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Synthesis, molecular docking and biological evaluation of N,N-disubstituted 2-aminothiazolines as a new class of butyrylcholinesterase and carboxylesterase inhibitors.
Bioorg Med Chem. 2016 Mar 01; 24(5):1050-62.BM

Abstract

A series of 31 N,N-disubstituted 2-amino-5-halomethyl-2-thiazolines was designed, synthesized, and evaluated for inhibitory potential against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carboxylesterase (CaE). The compounds did not inhibit AChE; the most active compounds inhibited BChE and CaE with IC50 values of 0.22-2.3μM. Pyridine-containing compounds were more selective toward BChE; compounds with the para-OMe substituent in one of the two dibenzyl fragments were more selective toward CaE. Iodinated derivatives were more effective BChE inhibitors than brominated ones, while there was no influence of halogen type on CaE inhibition. Inhibition kinetics for the 9 most active compounds indicated non-competitive inhibition of CaE and varied mechanisms (competitive, non-competitive, or mixed-type) for inhibition of BChE. Docking simulations predicted key binding interactions of compounds with BChE and CaE and revealed that the best docked positions in BChE were at the bottom of the gorge in close proximity to the catalytic residues in the active site. In contrast, the best binding positions for CaE were clustered rather far from the active site at the top of the gorge. Thus, the docking results provided insight into differences in kinetic mechanisms and inhibitor activities of the tested compounds. A cytotoxicity test using the MTT assay showed that within solubility limits (<30μM), none of the tested compounds significantly affected viability of human fetal mesenchymal stem cells. The results indicate that a new series of N,N-disubstituted 2-aminothiazolines could serve as BChE and CaE inhibitors for potential medicinal applications.

Authors+Show Affiliations

Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia.Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia.Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia; Emanuel Institute of Biochemical Physics Russian Academy of Sciences, Moscow 119334, Russia.Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia.Institute of Problems of Chemical Physics Russian Academy of Sciences, Chernogolovka 142432, Russia.Institute of Problems of Chemical Physics Russian Academy of Sciences, Chernogolovka 142432, Russia.Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia.Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia.Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia.Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: rjrich@umich.edu.

Pub Type(s)

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

Language

eng

PubMed ID

26827140

Citation

Makhaeva, Galina F., et al. "Synthesis, Molecular Docking and Biological Evaluation of N,N-disubstituted 2-aminothiazolines as a New Class of Butyrylcholinesterase and Carboxylesterase Inhibitors." Bioorganic & Medicinal Chemistry, vol. 24, no. 5, 2016, pp. 1050-62.
Makhaeva GF, Boltneva NP, Lushchekina SV, et al. Synthesis, molecular docking and biological evaluation of N,N-disubstituted 2-aminothiazolines as a new class of butyrylcholinesterase and carboxylesterase inhibitors. Bioorg Med Chem. 2016;24(5):1050-62.
Makhaeva, G. F., Boltneva, N. P., Lushchekina, S. V., Serebryakova, O. G., Stupina, T. S., Terentiev, A. A., Serkov, I. V., Proshin, A. N., Bachurin, S. O., & Richardson, R. J. (2016). Synthesis, molecular docking and biological evaluation of N,N-disubstituted 2-aminothiazolines as a new class of butyrylcholinesterase and carboxylesterase inhibitors. Bioorganic & Medicinal Chemistry, 24(5), 1050-62. https://doi.org/10.1016/j.bmc.2016.01.031
Makhaeva GF, et al. Synthesis, Molecular Docking and Biological Evaluation of N,N-disubstituted 2-aminothiazolines as a New Class of Butyrylcholinesterase and Carboxylesterase Inhibitors. Bioorg Med Chem. 2016 Mar 1;24(5):1050-62. PubMed PMID: 26827140.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis, molecular docking and biological evaluation of N,N-disubstituted 2-aminothiazolines as a new class of butyrylcholinesterase and carboxylesterase inhibitors. AU - Makhaeva,Galina F, AU - Boltneva,Natalia P, AU - Lushchekina,Sofya V, AU - Serebryakova,Olga G, AU - Stupina,Tatyana S, AU - Terentiev,Alexey A, AU - Serkov,Igor V, AU - Proshin,Alexey N, AU - Bachurin,Sergey O, AU - Richardson,Rudy J, Y1 - 2016/01/18/ PY - 2015/11/05/received PY - 2016/01/04/revised PY - 2016/01/17/accepted PY - 2016/2/1/entrez PY - 2016/2/2/pubmed PY - 2016/11/1/medline KW - Acetylcholinesterase KW - Alzheimer’s disease KW - Butyrylcholinesterase KW - Carboxylesterase KW - Molecular docking KW - N,N-Disubstituted 2-aminothiazolines SP - 1050 EP - 62 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 24 IS - 5 N2 - A series of 31 N,N-disubstituted 2-amino-5-halomethyl-2-thiazolines was designed, synthesized, and evaluated for inhibitory potential against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carboxylesterase (CaE). The compounds did not inhibit AChE; the most active compounds inhibited BChE and CaE with IC50 values of 0.22-2.3μM. Pyridine-containing compounds were more selective toward BChE; compounds with the para-OMe substituent in one of the two dibenzyl fragments were more selective toward CaE. Iodinated derivatives were more effective BChE inhibitors than brominated ones, while there was no influence of halogen type on CaE inhibition. Inhibition kinetics for the 9 most active compounds indicated non-competitive inhibition of CaE and varied mechanisms (competitive, non-competitive, or mixed-type) for inhibition of BChE. Docking simulations predicted key binding interactions of compounds with BChE and CaE and revealed that the best docked positions in BChE were at the bottom of the gorge in close proximity to the catalytic residues in the active site. In contrast, the best binding positions for CaE were clustered rather far from the active site at the top of the gorge. Thus, the docking results provided insight into differences in kinetic mechanisms and inhibitor activities of the tested compounds. A cytotoxicity test using the MTT assay showed that within solubility limits (<30μM), none of the tested compounds significantly affected viability of human fetal mesenchymal stem cells. The results indicate that a new series of N,N-disubstituted 2-aminothiazolines could serve as BChE and CaE inhibitors for potential medicinal applications. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/26827140/Synthesis_molecular_docking_and_biological_evaluation_of_NN_disubstituted_2_aminothiazolines_as_a_new_class_of_butyrylcholinesterase_and_carboxylesterase_inhibitors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(16)30033-5 DB - PRIME DP - Unbound Medicine ER -