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  1. Bioactive constituents from the marine crinoid Himerometra magnipinna
    Shao N, Yao G, Chang LC
    J Nat Prod, 2007 May;70(5):869-71.
    PMID: 17428090
    A new tetrabromospirocyclohexadienylisoxazole, (+)-12-hydroxyhomoaerothionin (1), together with the known compounds (+)-aerothionin (2) and crinemodin-rhodoptilometrin bianthrone (3), were isolated from the marine crinoid Himerometra magnipinna, which had been collected in the South China Sea, Malaysia. The structure of 1 was elucidated by interpretation of 1D 1H and 13C NMR spectra and 2D 1H-1H COSY, HMQC, and HMBC spectra. This is the first report of tetrabromospirocyclohexadienylisoxazole compounds from a crinoid of Himerometra. Compounds 1-3 were evaluated for their inhibitory activity with the hyphae formation inhibition assay in Streptomyces 85E.
    Matched MeSH terms: Spiro Compounds/isolation & purification*; Spiro Compounds/pharmacology; Spiro Compounds/chemistry
  2. Synthesis and discovery of novel piperidone-grafted mono- and bis-spirooxindole-hexahydropyrrolizines as potent cholinesterase inhibitors
    Kia Y, Osman H, Kumar RS, Murugaiyah V, Basiri A, Perumal S, et al.
    Bioorg Med Chem, 2013 Apr 1;21(7):1696-707.
    PMID: 23454132 DOI: 10.1016/j.bmc.2013.01.066
    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.
    Matched MeSH terms: Spiro Compounds/chemical synthesis; Spiro Compounds/pharmacology; Spiro Compounds/chemistry
  3. Antimycobacterial activity: a facile three-component [3+2]-cycloaddition for the regioselective synthesis of highly functionalised dispiropyrrolidines
    Wei AC, Ali MA, Yoon YK, Ismail R, Choon TS, Kumar RS, et al.
    Bioorg Med Chem Lett, 2012 Aug 1;22(15):4930-3.
    PMID: 22749825 DOI: 10.1016/j.bmcl.2012.06.047
    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.
    Matched MeSH terms: Spiro Compounds/chemical synthesis*; Spiro Compounds/pharmacology; Spiro Compounds/chemistry
  4. Synthesis and discovery of highly functionalized mono- and bis-spiro-pyrrolidines as potent cholinesterase enzyme inhibitors
    Kia Y, Osman H, Suresh Kumar R, Basiri A, Murugaiyah V
    Bioorg Med Chem Lett, 2014 Apr 1;24(7):1815-9.
    PMID: 24594354 DOI: 10.1016/j.bmcl.2014.02.019
    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.
    Matched MeSH terms: Spiro Compounds/chemical synthesis; Spiro Compounds/pharmacology*; Spiro Compounds/chemistry
  5. Fulltext Facile, regio- and diastereoselective synthesis of spiro-pyrrolidine and pyrrolizine derivatives and evaluation of their antiproliferative activities
    Almansour AI, Kumar RS, Beevi F, Shirazi AN, Osman H, Ismail R, et al.
    Molecules, 2014 Jul 10;19(7):10033-55.
    PMID: 25014532 DOI: 10.3390/molecules190710033
    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.
    Matched MeSH terms: Spiro Compounds/chemical synthesis*; Spiro Compounds/pharmacology*
  6. Fulltext Three-Component Access to Functionalized Spiropyrrolidine Heterocyclic Scaffolds and Their Cholinesterase Inhibitory Activity
    Boudriga S, Haddad S, Murugaiyah V, Askri M, Knorr M, Strohmann C, et al.
    Molecules, 2020 Apr 23;25(8).
    PMID: 32340203 DOI: 10.3390/molecules25081963
    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.
