{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:03:11Z","timestamp":1791925391938,"version":"4.3.4"},"reference-count":62,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T00:00:00Z","timestamp":1587600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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 \u03b1-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 \u00b5M. 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.<\/jats:p>","DOI":"10.3390\/molecules25081963","type":"journal-article","created":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T10:46:22Z","timestamp":1587638782000},"page":"1963","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Three-Component Access to Functionalized Spiropyrrolidine Heterocyclic Scaffolds and Their Cholinesterase Inhibitory Activity"],"prefix":"10.3390","volume":"25","author":[{"given":"Sarra","family":"Boudriga","sequence":"first","affiliation":[{"name":"Department of Chemistry, Laboratory of Heterocyclic Chemistry Natural Product and Reactivity\/CHPNR, Faculty of Science of Monastir, Monastir 5000, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saoussen","family":"Haddad","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Laboratory of Heterocyclic Chemistry Natural Product and Reactivity\/CHPNR, Faculty of Science of Monastir, Monastir 5000, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikneswaran","family":"Murugaiyah","sequence":"additional","affiliation":[{"name":"Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, USM 11800, Penang, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moheddine","family":"Askri","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Laboratory of Heterocyclic Chemistry Natural Product and Reactivity\/CHPNR, Faculty of Science of Monastir, Monastir 5000, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5647-8084","authenticated-orcid":false,"given":"Michael","family":"Knorr","sequence":"additional","affiliation":[{"name":"Institut UTINAM-UMR CNRS 6213, Universit\u00e9 Bourgogne Franche-Comt\u00e9, 16 Route de Gray, 25030 Besan\u00e7on, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4787-2135","authenticated-orcid":false,"given":"Carsten","family":"Strohmann","sequence":"additional","affiliation":[{"name":"Technische Universit\u00e4t Dortmund, Anorganische Chemie Otto-Hahn-Stra\u00dfe 6, 44221 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Golz","sequence":"additional","affiliation":[{"name":"Technische Universit\u00e4t Dortmund, Anorganische Chemie Otto-Hahn-Stra\u00dfe 6, 44221 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5514","DOI":"10.1039\/c1cs15119c","article-title":"New and Unusual Scaffolds in Medicinal Chemistry","volume":"40","author":"Marson","year":"2011","journal-title":"Chem. Soc. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3673","DOI":"10.1016\/j.bmcl.2014.06.081","article-title":"The Use of Spirocyclic Scaffolds in Drug Discovery","volume":"24","author":"Zheng","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Kotha, S., Panguluri, N.R., and Ali, R. (2017). Design and Synthesis of Spirocycles. Eur. J. Org. Chem., 5316\u20135342.","DOI":"10.1002\/ejoc.201700439"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.bioorg.2019.01.016","article-title":"Design, Synthesis, Molecular Docking and Biological Activity Evaluation of Some Novel Indole Derivatives as Potent Anticancer Active Agents and Apoptosis Inducers","volume":"85","author":"Ammar","year":"2019","journal-title":"Bioorg. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.jphotobiol.2018.01.026","article-title":"Regio- and Stereoselective Synthesis of New Spirooxindoles via 1,3-Dipolar Cycloaddition Reaction: Anticancer and Molecular Docking Studies","volume":"180","author":"Lotfy","year":"2018","journal-title":"J. Photochem. Photobiol. B Biol."},{"key":"ref_6","first-page":"5225","article-title":"Anti-proliferative, Cytotoxic and NF-\u0138B Inhibitory Properties of Spiro(Lactone-Cyclohexanone) Compounds in Human Leukemia","volume":"37","author":"Bouhenna","year":"2017","journal-title":"Anticancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3820","DOI":"10.3390\/molecules24213820","article-title":"Design, Synthesis and In Vitro Mechanistic Investigation of Novel Hexacyclic Cage-Like Hybrid Heterocycles","volume":"24","author":"Kumar","year":"2019","journal-title":"Molecules"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.compbiolchem.2018.03.001","article-title":"Design, Facile Synthesis, and Evaluation of Novel Spiro- and Pyrazolo[1,5-c]quinazolines as Cholinesterase Inhibitors: Molecular Docking and MM\/GBSA Studies","volume":"74","author":"Galvez","year":"2018","journal-title":"Comput. