Synthesis and screening for acetylcholinesterase inhibitor activity of some novel 2-butyl-1,3-diaza-spiro[4,4]non-1-en-4-ones: Derivatives of irbesartan key intermediate

• Published in: Bioorganic & medicinal chemistry 2007-12, Vol.15 (23), p.7391-7398
• Main Authors: Kavitha, C.V., Gaonkar, S.L., Narendra Sharath Chandra, J.N., Sadashiva, C.T., Rangappa, K.S.
• Format: Article
• Language: English
• Subjects: 2-Butyl-1,3-diaza-spiro[4,4]non-1-en-4-one; Acetylcholinesterase - blood; Acetylcholinesterase - drug effects; Acetylcholinesterase inhibitors; Animals; Aralkyl halides; Biological and medical sciences; Biphenyl Compounds - chemical synthesis; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacology; Brain - enzymology; Cholinergic system; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Eels; Enzyme Activation - drug effects; Humans; Inhibitory Concentration 50; Irbesartan; Medical sciences; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Rats; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Stereoisomerism; Structure-Activity Relationship; Tetrazoles - chemical synthesis; Tetrazoles - chemistry; Tetrazoles - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.07.014

A series of novel 2-butyl-1,3-diaza-spiro[4,4]non-1-en-4-one derivatives have been synthesized by interaction of 2-butyl-1,3-diaza-spiro[4,4]non-1-en-4-one with different bioactive aralkyl halides by two different methods viz., conventional and microwave irradiation. All the synthesized compounds have been screened for their efficacy as acetylcholinesterase (AChE) inhibitor. AChE inhibitory activity was carried out by using Ellman colorimetric assay with neostigmine as a reference standard. Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE. The association of bioactive nucleus with other pharmacological agents is hoped to improve the efficacy of the treatment by combining the effects of different pharmacological mechanisms of action. Keeping this in view, a series of 2-butyl-1,3-diaza-spiro[4,4]non-1-en-4-one derivatives have been synthesized by interaction of 2-butyl-1,3-diaza-spiro[4,4]non-1-en-4-one with different bioactive aralkyl halides in presence of powdered potassium carbonate by two different methods viz., conventional and microwave irradiation. The yields under conventional and microwave irradiation methods were in the range of 60–65% and 80–90%, respectively. The structure elucidation of the new compounds has been carried out with the help of elemental analysis and spectral data. All the synthesized compounds have been screened for their efficacy as acetylcholinesterase (AChE) inhibitor. AChE inhibitory activity study was carried out by using Ellman colorimetric assay with neostigmine as a reference standard against targets from different species, such as pure electric eel AChE, human serum AChE, and rat brain AChE. Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE.