A number of novel spiro-pyrrolidines/pyrrolizines derivatives were synthesized through [3+2]-cycloaddition of azomethine ylides with 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones 2a-n. Azomethine ylides were generated in situ from the reaction of 1H-indole-2,3-dione (isatin, 3) with N-methylglycine (sarcosine), phenylglycine, or proline. All compounds (50 μM) were evaluated for their antiproliferative activity against human breast carcinoma (MDA-MB-231), leukemia lymphoblastic (CCRF-CEM), and ovarian carcinoma (SK-OV-3) cells. N-α-Phenyl substituted spiro-pyrrolidine derivatives (5a-n) showed higher antiproliferative activity in MDA-MB-231 than other cancer cell lines. Among spiro-pyrrolizines 6a-n, a number of derivatives including 6a-c and 6i-m showed a comparable activity with doxorubicin in all three cell lines. Among all compounds in three classes, 6a, 6b, and 6m, were found to be the most potent derivatives showing 64%, 87%, and 74% antiproliferative activity in MDA-MB-231, SK-OV-3, and CCRF-CEM cells, respectively. Compound 6b showed an IC50 value of 3.6 mM in CCRF-CEM cells. These data suggest the potential antiproliferative activity of spiro-pyrrolidines/pyrrolizines.
A series of novel dimethoxyindanone embedded spiropyrrolidines were synthesized in ionic liquid, [bmim]Br and were evaluated for their inhibitory activities towards cholinesterases. Among the spiropyrrolidines, compound 4f exhibited the most potent activity with an IC50 value of 1.57 µM against acethylcholinesterase (AChE). Molecular docking simulation for the most active compound was employed with the aim of disclosing its binding mechanism to the active site of AChE receptor.
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.
A series of twelve dispiropyrrolidines were synthesized using [3+2]-cycloaddition reactions. The synthesized compounds were screened for their antimycobacterial activity against M. tuberculosis H(37)Rv and INH resistant M. tuberculosis strains using agar dilution method, four of them showed good activity with MIC of less than 1 μM. Compound 4'-[5-(4-fluorophenyl)pyridin-3-yl]-1'-methyldispiro[indan-2,2' pyrrolidine-3',2″-indan]-1,3,1″-trione (4b) was found to be the most active with MIC of 0.1215 and 5.121 μM, respectively.
Novel mono and bis spiropyrrolidine derivatives were synthesized via an efficient ionic liquid mediated, 1,3-dipolar cycloaddition methodology and evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 1.68 to 21.85 μM, wherein compounds 8d and 8j were found to be most active inhibitors against AChE and BChE with IC50 values of 1.68 and 2.75 μM, respectively. Molecular modeling simulation on Torpedo californica AChE and human BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
A series of novel hybrid spiro heterocycles comprising pyrrolizine, spiroxindole and piperidine moieties was synthesized chemo-, regio- and stereoselectively in good yields from 1,3-dipolar cycloaddition reaction of a series of 1-acryloyl-3,5-bisarylmethylidenepiperidin-4-ones with azomethine ylides generated in situ from 5-choloroisatin and l-proline in methanol. These cycloadducts displayed significant cholinesterase inhibitory activity. Among the compounds screened, 8g and 8e, showed maximum inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinestrase (BChE) with IC50 values of 3.33 and 3.13μM, respectively.
Pyrrolothiazolyloxindole analogues share vital pharmacological properties, considered useful in Alzheimer's disease (AD). The aim of this study was synthesis and evaluate pyralothiazolyloxindole analogues if possess acetyl cholinesterase (AChE) inhibitory activity. The easily accessible one-pot synthesis of these compounds resulted to be significantly less difficult and expensive than that of donepezil. Several compounds possess anti-cholinesterase activity in the order of micro and sub-micromolar. Particularly, compound was the most potent inhibitors of the series against acetyl cholinesterase enzyme with IC(50) 0.11μmol/L.