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2621","DOI":"10.1016\/j.bmc.2019.03.058","article-title":"Dispiropyrrolidinyl-piperidone Embedded Indeno[1,2-b]quinoxaline Heterocyclic Hybrids: Synthesis, Cholinesterase Inhibitory Activity and their Molecular Docking Simulation","volume":"27","author":"Arumugam","year":"2019","journal-title":"Bioorg. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6752","DOI":"10.1021\/acs.orglett.7b03516","article-title":"Organocatalytic Asymmetric Synthesis of Spiro-oxindole Piperidine Derivatives That Reduce Cancer Cell Proliferation by Inhibiting MDM2\u2013p53 Interaction","volume":"19","author":"Yang","year":"2017","journal-title":"Org. Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3453","DOI":"10.1080\/00397911.2019.1672746","article-title":"Regioselective Synthesis and Biological Evaluation of Novel Dispiropyrrolidine Derivatives via one-pot four-Component Reaction","volume":"49","author":"Hegde","year":"2019","journal-title":"Synth. Commun."},{"key":"ref_12","first-page":"69","article-title":"Synthesis and antimicrobial activity of Bis-Derivatives of 3a\u2032, 6a\u2032Dihydro-2\u2019H-Spiro[Indole-3,1\u2019-Pyrrolo[3,4-c]Pyrrole]-2,4\u2019,6\u2019(1H, 3\u2019H, 5\u2019H)-Trione","volume":"7","author":"Redkin","year":"2017","journal-title":"J. App. Pharm. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1962","DOI":"10.3390\/molecules24101962","article-title":"Domino Multicomponent Approach for the Synthesis of Functionalized Spiro-Indeno[1,2-b]quinoxaline Heterocyclic Hybrids and Their Antimicrobial Activity, Synergistic Effect and Molecular Docking Simulation","volume":"24","author":"Almansour","year":"2019","journal-title":"Molecules"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.jphotochemrev.2017.12.004","article-title":"Chirality and stereoselectivity in photochromic reactions","volume":"34","author":"Nakagawa","year":"2018","journal-title":"J. Photochem. Photobiol. C Photochem. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Coudret, C., Chernyshev, A.V., Metelitsa, A.V., and Micheau, J.C. (2017). New Trends in Spiro-compounds Photochromic Metals Sensors: Quantitative Aspects. Photon-Working Switches, Springer.","DOI":"10.1007\/978-4-431-56544-4_1"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"15057","DOI":"10.1021\/acs.joc.8b02301","article-title":"[1]Benzothiophene-Fused Chiral Spiro Polycyclic Aromatic Compounds: Optical Resolution, Functionalization, and Optical Properties","volume":"83","author":"Takase","year":"2018","journal-title":"J. Org. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1800809","DOI":"10.1002\/aenm.201800809","article-title":"Di-Spiro-Based Hole-Transporting Materials for Highly Efficient Perovskite Solar Cells","volume":"8","author":"Gao","year":"2018","journal-title":"Adv. Energy Mater."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8257","DOI":"10.1021\/cr500127b","article-title":"Four-Membered Ring-Containing Spirocycles: Synthetic Strategies and Opportunities","volume":"114","author":"Carreira","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10147","DOI":"10.1021\/acs.jmedchem.6b00900","article-title":"Discovery of Novel Spiro[3H-indole-3,2\u2032-pyrrolidin]-2(1H)-one Compounds as Chemically Stable and Orally Active Inhibitors of the MDM2\u2212p53 Interaction","volume":"59","author":"Gollner","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.4161\/cc.9.6.10956","article-title":"Structures of Low Molecular Weight Inhibitors Bound to MDMX and MDM2 Reveal New Approaches for p53-MDMX\/ MDM2 Antagonist Drug Discovery","volume":"9","author":"Popowicz","year":"2010","journal-title":"Cell Cycle"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/S0065-7743(00)35027-8","article-title":"Privileged Structures an Update","volume":"Volume 