Three-Component Access to Functionalized Spiropyrrolidine Heterocyclic Scaffolds and Their Cholinesterase Inhibitory Activity

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.

[1]  F. Mohammad,et al.  Design, Synthesis and In Vitro Mechanistic Investigation of Novel Hexacyclic Cage-Like Hybrid Heterocycles , 2019, Molecules.

[2]  Subramanya Hegde,et al.  Regioselective synthesis and biological evaluation of novel dispiropyrrolidine derivatives via one-pot four-component reaction , 2019, Synthetic Communications.

[3]  A. Almansour,et al.  Dispiropyrrolidinyl-piperidone embedded indeno[1,2-b]quinoxaline heterocyclic hybrids: Synthesis, cholinesterase inhibitory activity and their molecular docking simulation. , 2019, Bioorganic & medicinal chemistry.

[4]  Sarra Boudriga,et al.  Straightforward and Highly Diastereoselective Synthesis of a New Set of Functionalized Dispiropyrrolidines Involving Multicomponent 1,3‐Dipolar Cycloaddition with Azomethine Ylides , 2019, Journal of Heterocyclic Chemistry.

[5]  N. Al-Dhabi,et al.  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 , 2019, Molecules.

[6]  M. Knorr,et al.  Highly diastereoselective construction of novel dispiropyrrolo[2,1-a]isoquinoline derivatives via multicomponent 1,3-dipolar cycloaddition of cyclic diketones-based tetrahydroisoquinolinium N-ylides , 2019, RSC advances.

[7]  Julian E. Fuchs,et al.  Targeted Synthesis of Complex Spiro[3H‐indole‐3,2′‐pyrrolidin]‐2(1H)‐ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2–p53 Inhibitors , 2018, ChemMedChem.

[8]  K. Noguchi,et al.  [1]Benzothiophene-Fused Chiral Spiro Polycyclic Aromatic Compounds: Optical Resolution, Functionalization, and Optical Properties. , 2018, The Journal of organic chemistry.

[9]  Hongling Zhao,et al.  Synthesis, in vitro stability, and antiproliferative effect of d‐cysteine modified GnRH‐doxorubicin conjugates , 2018, Journal of peptide science : an official publication of the European Peptide Society.

[10]  P. Alagusundaram,et al.  Crystal Structure, Spectral, Electronic, NLO Studies, and Bioactivity of 3′-(1-Benzyl-5-Methyl-1H-1,2,3-Triazole-4-Carbonyl)-4′-(4-Bromophenyl)-1′-Methyl-2H-Spiro [Acenaphthylene-1,2′-Pyrrolidine]-2-One , 2018, Brazilian Journal of Physics.

[11]  A. Almansour,et al.  Synthesis of spiro-linked quinolinone-pyrrolidine/pyrrolo[1,2-c]thiazole-oxindole/acenaphthalene hybrids via multi-component [3 + 2] cycloaddition , 2018, Tetrahedron Letters.

[12]  J. Wang,et al.  Diastereospecific entry to pyrrolidinyldispirooxindole skeletons via three-component 1,3-dipolar cycloadditions , 2018, Tetrahedron.

[13]  P. Wlaź,et al.  KA-11, a Novel Pyrrolidine-2,5-dione Derived Broad-Spectrum Anticonvulsant: Its Antiepileptogenic, Antinociceptive Properties and in Vitro Characterization. , 2018, ACS chemical neuroscience.

[14]  S. Murugavel,et al.  Structure investigation, spectral characterization, electronic properties, and antimicrobial and molecular docking studies of 3′-(1-benzyl-5-methyl-1H -1,2,3-triazole-4-carbonyl)-1′-methyl-4′-phenyl-2H -spiro[acenaphthylene-1,2′-pyrrolidine]-2-one , 2018, Journal of the Chinese Chemical Society.

[15]  A. Almansour,et al.  Spiropyrrolidine/spiroindolizino[6,7-b]indole heterocyclic hybrids: Stereoselective synthesis, cholinesterase inhibitory activity and their molecular docking study. , 2018, Bioorganic chemistry.

