Skip to main content

Advertisement

SpringerLink
Log in

Design, synthesis, and molecular docking of new 5-HT reuptake inhibitors based on modified 1,2-dihydrocyclopenta[b]indol-3(4H)-one scaffold

  • Regular Article
  • Published:
Journal of Chemical Sciences Aims and scope Submit manuscript

Abstract

A new group of serotonin reuptake inhibitors containing 1,2-dihydrocyclopenta[b]indol-3(4H)-one scaffold was synthesized, starting from indole 5-((1H-indol-3-yl)(1,3-dioxane-4,6-diones as a key intermediates. Following three transformations including intramolecular cyclization and formation of imines, a series of new ligand for human serotonin transporter was obtained. The ability of these ligands to inhibit human TS3 serotonin transporter as well as selectivity toward human D3 dopamine receptor and dopamine transporter were tested in silico using docking software.

Graphical Abstract

SYNOPSIS A series of new serotonin reuptake inhibitors containing 1,2-dihydrocyclopenta[b]indol-3(4H)-one scaffold were designed and synthesized. Affinity to human TS3 transporter and D3 receptor were tested in silico.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Fig. 1
Scheme 2
Scheme 3
Scheme 4
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Humber L G, Ferdinandi E, Demerson C A, Ahmed S, Shah U, Mobilio D, Sabatucci J, De Lange B and Labbadia F 1998 Etodolac, a novel antiinflammatory agent. The syntheses and biological evaluation of its metabolites J. Med. Chem. 31 1712

    Article  CAS  Google Scholar 

  2. Dejaco Ch, Duftner Ch and Schirmer M 2007 Lack of influence of body mass index on efficacy and tolerance of acemetacin in short-term treatment of musculoskeletal diseases Rheumatol. Int. 27 351

    Article  CAS  Google Scholar 

  3. Hughes P, DeVirgilio J, Humber L G, Weichman B and Neuman G 1989 Synthesis and biological evaluation of 4,6-diethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole-4-acetic acid, an isomer of etodolac J. Med. Chem. 32 2134

    Article  CAS  Google Scholar 

  4. Lione A and Scialli A R 1995 The developmental toxicity of indomethacin and sulindac Reprod. Toxicol. 9 7

    Article  CAS  Google Scholar 

  5. Bellamy N 1997 Etodolac in the management of pain: a clinical review of a multipurpose analgesic Inflammopharmacology 5 139

    Article  CAS  Google Scholar 

  6. Affonso V Bizzo H Lage C and Sato A 2009 Influence of growth regulators in biomass production and volatile profile of in vitro plantlets of Thymus vulgaris L J. Agric. Food Chem. 57 6392

    Article  CAS  Google Scholar 

  7. Abel S 2007 Auxin Is Surfacing ACS Chem. Biol. 2 380

    Article  CAS  Google Scholar 

  8. Michnovicz J J 1991 Altered estrogen metabolism and excretion in humans following consumption of indole-3-carbinol Nutr. Cancer 16 59

    Article  CAS  Google Scholar 

  9. Michnovicz J J 1997 Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans Natl. Cancer Inst. 89 718

    Article  CAS  Google Scholar 

  10. Holt D A, Yamashita D S, Konialian-Beck A L, Luengo J I, Abel A D, Bergsma D J, Brandt S M and Levy M A 1995 Benzophenone- and indolecarboxylic acids: potent Type-2 specific inhibitors of human steroid 5a-reductase J. Med. Chem. 38 13

    Article  CAS  Google Scholar 

  11. Boggs S D, Catalano J G, Gudmundsson K S, Richardson L D and Sebahar P R 2006 Novel cycloalkyl condensed Indoles U. S. Patent 0281804 A1

  12. Baganz N L and Blakely R D A 2013 Dialogue between the immune system and brain, spoken in the language of serotonin ACS Chem. Neurosci. 4 48

    Article  CAS  Google Scholar 

  13. Angoa-Pérez M, Kane M J, Briggs D I, Herrera-Mundo N, Sykes C E, Francescutti D M and Kuhn D M 2014 Mice genetically depleted of brain serotonin do not display a depression-like behavioral phenotype ACS Chem. Neurosci. 5 908