    Matched MeSH terms: Spiro Compounds/pharmacology*; Spiro Compounds/chemistry*
  7. Potent antibacterial activity of halogenated metabolites from Malaysian red algae, Laurencia majuscula (Rhodomelaceae, Ceramiales)
    Vairappan CS
    Biomol. Eng., 2003 Jul;20(4-6):255-9.
    PMID: 12919806
    Red algae genus Laurencia (Rhodomelaceae, Ceramiales) are known to produce a wide range of chemically interesting secondary halogenated metabolites. This investigation delves upon extraction, isolation, structural elucidation and antibacterial activity of inherently available secondary metabolites of Laurencia majuscula Harvey collected from two locations in waters of Sabah, Malaysia. Two major halogenated compounds, identified as elatol (1) and iso-obtusol (2) were isolated. Structures of these compounds were determined from their spectroscopic data such as IR, 1H-NMR, 13C-NMR and optical rotation. Antibacterial bioassay against human pathogenic bacteria was conducted using disc diffusion (Kirby-Bauer) method. Elatol (1) inhibited six species of bacteria, with significant antibacterial activities against Staphylococcus epidermis, Klebsiella pneumonia and Salmonella sp. while iso-obtusol (2) exhibited antibacterial activity against four bacterial species with significant activity against K. pneumonia and Salmonella sp. Elatol (1) showed equal and better antibacterial activity compared with tested commercial antibiotics while iso-obtusol (2) only equaled the potency of commercial antibiotics against K. pneumonia and Salmonella sp. Further tests conducted using dilution method showed both compounds as having bacteriostatic mode of action against the tested bacteria.
    Matched MeSH terms: Spiro Compounds/metabolism; Spiro Compounds/pharmacology*; Spiro Compounds/chemistry*
  8. A facile chemo-, regio- and stereoselective synthesis and cholinesterase inhibitory activity of spirooxindole-pyrrolizine-piperidine hybrids
    Kia Y, Osman H, Kumar RS, Murugaiyah V, Basiri A, Perumal S, et al.
    Bioorg Med Chem Lett, 2013 May 15;23(10):2979-83.
    PMID: 23570788 DOI: 10.1016/j.bmcl.2013.03.027
    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.
    Matched MeSH terms: Spiro Compounds/chemical synthesis; Spiro Compounds/pharmacology*; Spiro Compounds/chemistry
  9. Fulltext Characterization of agarwood incense using gas chromatography - mass spectrometry (GC-MS) coupled with Solid Phase Micro Extraction (SPME) and Gas Chromatography - Flame Ionization Detector (GC-FID)
    Nurlaila Ismail, Mohd Hezri Fazalul Rahiman, Mohd Nasir Taib, Mastura Ibrahim, Seema Zareen, Saiful Nizam Tajuddin
    Scientific Research Journal, 2015;12(2):0-0.
    MyJurnal
    This paper presents the application of Solid Phase Micro Extraction (SPME) coupled with Gas Chromatography - Mass Spectrometry (GC-MS) and Gas Chromatography - Flame Ionization Detector (GC-FID) in characterizing the agarwood incense. The work involved three types of SPME fibres at 30 minute sampling time. The fibres are 50/30 μm divinylbenzene-carboxen-polydimethysiloxane (DVB-CAR-PDMS), 65 μm polydi methylsiloxane-divinylbenzene (PDMS-DVB) and 85 μm carboxen-polydimethyl siloxane (CAR-PDMS). The results showed that among the many compounds extracted by GC-MS coupled with SPME, six compounds were substantially found in high quality agarwood incense due to their high percentage area (%). They are β-maaliene, α-elemol, β-selinene, 10-epi-γ-eudesmol, agarospirol and caryophellene oxide. The finding offers a new approach for establishing the volatile profile of agarwood incense components as well as for agarwood grading and discrimination.
    Matched MeSH terms: Spiro Compounds
  10. Fulltext A Basis for Rapid Clearance of Circulating Ring-Stage Malaria Parasites by the Spiroindolone KAE609
    Zhang R, Suwanarusk R, Malleret B, Cooke BM, Nosten F, Lau YL, et al.
    J Infect Dis, 2016 Jan 1;213(1):100-4.
    PMID: 26136472 DOI: 10.1093/infdis/jiv358
    Recent clinical trials revealed a surprisingly rapid clearance of red blood cells (RBCs) infected with malaria parasites by the spiroindolone KAE609. Here, we show that ring-stage parasite-infected RBCs exposed to KAE609 become spherical and rigid, probably through osmotic dysregulation consequent to the disruption of the parasite's sodium efflux pump (adenosine triphosphate 4). We also show that this peculiar drug effect is likely to cause accelerated splenic clearance of the rheologically impaired Plasmodium vivax- and Plasmodium falciparum-infected RBCs.
    Matched MeSH terms: Spiro Compounds/pharmacology*
  11. Fulltext A facile ionic liquid promoted synthesis, cholinesterase inhibitory activity and molecular modeling study of novel highly functionalized spiropyrrolidines
    Almansour AI, Kumar RS, Arumugam N, Basiri A, Kia Y, Ali MA, et al.
    Molecules, 2015 Jan 29;20(2):2296-309.
    PMID: 25642838 DOI: 10.3390/molecules20022296
    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.
    Matched MeSH terms: Spiro Compounds/chemical synthesis*
  12. New anti-bacterial halogenated tricyclic sesquiterpenes from Bornean Laurencia majuscula (Harvey) Lucas
    Kamada T, Phan CS, Vairappan CS
    Nat Prod Res, 2019 Feb;33(4):464-471.
    PMID: 29092618 DOI: 10.1080/14786419.2017.1396593
    Three new halogenated tricyclic sesquiterpenes, omphalaurediol (1), rhodolaurenones B (2) and C (3) were isolated together with nine known haloganated sesquiterpenes such as rhodolaurenone A (4), rhodolaureol (5), isorhodolaureol (6), (-)-laurencenone D (7), elatol (8), (+)-deschloroelatol (9), cartilagineol (10), (+)-laurencenone B (11) and 2-chloro-3-hydroxy-α-chamigren-9-one (12) from a population of Bornean red algae Laurencia majuscula. The structures of three new metabolites were determined based on their spectroscopic data (IR, 1D and 2D NMR, and MS). These compounds showed antibacterial activity against three human pathogenic bacteria (Escherichia coli, Salmonella typhi and Vibrio cholera).
    Matched MeSH terms: Spiro Compounds/pharmacology; Spiro Compounds/chemistry
  13. AChE inhibitor: a regio- and stereo-selective 1,3-dipolar cycloaddition for the synthesis of novel substituted 5,6-dimethoxy spiro[5.3']-oxindole-spiro-[6.3″]-2,3-dihydro-1H-inden-1″-one-7-(substituted aryl)-tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole
    Ashraf Ali M, Ismail R, Choon TS, Kumar RS, Osman H, Arumugam N, et al.
    Bioorg Med Chem Lett, 2012 Jan 1;22(1):508-11.
    PMID: 22142546 DOI: 10.1016/j.bmcl.2011.10.087
    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.
    Matched MeSH terms: Spiro Compounds/chemical synthesis*; Spiro Compounds/pharmacology
  14. A facile stereoselective synthesis of dispiro-indeno pyrrolidine/pyrrolothiazole-thiochroman hybrids and evaluation of their antimycobacterial, anticancer and AchE inhibitory activities
    Bharkavi C, Vivek Kumar S, Ashraf Ali M, Osman H, Muthusubramanian S, Perumal S
    Bioorg Med Chem, 2016 11 15;24(22):5873-5883.
    PMID: 27687968 DOI: 10.1016/j.bmc.2016.09.044
    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.
    Matched MeSH terms: Spiro Compounds/pharmacology; Spiro Compounds/chemistry
  15. Ionic liquid mediated synthesis of mono- and bis-spirooxindole-hexahydropyrrolidines as cholinesterase inhibitors and their molecular docking studies
    Kia Y, Osman H, Kumar RS, Basiri A, Murugaiyah V
    Bioorg Med Chem, 2014 Feb 15;22(4):1318-28.
    PMID: 24461561 DOI: 10.1016/j.bmc.2014.01.002
    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.
    Matched MeSH terms: Spiro Compounds/chemistry*
  16. Substituted spiro [2.3'] oxindolespiro [3.2″]-5,6-dimethoxy-indane-1″-one-pyrrolidine analogue as inhibitors of acetylcholinesterase
    Ali MA, Ismail R, Choon TS, Yoon YK, Wei AC, Pandian S, et al.
    Bioorg Med Chem Lett, 2010 Dec 1;20(23):7064-6.
    PMID: 20951037 DOI: 10.1016/j.bmcl.2010.09.108
    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.
    Matched MeSH terms: Spiro Compounds
  17. Exploring the Chemistry of Alkaloids from Malaysian Mitragyna speciosa (Kratom) and the Role of Oxindoles on Human Opioid Receptors
    Chear NJ, León F, Sharma A, Kanumuri SRR, Zwolinski G, Abboud KA, et al.
    J Nat Prod, 2021 04 23;84(4):1034-1043.
    PMID: 33635670 DOI: 10.1021/acs.jnatprod.0c01055
    Ten indole and oxindole alkaloids (1-10) were isolated from the freshly collected leaves of Malaysian Mitragyna speciosa (Kratom). The chemical structures of these compounds were established on the basis of extensive 1D and 2D NMR and HRMS data analysis. The spectroscopic data of mitragynine oxindole B (4) are reported herein for the first time. The spatial configuration of mitragynine oxindole B (4) was confirmed by single-crystal X-ray diffraction. Simultaneous quantification of the isolated alkaloids in the M. speciosa leaf specimens collected from different locations in the northern region of Peninsular Malaysia was also performed using UPLC-MS/MS. The oxindole alkaloids (1-4) and the indole alkaloid (10) were assessed for binding affinity at opioid receptors. Corynoxine (1) showed high binding affinity to μ-opioid receptors with a Ki value of 16.4 nM. Further, corynoxine (1) was 1.8-fold more potent than morphine in rats subjected to a nociceptive hot plate assay. These findings have important implications for evaluating the combined effects of the minor oxindole alkaloids in the overall therapeutic activity of M. speciosa.
    Matched MeSH terms: Spiro Compounds
  18. Rolapitant improves quality of life of patients receiving highly or moderately emetogenic chemotherapy
    Chasen M, Urban L, Schnadig I, Rapoport B, Powers D, Arora S, et al.
    Support Care Cancer, 2017 01;25(1):85-92.
    PMID: 27557833
    PURPOSE: Addition of rolapitant to standard antiemetic therapy improved protection against chemotherapy-induced nausea and vomiting (CINV) in phase 3 trials of patients receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC). Here, we assessed the impact of CINV on the daily lives of patients receiving HEC or MEC using the Functional Living Index-Emesis (FLIE).

    METHODS: In three double-blind phase 3 studies, patients receiving HEC or MEC were randomized 1:1 to receive oral rolapitant 180 mg or placebo prior to chemotherapy plus 5-hydroxytryptamine type 3 receptor antagonist and dexamethasone therapy. Patients completed the FLIE questionnaire on day 6 of cycle 1. Endpoints included FLIE total score, nausea and vomiting domain scores, and the proportion of patients with no impact on daily life (total score >108 [range 18-126]). We performed a prespecified analysis of the MEC/anthracycline-cyclophosphamide (AC) study and a post hoc analysis of two pooled cisplatin-based HEC studies.

    RESULTS: In the pooled HEC studies, rolapitant significantly improved the FLIE total score (114.5 vs 109.3, p 

    Matched MeSH terms: Spiro Compounds/therapeutic use*
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