[16]  I. Yavari,et al.  Recent Advances in the Synthesis of Hetero- and Carbocyclic Compounds and Complexes Based on Acenaphthylene-1,2-dione , 2018, Synthesis.

[17]  G. Periyasami,et al.  Dipolar cycloaddition based multi-component reaction: Synthesis of spiro tethered acenaphthylene–indolizine–pyridinone hybrids , 2018, Tetrahedron Letters.

[18]  A. Jen,et al.  Di‐Spiro‐Based Hole‐Transporting Materials for Highly Efficient Perovskite Solar Cells , 2018 .

[19]  Margarita Gutiérrez,et al.  Design, facile synthesis, and evaluation of novel spiro- and pyrazolo[1, 5-c]quinazolines as cholinesterase inhibitors: Molecular docking and MM/GBSA studies , 2018, Comput. Biol. Chem..

[20]  E. S. E. El Tamany,et al.  Regio- and stereoselective synthesis of new spirooxindoles via 1,3-dipolar cycloaddition reaction: Anticancer and molecular docking studies. , 2018, Journal of photochemistry and photobiology. B, Biology.

[21]  Gu He,et al.  Organocatalytic Asymmetric Synthesis of Spiro-oxindole Piperidine Derivatives That Reduce Cancer Cell Proliferation by Inhibiting MDM2-p53 Interaction. , 2017, Organic letters.

[22]  T. Ubukata,et al.  Chirality and stereoselectivity in photochromic reactions , 2017 .

[23]  S. Kotha,et al.  Design and Synthesis of Spirocycles , 2017 .

[24]  K. Bacharı,et al.  Anti-proliferative, Cytotoxic and NF-ĸB Inhibitory Properties of Spiro(Lactone-Cyclohexanone) Compounds in Human Leukemia. , 2017, Anticancer research.

[25]  A. Almansour,et al.  A One-Pot Multicomponent 1,3-Dipolar Cycloaddition Strategy: Combinatorial Synthesis of Dihydrothiophenone-Engrafted Dispiro Hybrid Heterocycles. , 2017, ACS combinatorial science.

[26]  Liu Liu,et al.  Discovery of 4-((3′R,4′S,5′R)-6″-Chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development , 2017, Journal of medicinal chemistry.

[27]  Markus J. Bauer,et al.  Discovery of Novel Spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one Compounds as Chemically Stable and Orally Active Inhibitors of the MDM2-p53 Interaction. , 2016, Journal of medicinal chemistry.

[28]  G. Jeyabalan,et al.  Review of synthesis and various biological activities of spiro heterocyclic compounds comprising oxindole and pyrrolidine moities , 2016 .

[29]  H. Osman,et al.  Design, Synthesis and Antimycobacterial Activity of Dispiropyrrolidines Derivatives , 2016 .

[30]  A. Rapacz,et al.  Anticonvulsant and antinociceptive activity of new amides derived from 3-phenyl-2,5-dioxo-pyrrolidine-1-yl-acetic acid in mice. , 2016, European journal of pharmacology.

[31]  J. Menéndez,et al.  One-Pot Access to a Library of Dispiro Oxindole-pyrrolidine/pyrrolothiazole-thiochromane Hybrids via Three-Component 1,3-Dipolar Cycloaddition Reactions. , 2016, ACS combinatorial science.

[32]  P. Yogeeswari,et al.  Design of novel dispirooxindolopyrrolidine and dispirooxindolopyrrolothiazole derivatives as potential antitubercular agents. , 2015, Bioorganic & medicinal chemistry letters.

[33]  M. Knorr,et al.  Regio- and Stereoselective Synthesis of Spiropyrrolizidines and Piperazines through Azomethine Ylide Cycloaddition Reaction. , 2015, The Journal of organic chemistry.

[34]  P. Yogeeswari,et al.  Synthesis of novel dispiropyrrolothiazoles by three-component 1,3-dipolar cycloaddition and evaluation of their antimycobacterial activity , 2014 .

[35]  S. S. Rajput,et al.  SUCCINIMIDES: SYNTHESIS, REACTION AND BIOLOGICAL ACTIVITY , 2014 .

