Synthesis and in vitro evaluation of new derivatives of 2-substituted-6-fluorobenzo[d]thiazoles as cholinesterase inhibitors

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• 作者：Ale&scaron ; Imramovsk&yacute ; ^a ; ^{Ales.Imramovsky@upce.cz} ; Vladimí ; r Pejchal^a ; &Scaron ; á ; rka &Scaron ; t¨§pá ; nková ; ^b ; Katarí ; na Vor?á ; ková ; ^c ; Josef Jampí ; lek^d ; Já ; n Van?o^d ; Petr &Scaron ; im?nek^a ; Karel Krá ; lovec^b ; Lenka Br??ková ; ^b ; Jana Mandí ; ková ; ^e ; Franti&scaron ; ek Trejtnar^e
• 关键词：6-Fluorobenzo[d]thiazole ; Lipophilicity ; Acetylcholinesterase ; Butyrylcholinesterase ; Cholinesterase inhibition ; In vitro cytotoxicity ; Molecular docking ; Structure&ndash ; activity relationships
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：1 April, 2013
• 年：2013
• 卷：21
• 期：7
• 页码：1735-1748
• 全文大小：662 K

文摘

A series of novel cholinesterase inhibitors based on 2-substituted 6-fluorobenzo[d]thiazole were synthesised and characterised by IR, ¹H, ¹³C and ¹⁹F NMR spectroscopy and HRMS. Purity was checked by elemental analyses. The novel carbamates were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The toxicity of the most active compounds was investigated using a standard in vitro test with HepG2 cells, and the ratio between biological activity and toxicity was determined. In addition, the toxicity of the most active compounds was evaluated against MCF7 cells using the xCELLigence system. Structure-activity relationships reflecting the dependence of cholinesterase inhibitors on the lipophilicity of the compounds as well as on the Taft polar and steric substituent constants are discussed. The specific orientation of the inhibitors in the binding site of acetylcholinesterase was determined using molecular docking of the most active compound.