Ionic liquid mediated synthesis of mono- and bis-spirooxindole-hexahydropyrrolidines as cholinesterase inhibitors and their molecular docking studies.
One pot, three-component reaction of 1-acryloyl-3,5-bisarylmethylidenepiperidin-4-ones with isatin and sarcosine in molar ratios of 1:1:1 and 1:2:2 furnished to mono- and bis-spiropyrrolidine heterocyclic hybrids comprising functionalized piperidine, pyrrolidine and oxindole structural motifs. Both mono and bis-spiropyrrolidines displayed good inhibitory activity against acetylcholinesterase (AChE) with IC₅₀ values of 2.36-9.43 μM. For butyrylcholinesterase (BChE), mono-cycloadducts in series 8 with IC₅₀ values of lower than 10 μM displayed better inhibitory activities than their bis-cycloadduct analogs in series 9 with IC₅₀ values of 7.44-19.12 μM. The cycloadducts 9j and 8e were found to be the most potent AChE and BChE inhibitors with IC₅₀ values of 2.35 and 3.21 μM, respectively. Compound 9j was found to be competitive inhibitor of AChE while compound 8e was a mixed-mode inhibitor of BChE with calculated Ki values of 2.01 and 6.76 μM, respectively. Molecular docking on Torpedo californica AChE and human BChE showed good correlation between IC₅₀ values and free binding energy values of the synthesized compounds docked into the active site of the enzymes.
School of Chemical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia.
Yalda
Y
Kia
School of Chemical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia. Electronic address: osman.hasnah2012@yahoo.com.
Hasnah
H
Osman
Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh, Saudi Arabia. Electronic address: sraju@ksu.edu.sa.
Raju Suresh
RS
Kumar
School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia.
Alireza
A
Basiri
School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia.
Vikneswaran
V
Murugaiyah
D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D052578:Ionic Liquids / Q000737:chemistry*; D007700:Kinetics; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D000078183:Oxindoles; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry*; D014101:Torpedo / Q000378:metabolism
D002800:Cholinesterase Inhibitors; D007211:Indoles; D052578:Ionic Liquids; D000078183:Oxindoles; D011759:Pyrrolidines; D013141:Spiro Compounds; C022960:2-oxindole; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
1,3-Dipolar cycloaddition; AChE; Alzheimer’s disease; BChE; Enzyme kinetic study and molecular docking; Spiropyrrolidines