Publication Type:

Journal Article


European Journal of Pharmaceutical Sciences, Volume 47, Number 1, p.190-205 (2012)



1 chloroacetyl 6 ethyl 2, 1 [n [2 (3, 3 benzyl 1 chloroacetyl 6 ethyl 2, 3 benzyl 1 [n [2 (3, 3 benzyl 6 ethyl 1h thieno[2, 3 benzyl 6 ethyl 2, 3 b][1, 3 dihydro 1h thieno[2, 3 dihydro 2 thioxo 1h thieno[2, 3 dihydro 3 (4 methoxybenzylidene) 1h thieno[2, 4 dimethoxyphenyl)ethyl] n methylaminoacetyl] 6 ethyl 2, 4]thiazin 2(3h) one, 4]thiazine, 4]thiazine 2(3h) thione, 4]thiazine 6 carboxylate, 6 acetyl 3 benzyl 1h thieno[2, 6 ethyl 1 methyl 1h thieno[2, 6 ethyl 2, 6 ethyl 3 (4 methoxybenzylidene) 1h thieno[2, Acetylcholine, Alzheimer disease, animal cell, Animals, article, binding site, Brain, Butyrylcholinesterase, Caco-2 Cells, catalysis, Cell Line, cholinesterase, cholinesterase inhibitor, Cholinesterase Inhibitors, controlled study, cytotoxicity, drug binding, drug potency, enzyme activity, enzyme inhibition, ethyl 2, Follow-Up Studies, Hep G2 Cells, human, human cell, Humans, hydrolase, IC 50, Mice, molecular probe, mouse, nonhuman, pharmacophore, Phenothiazines, priority journal, structure activity relation, Structure-Activity Relationship, thiazine derivative, Thiazines, thienothiazine derivative, Tumor, unclassified drug


The role of butyrylcholinesterase (BChE) in the progression of Alzheimer's disease (AD) has recently become more crucial. In the AD brain, selective BChE inhibitors have been demonstrated to have a beneficial effect in vivo, probably by recovering cholinergic activity and/or by restoring AChE:BChE activity ratios to the levels observed in the healthy brain. Thienothiazines are compounds sharing some structural features with phenothiazines, which are known to be potent BChE inhibitors. Thus, in this contribution 45 thienothiazines were investigated for their BChE inhibitory activity. Six of them were proven to be potent and selective inhibitors of equine BChE's hydrolase activity. Structure-activity relationships were laid out, and a tentative pharmacophore model for BChE inhibitors of the thienothiazine type was proposed. The most active compound, 3f, displayed a mixed type of inhibition and was also active against the human BChE (huBChE) with an IC50 huBChE of 0.51 ± 0.07 μM. Computational studies suggested that 3f likely binds to the catalytic site and nearby to the peripheral site of the huBChE in an extended form. In addition, the chemical space occupied by the active thienothiazines, as opposed to phenothiazines and other representative chemical classes of BChE inhibitors, was explored with the aid of ChemGPS-NP, and the relevant chemical space regions were identified. This study shows for the first time that thienothiazines represent a new group of BChE inhibitors that can be used as molecular probes for studying the role of BChE in the brain or for developing newer drug leads for AD therapy. © 2012 Elsevier B.V. All rights reserved.


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Cite this Research Publication

Da Karlsson, Fallarero, Aa, Brunhofer, Gab, Mayer, Cb, Prakash, Oc, Mohan, C. Gc, Vuorela, Pa, and Erker, Tb, “The exploration of thienothiazines as selective butyrylcholinesterase inhibitors”, European Journal of Pharmaceutical Sciences, vol. 47, pp. 190-205, 2012.