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 novel one-pot [3+2]-cycloaddition reaction of (E)-3-arylidene-1-phenyl-succinimides, cyclic 1,2-diketones (isatin, 5-chloro-isatin and acenaphtenequinone), and diverse α-aminoacids such as 2-phenylglycine or sarcosine is reported. The reaction provides succinimide-substituted dispiropyrrolidine derivatives with high regio- and diastereoselectivities under mild reaction conditions. The stereochemistry of these N-heterocycles has been confirmed by four X-ray diffraction studies. Several synthetized compounds show higher inhibition on acetylcholinesterase (AChE) than butyrylcholinesterase (BChE). Of the 17 synthesized compounds tested, five exhibit good AChE inhibition with IC50 of 11.42 to 22.21 µM. A molecular docking study has also been undertaken for compound 4n possessing the most potent AChE inhibitory activity, disclosing its binding to the peripheral anionic site of AChE enzymes.
Series of pyrolidine analogues were synthesized and examined as acetylcholinesterase (AChE) inhibitors. Among the compounds, compounds 4k and 6k were the most potent inhibitors of the series. Compound 4k, showed potent inhibitory activity against acetyl cholinesterase enzyme with IC(50) 0.10 μmol/L. Pyrolidine analogues might be potential acetyl cholinesterase agents for AD.
A series of fourteen dispiropyrrolidines were synthesized using [3+2]-cycloaddition reactions and were screened for their antimycobacterial activity against Mycobacterium tuberculosis H(37)Rv in HTS (High Throughput Screen). Most of the compounds showed moderate to good activity with MIC of less than 20 μM. Compound 4'-(4-bromophenyl)-1'-methyldispiro[acenaphthylene-1,2'-pyrrolidine-3',2″-indane]-2,1″(1H)-dione (4c) was found to be the most active with MIC of 12.50 μM.
The aim of this study was to investigate the in vitro cellular activity of novel spiroisoxazoline type compounds against normal and cancer cell lines from lung tissue (Hs888Lu), neuron-phenotypic cells (SH-SY5Y), neuroblastoma (SH-SY5Y), human histiocytic lymphoma (U937), lung cancer (A549), and leukaemia (HL-60). Our bioassay program revealed that the spiroisoxazoline type compounds show cytotoxicity only in lymphoma cell lines, which is in contrast with the pyrrolidine precursor of these spiroisoxazoline compounds, where significant cytotoxicity is seen in all normal and cancer cell lines. These data suggest a tumour-specific mechanism of action. In addition these data also show that spiroisoxazoline compounds are non-toxic in the human neuronphenotypic neuroblastoma SH-SY5Y cell line, and furthermore that they might protect cells from neurodegenerative disease.
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.
This study was carried out to determine the antinociceptive activity of a novel synthetic oxopyrrolidine-based compound, (2R,3R,4S)-ethyl 4-hydroxy-1,2-dimethyl-5-oxopyrrolidine-3-carboxylate (ASH21374), and to elucidate the involvement of the opioid, vanilloid, glutamate, and nitric oxide - cyclic guanosine monophosphate (NO/cGMP) systems in modulating the observed antinociception. ASH21374, in the doses of 2, 10, and 100 mg/kg body mass, was administered orally to mice 60 mins prior to exposure to various antinociceptive assays. From the results obtained, ASH21374 exhibited significant (P < 0.05) antinociceptive activity in the abdominal constriction, hot-plate, and formalin tests that was comparable with 100 mg/kg acetylsalicylic acid or 5 mg/kg morphine, respectively. ASH21374 also attenuated capsaicin- and glutamate-induced paw licking. Pre-treatment with 5 mg/kg naloxone significantly (P < 0.05) inhibited the activity in all assays, while pretreatment with 10 mg/kg β-funaltraxamine, 1 mg/kg naltrindole, or 1 mg/kg nor-binaltorphimine significantly (P < 0.05) reversed the activity in the abdominal constriction test. l-Arginine, N(G)-nitro-l-arginine methyl esters (l-NAME), methylene blue, and their combinations, failed to inhibit the ASH21374 antinociceptive activity. In conclusion, ASH21374 demonstrated antinociceptive activities on the peripheral and central nervous systems, mediated through the activation of opioid receptors, inhibition of the glutamatergic system, and attenuation of vanilloid-mediated nociceptive transmission. Further studies have been planned to determine the pharmacological potential of ASH21374.
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder, which affected 35 million people in the world. The most practiced approach to improve the life expectancy of AD patients is to increase acetylcholine neurotransmitter level at cholinergic synapses by inhibition of cholinesterase enzymes. A series of unreported piperidone grafted spiropyrrolidines 8(a-p) were synthesized and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. Therein, compounds 8h and 8l displayed more potent AChE enzyme inhibition than standard drug with IC50 values of 1.88 and 1.37 µM, respectively. Molecular docking simulations for 8l possessing the most potent AChE inhibitory activities, disclosed its interesting binding templates to the active site channel of AChE enzymes. These compounds are remarkable AChE inhibitors and have potential as AD drugs.
A facile stereoselective synthesis of novel dispiro indeno pyrrolidine/pyrrolothiazole-thiochroman hybrids has been achieved by 1,3-dipolar cycloaddition of azomethine ylides, generated in situ from ninhydrin and sarcosine/thiaproline, on a series of 3-benzylidenethiochroman-4-ones. The synthesised compounds were screened for their antimycobacterial, anticancer and AchE inhibition activities. Compound 4l (IC50 1.07μM) has been found to exhibit the most potent antimycobacterial activity compared to cycloserine (12 times), pyrimethamine (37 times) and ethambutol (IC50 <1.56μM) and 6l (IC50=2.87μM) is more active than both cycloserine (4 times) and pyrimethamine (12 times). Three compounds, 4a, 6b and 6i, display good anticancer activity against CCRF-CEM cell lines. Compounds 6g and 4g display maximum AchE inhibitory activity with IC50 values of 1.10 and 1.16μmol/L respectively.
Orexins (also called hypocretins) are implicated in reward and addiction, but little is known about their role(s) in the association between hippocampal synaptic plasticity and drug preference. Previously, we found that exogenous orexin via OX1 and OX2 receptors can impair low frequency stimulation-induced depotentiation, i.e. restoring potentiation of excitatory synaptic transmission (re-potentiation) in mouse hippocampal slices. Here, we found this re-potentiation in hippocampal slices from mice that had acquired conditioned place preference (CPP) to cocaine. Both 10 and 20 mg/kg of cocaine induced similar magnitudes of CPP in mice and re-potentiation in their hippocampal slices, but differed in their susceptibility to TCS1102, a dual (OX1 and OX2 ) orexin receptor antagonist. TCS1102 significantly attenuated CPP and hippocampal re-potentiation induced by cocaine at 10 mg/kg but not at 20 mg/kg. Nonetheless, SCH23390, an antagonist of dopamine D1-like receptors (D1-likeRs), inhibited the effects induced by both doses of cocaine. SKF38393, a D1-likeR-selective agonist, also induced hippocampal re-potentiation in vitro. Interestingly, this effect was attenuated by TCS1102. Conversely, SCH23390 prevented orexin A-induced hippocampal re-potentiation. These results suggest that endogenous orexins are released in mice during cocaine-CPP acquisition, which sustains potentiated hippocampal transmission via OX1 /OX2 receptors and may contribute to the addiction memory of cocaine. This effect of endogenous orexins, however, may be substituted by dopamine that may dominate hippocampal re-potentiation and CPP via D1-likeRs when the reinforcing effect of cocaine is high.