35","author":"Doherty","year":"2000","journal-title":"Annual Reports in Medicinal Chemistry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2819","DOI":"10.1021\/acs.jmedchem.6b01665","article-title":"Discovery of 4-((3\u2032R,4\u2032S,5\u2032R)-6\u2033-Chloro-4\u2032-(3-chloro-2-fluorophenyl)-1\u2032-ethyl-2\u2033-oxodispiro[cyclohexane-1,2\u2032-pyrrolidine-3\u2032,3\u2033-indoline]-5\u2032-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115\/APG115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development","volume":"60","author":"Aguilar","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"8748","DOI":"10.1002\/anie.200701342","article-title":"Pyrrolidinyl-Spirooxindole Natural Products as Inspirations for the Development of Potential Therapeutic Agents","volume":"46","author":"Gallifordand","year":"2007","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1016\/j.bmcl.2013.01.023","article-title":"Facile One-Pot Synthesis of Novel Dispirooxindole-Pyrrolidine Derivatives and Their Antimicrobial and Anticancer Activity Against A549 Human Lung Adenocarcinoma Cancer Cell Line","volume":"23","author":"Arun","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1016\/j.bmcl.2012.12.069","article-title":"A Facile Three-Component [3+2]-Cycloaddition for the Regioselective Synthesis of Highly Functionalised Dispiropyrrolidines Acting as Antimycobacterial Agents","volume":"23","author":"Wei","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"59462","DOI":"10.1039\/C4RA11940A","article-title":"Synthesis of Novel Dispiropyrrolothiazoles by Three-Component 1,3-Cipolar Cycloaddition and Evaluation of Their Antimycobacterial Activity","volume":"4","author":"Haddad","year":"2014","journal-title":"RSC Adv."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.bioorg.2018.04.025","article-title":"Spiropyrrolidine\/spiroindolizino[6,7-b]indole heterocyclic hybrids: Stereoselective Synthesis, Cholinesterase Inhibitory Activity and Their Molecular Docking Study","volume":"79","author":"Arumugama","year":"2018","journal-title":"Bioorg. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3947","DOI":"10.1055\/s-0037-1610209","article-title":"Recent Advances in the Synthesis of Hetero- and Carbocyclic Compounds and Complexes Based on Acenaphthylene-1,2-dione","volume":"50","author":"Yavari","year":"2018","journal-title":"Synthesis"},{"key":"ref_29","first-page":"312","article-title":"Synthesis, Characterisation and Anti-Microbial Activity Studies of Novel Dispiro-Oxindolopyrrolizidines","volume":"2","author":"Babu","year":"2008","journal-title":"Curr. Chem. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1002\/cmdc.201800617","article-title":"Targeted Synthesis of Complex Spiro[3H-indole-3,2\u00b4-pyrrolidin]-2(1H)-ones by a Novel Intramolecular Cyclization of Azomethine Ylides as Highly Potent MDM2\u2013p53 Inhibitors","volume":"14","author":"Gollner","year":"2019","journal-title":"Chem. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1080\/00397911.2016.1211704","article-title":"Review of synthesis and various biological activities of spiro heterocyclic compounds comprising oxindole and pyrrolidine moieties","volume":"46","author":"Saraswat","year":"2016","journal-title":"Synth. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1007\/s13538-018-0613-5","article-title":"Crystal Structure, Spectral, Electronic, NLO Studies, and Bioactivity of 3\u2032-(1-Benzyl-5-Methyl-1H-1,2,3-Triazole-4-Carbonyl)-4\u2032-(4-Bromophenyl)-1\u2032-Methyl-2H-Spiro [Acenaphthylene-1,2\u2032-Pyrrolidine]-2-One","volume":"49","author":"Jesudoss","year":"2018","journal-title":"Braz. J. Phys."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1002\/jccs.201800128","article-title":"Structure Investigation, Spectral Characterization, Electronic Properties, and Antimicrobial and Molecular Docking Studies of 3\u2019-(1-benzyl-5-methyl-1H-1,2,3-triazole-4-carbonyl)-1\u2019-methyl4\u2019-phenyl-2H-spiro[acenaphthylene-1,2\u2019-pyrrolidine]-2-one","volume":"66","author":"Malarkodi","year":"2019","journal-title":"J. Chin. Chem. Soc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"486","DOI":"10.4172\/2161-0444.1000387","article-title":"Design, Synthesis and Antimycobacterial Activity of Dispiropyrrolidines Derivatives","volume":"6","author":"Hassan","year":"2016","journal-title":"Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6821","DOI":"10.1016\/j.tet.2018.09.055","article-title":"Diastereospecific Entry to Pyrrolidinyldispirooxindole Skeletons via three-Component 1,3-Dipolar Cycloadditions","volume":"74","author":"Qian","year":"2018","journal-title":"Tetrahedron"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3336","DOI":"10.1016\/j.tetlet.2018.07.051","article-title":"Dipolar Cycloaddition Based Multi-Component Reaction: Synthesis of Spiro Tethered Acenaphthylene\u2013Indolizine\u2013Pyridinone Hybrids","volume":"59","author":"Kumar","year":"2018","journal-title":"Tetrahedron Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4086","DOI":"10.1016\/j.tetlet.2018.10.002","article-title":"Synthesis of Spiro-Linked Quinolinone-Pyrrolidine\/Pyrrolo[1,2-c] Thiazole-Oxindole\/Acenaphthalene Hybrids via Multi-component [3 + 2] Cycloaddition","volume":"59","author":"Sumesh","year":"2018","journal-title":"Tetrahedron Lett."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1021\/acscombsci.6b00011","article-title":"One-pot Access to a Library of Dispiro Oxindole-Pyrrolidine\/Pyrrolothiazolethiochromane Hybrids via Three-component 1,3-Dipolar Cycloaddition Reactions","volume":"18","author":"Rani","year":"2016","journal-title":"ACS Comb. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1021\/acscombsci.6b00186","article-title":"A One-Pot Multicomponent 1,3-Dipolar Cycloaddition Strategy: Combinatorial Synthesis of Dihydrothiophenone-Engrafted Dispiro Hybrid Heterocycles","volume":"19","author":"Rani","year":"2017","journal-title":"ACS Comb. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5358","DOI":"10.1016\/j.tet.2018.04.032","article-title":"Regio- and Diastereoselective Synthesis of Anticancer Spirooxindoles Derived from Tryptophan and Histidine via Three-Component 1,3-Dipolar Cycloadditions in an Ionic Liquid","volume":"74","author":"Arumugam","year":"2018","journal-title":"Tetrahedron"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1080\/00397911.2018.1425726","article-title":"Efficient Synthesis of Spirooxindole-Pyrrolizidines and Dispirooxindole-Piperazines","volume":"48","author":"Tiwari","year":"2018","journal-title":"Synth. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.ejphar.2007.06.058","article-title":"Lurasidone (SM-13496), A Novel Atypical Antipsychotic Drug, Reverses MK-801-Induced Impairment of Learning and Memory in The Rat Passive-Avoidance Test","volume":"572","author":"Ishiyama","year":"2007","journal-title":"Eur. J. Pharmacol."},{"key":"ref_43","first-page":"8","article-title":"Succinimides: Synthesis, Reaction and Biological Activity","volume":"6","author":"Patil","year":"2014","journal-title":"Int. J. Pharm. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5577","DOI":"10.1016\/j.tet.2005.03.099","article-title":"Hirsutellones A\u2014E, Antimycobacterial Alkaloids from the Insect Pathogenic Fungus Hirsutella nivea BCC 2594","volume":"61","author":"Isaka","year":"2005","journal-title":"Tetrahedron"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.ejmech.2013.10.069","article-title":"Synthesis of 3-Heteryl Substituted Pyrrolidine-2,5-diones via Catalytic Michael Reaction and Evaluation of Their Inhibitory Activity Against InhA and Mycobacterium Tuberculosis","volume":"71","author":"Matviiuk","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e3135","DOI":"10.1002\/psc.3135","article-title":"Synthesis, in vitro Stability, and Antiproliferative Effect of D-cysteine Modified GnRH-doxorubicin Conjugates","volume":"25","author":"Zhao","year":"2019","journal-title":"J. Pept. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1021\/acschemneuro.8b00476","article-title":"KA-11, A Novel Pyrrolidine-2,5-dione Derived Broad-Spectrum Anticonvulsant: Its Antiepileptogenic, Antinociceptive Properties and in vitro Characterization","volume":"10","author":"Socala","year":"2019","journal-title":"ACS Chem. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.ejphar.2016.04.033","article-title":"Anticonvulsant and antinociceptive activity of new amides derived from 3-phenyl-2,5-dioxo-pyrrolidine-1-yl-acetic acid in mice","volume":"781","author":"Rapacz","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1002\/jhet.3532","article-title":"Straightforward and Highly Diastereoselective Synthesis of a New Set of Functionalized Dispiropyrrolidines Involving Multicomponent 1,3-Dipolar Cycloaddition with Azomethine Ylides","volume":"56","author":"Boudriga","year":"2019","journal-title":"J. Het. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"11082","DOI":"10.1039\/C8RA09884K","article-title":"Highly Diastereoselective Donstruction of Noveldispiropyrrolo[2,1-a]isoquinoline Derivatives via Multicomponent 1,3-Dipolar Dycloaddition of Dyclic Diketones-Based Tetrahydroisoquinolinium N-Ylides","volume":"9","author":"Boudriga","year":"2019","journal-title":"RSC Adv."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1039\/C4NJ01008F","article-title":"A Strategic Approach to the Synthesis of Functionalized Spirooxindole Pyrrolidine Derivatives: In vitro Antibacterial, Antifungal, Antimalarial and Antitubercular studies","volume":"39","author":"Haddad","year":"2015","journal-title":"New J. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"9064","DOI":"10.1021\/acs.joc.5b01399","article-title":"Regio- and Stereoselective Synthesis of Spiropyrrolizidines and Piperazines through Azomethine Ylide Cycloaddition Reaction","volume":"80","author":"Haddad","year":"2015","journal-title":"J. Org. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4308","DOI":"10.1016\/j.bmcl.2015.07.069","article-title":"Design of Novel Dispirooxindolopyrrolidine and Dispirooxindolopyrrolothiazole Derivatives as Potential Antitubercular Agents","volume":"25","author":"Mhiri","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2621","DOI":"10.1016\/S0040-4039(01)98296-6","article-title":"The Role of Secondary Orbital Interactions in Cycloaddition Reactions","volume":"30","author":"Houk","year":"1970","journal-title":"Tetrahedron Lett."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"32303","DOI":"10.1039\/C4RA03508A","article-title":"Regio- and Stereoselective Synthesis of Novel Spiropyrrolidines through 1,3-dipolar Cycloaddition Reactions of Azomethine Ylides and 2-Styrylquinazolin-4(3H)-ones","volume":"4","author":"Maurya","year":"2014","journal-title":"RSC Adv."},{"key":"ref_56","first-page":"103","article-title":"Synthesis of Novel Spirooxindolo-Pyrrolidines, Pyrrolizidines, and Pyrrolothiazoles via a Regioselective three-Component [3+2] Cycloaddition and their Preliminary Antimicrobial Evaluation","volume":"43","author":"Rosenberry","year":"1975","journal-title":"Adv. Enzymol. Relat. Areas Mol. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"105","DOI":"10.2174\/157488906775245246","article-title":"Galanthamine, a Natural Product for the Treatment of Alzheimer\u2019s Disease","volume":"1","author":"Marco","year":"2006","journal-title":"Recent Pat. CNS Drug Discov."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2500","DOI":"10.1529\/biophysj.108.129601","article-title":"Flexibility of Aromatic Residues in the Active-Site Gorge of Acetylcholinesterase: X-ray versus Molecular Dynamics","volume":"95","author":"Xu","year":"2008","journal-title":"Biophysical J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1107\/S0021889808042726","article-title":"OLEX2: A Complete Structure Solution, Refinement and Analysis Program","volume":"42","author":"Dolomanov","year":"2009","journal-title":"J. Appl. Crystallogr."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1107\/S0108767307043930","article-title":"A short history of SHELX","volume":"A64","author":"Sheldrick","year":"2008","journal-title":"Acta Crystallogr."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1002\/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B","article-title":"Automated Docking Using a Lamarckian Genetic Algorithm and An Empirical Binding Free Energy Function","volume":"19","author":"Morris","year":"1998","journal-title":"J. Comput. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"15405","DOI":"10.1021\/ja0466154","article-title":"The Complex of a Bivalent Derivative of Galanthamine with Torpedo Acetylcholinesterase Displays Drastic Deformation of the Active-Site Gorge: Implications for Structure-Based Drug Design","volume":"126","author":"Greenblatt","year":"2004","journal-title":"J. Am. Chem. 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