title: Synthesis and discovery of novel piperidone-grafted mono- and bis-spirooxindole-hexahydropyrrolizines as potent cholinesterase inhibitors.
abstract: Three-component reaction of a series of 1-acryloyl-3,5-bisbenzylidenepiperidin-4-ones with isatin and L-proline in 1:1:1 and 1:2:2 molar ratios in methanol afforded, respectively the piperidone-grafted novel mono- and bisspiro heterocyclic hybrids comprising functionalized piperidine, pyrrolizine and oxindole ring systems in good yields. The in vitro evaluation of cholinesterase enzymes inhibitory activity of these cycloadducts disclosed that monospiripyrrolizines (8a-k), are more active with IC50 ranging from 3.36 to 20.07 μM than either the dipolarophiles (5a-k) or bisspiropyrrolizines (9a-k). The compounds, 8i and 8e with IC50 values of 3.36 and 3.50 μM, respectively showed the maximum inhibition of acethylcholinesterase (AChE) and butrylylcholinestrase (BuChE). Molecular modeling simulation, disclosed the binding interactions of the most active compounds to the active site residues of their respective enzymes. The docking results were in accordance with the IC50 values obtained from in vitro cholinesterase assay.
authors: School of Chemical Sciences, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia.
authors: Yalda
authors: Y
authors: Kia
authors: Hasnah
authors: H
authors: Osman
authors: Raju Suresh
authors: RS
authors: Kumar
authors: Vikneswaran
authors: V
authors: Murugaiyah
authors: Alireza
authors: A
authors: Basiri
authors: Subbu
authors: S
authors: Perumal
authors: Habibah A
authors: HA
authors: Wahab
authors: Choi Sy
authors: CS
authors: Bing
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D000078183:Oxindoles; D010881:Piperidones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D007211:Indoles; D000078183:Oxindoles; D010881:Piperidones; D011758:Pyrroles; D013141:Spiro Compounds; C022960:2-oxindole; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase