One-pot synthesis of tetrazole-1,2,5,6-tetrahydronicotinonitriles and cholinesterase inhibition: Probing the plausible reaction mechanism via computational studies

• Published in: Bioorganic chemistry 2016-04, Vol.65, p.38-47
• Main Authors: Hameed, Abdul, Zehra, Syeda Tazeen, Abbas, Saba, Nisa, Riffat Un, Mahmood, Tariq, Ayub, Khurshid, al-Rashida, Mariya, Bajorath, Jürgen, Khan, Khalid Mohammed, Iqbal, Jamshed
• Format: Article
• Language: English
• Subjects: 1,2,5,6-Tetrahydronicotinonitrile; Acetylcholinesterase (AChE); Acetylcholinesterase - metabolism; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Butyrylcholinesterase (BChE); Butyrylcholinesterase - metabolism; Cholinergic Agents - chemical synthesis; Cholinergic Agents - chemistry; Cholinergic Agents - pharmacology; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Click chemistry; Density Functional Theory (DFT); Dose-Response Relationship, Drug; Humans; Ionic liquids; Molecular Structure; Nitriles - chemical synthesis; Nitriles - chemistry; Nitriles - pharmacology; Quantum Theory; Structure-Activity Relationship; Tetrazole
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2016.01.004

[Display omitted] •A series of tetrazole-1,2,5,6-tetrahydronicotinonitriles was synthesized.•Tetrazole-1,2,5,6-tetrahydronicotinonitriles as cholinesterase inhibitors.•Plausible reaction mechanism was studied via computational methods. In the present study, one-pot synthesis of 1H-tetrazole linked 1,2,5,6-tetrahydronicotinonitriles under solvent-free conditions have been carried out in the presence of tetra-n-butyl ammonium fluoride trihydrated (TBAF) as catalyst and solvent. Computational studies have been conducted to elaborate two plausible mechanistic pathways of this one-pot reaction. Moreover, the synthesized compounds were screened for cholinesterases (acetylcholinesterase and butyrylcholinesterase) inhibition which are consider to be major malefactors of Alzheimer’s disease (AD) to find lead compounds for further research in AD therapy.