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Synthesis and biological evaluation of 1,3,4-thiadiazole analogues as novel AChE and BuChE inhibitors.
Eur J Med Chem. 2013 Apr; 62:311-9.EJ

Abstract

In this paper a series of new 1,3,4-thiadiazole derivatives has been designed, synthesized and evaluated as the acetyl- and butyrylcholinesterase inhibitors. Some analogues showed promising inhibition of both enzymes in vitro in the nM range. Generally, inhibitory potency of compounds was stronger against AChE than BuChE, and one of them was 1154-fold more active inhibiting AChE (IC50 = 0.17 μM) than BuChE. The kinetic studies showed that one of the most active analogues 8 (IC50 = 0.09 μM, AChE) acted as a non-competitive AChE inhibitor and was characterized by the high selectivity index (300). The other derivative (1) exhibited a mixed-type of AChE inhibition. Docking simulations enabled the detection of key binding interactions of the compounds with AChE and revealed that they occupied mainly the catalytic active site. The scoring function for the novel compounds was similar or higher than for the reference inhibitor. Additionally, based on Lipinski and other filters, the drug-likeness of compounds was assessed. They revealed that the compounds possess properties which can suggest the favourable pharmacokinetics in the human body after oral admission.

Authors+Show Affiliations

Department of Chemistry, University of Life Sciences, Akademicka 15, 20-950 Lublin, Poland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

23376249

Citation

Skrzypek, Alicja, et al. "Synthesis and Biological Evaluation of 1,3,4-thiadiazole Analogues as Novel AChE and BuChE Inhibitors." European Journal of Medicinal Chemistry, vol. 62, 2013, pp. 311-9.
Skrzypek A, Matysiak J, Niewiadomy A, et al. Synthesis and biological evaluation of 1,3,4-thiadiazole analogues as novel AChE and BuChE inhibitors. Eur J Med Chem. 2013;62:311-9.
Skrzypek, A., Matysiak, J., Niewiadomy, A., Bajda, M., & Szymański, P. (2013). Synthesis and biological evaluation of 1,3,4-thiadiazole analogues as novel AChE and BuChE inhibitors. European Journal of Medicinal Chemistry, 62, 311-9. https://doi.org/10.1016/j.ejmech.2012.12.060
Skrzypek A, et al. Synthesis and Biological Evaluation of 1,3,4-thiadiazole Analogues as Novel AChE and BuChE Inhibitors. Eur J Med Chem. 2013;62:311-9. PubMed PMID: 23376249.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis and biological evaluation of 1,3,4-thiadiazole analogues as novel AChE and BuChE inhibitors. AU - Skrzypek,Alicja, AU - Matysiak,Joanna, AU - Niewiadomy,Andrzej, AU - Bajda,Marek, AU - Szymański,Paweł, Y1 - 2013/01/11/ PY - 2012/09/08/received PY - 2012/11/19/revised PY - 2012/12/22/accepted PY - 2013/2/5/entrez PY - 2013/2/5/pubmed PY - 2013/10/18/medline SP - 311 EP - 9 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 62 N2 - In this paper a series of new 1,3,4-thiadiazole derivatives has been designed, synthesized and evaluated as the acetyl- and butyrylcholinesterase inhibitors. Some analogues showed promising inhibition of both enzymes in vitro in the nM range. Generally, inhibitory potency of compounds was stronger against AChE than BuChE, and one of them was 1154-fold more active inhibiting AChE (IC50 = 0.17 μM) than BuChE. The kinetic studies showed that one of the most active analogues 8 (IC50 = 0.09 μM, AChE) acted as a non-competitive AChE inhibitor and was characterized by the high selectivity index (300). The other derivative (1) exhibited a mixed-type of AChE inhibition. Docking simulations enabled the detection of key binding interactions of the compounds with AChE and revealed that they occupied mainly the catalytic active site. The scoring function for the novel compounds was similar or higher than for the reference inhibitor. Additionally, based on Lipinski and other filters, the drug-likeness of compounds was assessed. They revealed that the compounds possess properties which can suggest the favourable pharmacokinetics in the human body after oral admission. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/23376249/Synthesis_and_biological_evaluation_of_134_thiadiazole_analogues_as_novel_AChE_and_BuChE_inhibitors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(13)00021-4 DB - PRIME DP - Unbound Medicine ER -