Synthesis, structural characterization, docking, lipophilicity and cytotoxicity of 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3-alkyl carbamates, novel acetylcholinesterase and butyrylcholinesterase pseudo-irreversible inhibitors

0459172 - ÚOCHB 2017 RIV GB eng J - Journal Article
Pejchal, V. - Štěpánková, Š. - Pejchalová, M. - Královec, K. - Havelek, R. - Růžičková, Z. - Ajani, Haresh - Lo, Rabindranath - Lepšík, Martin
Synthesis, structural characterization, docking, lipophilicity and cytotoxicity of 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3-alkyl carbamates, novel acetylcholinesterase and butyrylcholinesterase pseudo-irreversible inhibitors.
Bioorganic & Medicinal Chemistry. Roč. 24, č. 7 (2016), s. 1560-1572. ISSN 0968-0896. E-ISSN 1464-3391
R&D Projects: GA ČR GBP208/12/G016
Institutional support: RVO:61388963
Keywords : halogenated benzothiazole * carbamates * acetylcholinesterase * butyrylcholinesterase inhibition * pseudo-irreversible mechanism * covalent docking
Subject RIV: CC - Organic Chemistry
Impact factor: 2.930, year: 2016

In the current study, sixteen novel derivatives of (R)-1-(6-fluorobenzo[d]thiazol-2-yl) ethanamine were synthesized as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. Chemical structures together with purity of the synthesized compounds were substantiated by IR, H-1, C-13, F-19 NMR, high resolution mass spectrometry and elemental analysis. The optical activities were confirmed by optical rotation measurements. The synthesized compounds were evaluated for their AChE and BChE inhibitory activities. In addition, the cytotoxicity of the most active compounds was investigated against human cell lines employing XTT tetrazolium salt reduction assay and xCELLigence system allowing a label-free assessment of the cells proliferation. Our results demonstrated that the inhibitory mechanism was confirmed to be pseudo-irreversible, in line with previous studies on carbamates. Compounds indicated as 3b, 3d, 3l and 3n showed the best AChE inhibitory activity of all the evaluated compounds and were up to tenfold more potent than standard drug rivastigmine. The binding mode was determined using state-of-the-art covalent docking and scoring methodology. The obtained data clearly demonstrated that 3b, 3d, 3l and 3n benzothiazole carbamates possess high inhibitory activity against AChE and BChE and concurrently negligible cytotoxicity. In conclusion, our results indicate, that these derivatives could be promising in an effective therapeutic intervention for Alzheimer's disease.
Permanent Link: http://hdl.handle.net/11104/0259410