[36]  Suresh B. Singh,et al.  The use of spirocyclic scaffolds in drug discovery. , 2014, Bioorganic & medicinal chemistry letters.

[37]  J. Nanubolu,et al.  Regio- and stereoselective synthesis of novel spiropyrrolidines through 1,3-dipolar cycloaddition reactions of azomethine ylides and 2-styrylquinazolin-4(3H)-ones , 2014 .

[38]  E. Carreira,et al.  Four-membered ring-containing spirocycles: synthetic strategies and opportunities. , 2014, Chemical reviews.

[39]  M. Pasca,et al.  Synthesis of 3-heteryl substituted pyrrolidine-2,5-diones via catalytic Michael reaction and evaluation of their inhibitory activity against InhA and Mycobacterium tuberculosis. , 2014, European journal of medicinal chemistry.

[40]  P. T. Perumal,et al.  Facile one-pot synthesis of novel dispirooxindole-pyrrolidine derivatives and their antimicrobial and anticancer activity against A549 human lung adenocarcinoma cancer cell line. , 2013, Bioorganic & medicinal chemistry letters.

[41]  L. Ouyang,et al.  Synthesis of novel spirooxindolo-pyrrolidines, pyrrolizidines, and pyrrolothiazoles via a regioselective three-component [3+2] cycloaddition and their preliminary antimicrobial evaluation , 2013, Molecular Diversity.

[42]  Raju Suresh Kumar,et al.  A facile three-component [3+2]-cycloaddition for the regioselective synthesis of highly functionalised dispiropyrrolidines acting as antimycobacterial agents. , 2013, Bioorganic & medicinal chemistry letters.

[43]  C. Marson,et al.  New and unusual scaffolds in medicinal chemistry. , 2011, Chemical Society reviews.

[44]  Wei Wang,et al.  Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery , 2010, Cell cycle.

[45]  Richard J. Gildea,et al.  OLEX2: a complete structure solution, refinement and analysis program , 2009 .

[46]  Hualiang Jiang,et al.  Flexibility of aromatic residues in the active-site gorge of acetylcholinesterase: X-ray versus molecular dynamics. , 2008, Biophysical journal.

[47]  D. Velmurugan,et al.  Synthesis, Characterisation, Anti-Microbial Activity and Docking Studies of Novel Dispiro- Oxindolopyrrolidines , 2008 .

[48]  K. Scheidt,et al.  Pyrrolidinyl-spirooxindole natural products as inspirations for the development of potential therapeutic agents. , 2007, Angewandte Chemie.

[49]  Y. Ohno,et al.  Lurasidone (SM-13496), a novel atypical antipsychotic drug, reverses MK-801-induced impairment of learning and memory in the rat passive-avoidance test. , 2007, European journal of pharmacology.

[50]  P. Kongsaeree,et al.  Hirsutellones A—E, Antimycobacterial Alkaloids from the Insect Pathogenic Fungus Hirsutella nivea BCC 2594. , 2005 .

[51]  P. Kongsaeree,et al.  Hirsutellones A-E, antimycobacterial alkaloids from the insect pathogenic fungus Hirsutella nivea BCC 2594 , 2005 .

[52]  Joel L Sussman,et al.  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. , 2004, Journal of the American Chemical Society.

[53]  David S. Goodsell,et al.  Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function , 1998, J. Comput. Chem..

[54]  J. Micheau,et al.  New Trends in Spiro-compounds Photochromic Metals Sensors: Quantitative Aspects , 2017 .

[55]  M. Knorr,et al.  A strategic approach to the synthesis of functionalized spirooxindole pyrrolidine derivatives: in vitro antibacterial, antifungal, antimalarial and antitubercular studies , 2015 .

[56]  G. Sheldrick.  A short history of SHELX. , 2008, Acta crystallographica. Section A, Foundations of crystallography.

[57]  Maria do Carmo Carreiras,et al.  Galanthamine, a natural product for the treatment of Alzheimer's disease. , 2006, Recent patents on CNS drug discovery.

[58]  Arthur A. Patchett,et al.  Chapter 26. Privileged structures — An update , 2000 .

[59]  K. Houk.  The role of secondary orbital interactions in cycloaddition reactions , 1970 .