inhibition of butyrylcholinesterase (IC50 = 8.0 nm), also higher than tacrine (IC50 = 16.3 nm). In the kinetic studies, compound 3f revealed mixed type of acetylcholinesterase inhibition. The computer modeling was carried out. The most active compound 3f was confirmed as peripheral anionic site inhibitor of acetylcholinesterase. Moreover, molecule 3f inhibited β-amyloid aggregation (at the concentration 10 μm-24.96% of inhibition, 25 μm-72%, 50 μm-78.44%, and 100 μm-84.92%). Therefore, among all examined, compound 3f is the most promising molecule for further, more detailed research of novel multifunctional agents in the therapy of Alzheimer's disease.

Authors+Show Affiliations

Department of Medicinal Chemistry, Pharmaceutical Faculty, Medical University of Lublin, Lublin, Poland.Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University, Łódź, Poland.Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University, Łódź, Poland.Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University, Łódź, Poland.Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University, Łódź, Poland.Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University, Łódź, Poland.Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University, Łódź, Poland.

Pub Type(s)

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

Language

eng

PubMed ID

28944565

Citation

Skibiński, Robert, et al. "Novel Tetrahydroacridine Derivatives With Iodobenzoic Acid Moiety as Multifunctional Acetylcholinesterase Inhibitors." Chemical Biology & Drug Design, vol. 91, no. 2, 2018, pp. 505-518.
Skibiński R, Czarnecka K, Girek M, et al. Novel tetrahydroacridine derivatives with iodobenzoic acid moiety as multifunctional acetylcholinesterase inhibitors. Chem Biol Drug Des. 2018;91(2):505-518.
Skibiński, R., Czarnecka, K., Girek, M., Bilichowski, I., Chufarova, N., Mikiciuk-Olasik, E., & Szymański, P. (2018). Novel tetrahydroacridine derivatives with iodobenzoic acid moiety as multifunctional acetylcholinesterase inhibitors. Chemical Biology & Drug Design, 91(2), 505-518. https://doi.org/10.1111/cbdd.13111
Skibiński R, et al. Novel Tetrahydroacridine Derivatives With Iodobenzoic Acid Moiety as Multifunctional Acetylcholinesterase Inhibitors. Chem Biol Drug Des. 2018;91(2):505-518. PubMed PMID: 28944565.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel tetrahydroacridine derivatives with iodobenzoic acid moiety as multifunctional acetylcholinesterase inhibitors. AU - Skibiński,Robert, AU - Czarnecka,Kamila, AU - Girek,Małgorzata, AU - Bilichowski,Ireneusz, AU - Chufarova,Nina, AU - Mikiciuk-Olasik,Elżbieta, AU - Szymański,Paweł, Y1 - 2017/10/24/ PY - 2017/05/21/received PY - 2017/08/16/revised PY - 2017/08/24/accepted PY - 2017/9/26/pubmed PY - 2019/1/27/medline PY - 2017/9/26/entrez KW - Alzheimer's disease KW - Ellman method KW - acetylcholinesterase inhibitors KW - molecular modeling KW - tacrine derivatives KW - β-amyloid SP - 505 EP - 518 JF - Chemical biology & drug design JO - Chem Biol Drug Des VL - 91 IS - 2 N2 - New synthesized series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with iodobenzoic acid moiety were studied for their inhibitory activity toward cholinesterase and against β-amyloid aggregation. All novel molecules 3a-3i interacted with both cholinesterases-acetylcholinesterase and butyrylcholinesterase-delivered nanomolar IC50 values. The structure-activity relationship showed that N-butyl moiety derivatives are stronger inhibitors toward AChE and BuChE than N-ethyl and N-propyl moieties compounds. The most potent compound toward acetylcholinesterase was inhibitor 3f (IC50 = 31.2 nm), and it was more active than reference drug, tacrine (IC50 = 100.2 nm). Compound 3f showed strong inhibition of butyrylcholinesterase (IC50 = 8.0 nm), also higher than tacrine (IC50 = 16.3 nm). In the kinetic studies, compound 3f revealed mixed type of acetylcholinesterase inhibition. The computer modeling was carried out. The most active compound 3f was confirmed as peripheral anionic site inhibitor of acetylcholinesterase. Moreover, molecule 3f inhibited β-amyloid aggregation (at the concentration 10 μm-24.96% of inhibition, 25 μm-72%, 50 μm-78.44%, and 100 μm-84.92%). Therefore, among all examined, compound 3f is the most promising molecule for further, more detailed research of novel multifunctional agents in the therapy of Alzheimer's disease. SN - 1747-0285 UR - https://www.unboundmedicine.com/medline/citation/28944565/Novel_tetrahydroacridine_derivatives_with_iodobenzoic_acid_moiety_as_multifunctional_acetylcholinesterase_inhibitors_ L2 - https://doi.org/10.1111/cbdd.13111 DB - PRIME DP - Unbound Medicine ER -