    Article  Google Scholar 

  14. Kochanowska-Karamyan A J and Hamann M T 2010 Marine Indole alkaloids: potential new drug leads for the control of depression and anxiety Chem. Rev. 110 4489

    Article  CAS  Google Scholar 

  15. Ikarashi Y, Sekiguchi K and Mizoguchi K 2017 Serotonin receptor binding characteristics of Geissoschizine methyl ether, an indole alkaloid in Uncaria Hook Cur. Med. Chem. 24 1

    Google Scholar 

  16. Vangveravong S, Kanthasamy A, Lucaites V L, Nelson D L and Nichols D E 1998 Synthesis and serotonin receptor affinities of a series of trans-2-(Indol-3-yl)cyclopropylamine derivatives J. Med. Chem. 41 4995

    Article  CAS  Google Scholar 

  17. Wong D T, Horng J S, Bymaster F P, Hauser K L and Molloy B B 1974 A selective inhibitor of serotonin uptake: Lilly 110140, 3-(p-Trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine Life Sci. 15 471

    Article  CAS  Google Scholar 

  18. Wong D T, Bymaster F P and Engleman E A 1995 Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: twenty years since its first publication Life Sci. 57 411

    Article  CAS  Google Scholar 

  19. Sanchez C, Reines E H and Montgomery S A 2014 A comparative review of escitalopram, paroxetine, and sertraline: Are they all alike? Int. Clin. Psychopharmacol. 29 185

    Article  Google Scholar 

  20. Al-Harbi K S 2012 Treatment-resistant depression: therapeutic trends, challenges, and future directions Patient Prefer. Adherence. 6 369

    Article  Google Scholar 

  21. Nischal A, Tripathi A, Nischal A and Trivedi J K 2012 Suicide and antidepressants: what current evidence indicates Mens Sana Monogr. 10 33

    Article  Google Scholar 

  22. Pompili M, Serafini G, Innamorati M, Ambrosi E, Giordano G, Girardi P, Tatarelli R and Lester D 2010 Antidepressants and suicide risk: a comprehensive overview Pharmaceuticals 3 2861

    Article  Google Scholar 

  23. Porter R A and Vimal M 1995 Teterahydricarbazole derivatives as 5-HT1-like agonists EP 0674622 B1

  24. Bromidge S M 2000 Indole Derivatives as 5-HT Receptor Antagonist U. S. Patent 6028085

  25. Oikawa Y, Hirasawa H and Yonemitsu O 1978 Meldrum’s acid in organic synthesis. A convenient one-pot synthesis of ethyl indolepropionates. A convenient one-pot synthesis of ethyl indolepropionates Tetrahedron Lett. 20 1759

    Article  Google Scholar 

  26. Armstrong E L, Grover H K and Kerr M A 2013 Scandium triflate-catalyzed nucleophilic additions to indolylmethyl meldrum’s acid derivatives via a gramine-type fragmentation: synthesis of substituted indolemethanes J. Org. Chem. 78 10534

    Article  CAS  Google Scholar 

  27. Lü Ch, Wang J, Liu Y, Shan W, Sun Q and Shi L 2017 A combination of green solvent and ultrasonic irradiation promotes the catalyst-free reaction of aldehydes, indoles and Meldrum’s acid Res. Chem. Intermed. 43 943

    Article  Google Scholar 

  28. Adamo M F A and Konda V R 2007 Multicomponent synthesis of 3-indolepropionic acids Org. Lett. 9 303

    Article  CAS  Google Scholar 

  29. Vickerman K L and Stanley L M 2017 Catalytic, enantioselective synthesis of polycyclic nitrogen, oxygen, and sulfur heterocycles via Rh-catalyzed alkene hydroacylation Org. Lett. 19 5054

    Article  CAS  Google Scholar 

  30. Trott O and Olson A J 2010 AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31 455

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Coleman J A, Green E M and Gouaux E 2016 X-ray structure of the ts3 human serotonin transporter complexed with paroxetine at the central site Nature 532 334

  32. Chien E Y, Liu W, Zhao Q, Katritch V, Han G W, Hanson M A, Shi L, Newman A H, Javitch J A, Cherezov V and Stevens R C 2010 Structure of the human dopamine d3 receptor in complex with a d2/d3 selective antagonist Science 330 1091

  33. Wang K H, Penmatsa A and Gouaux E 2015 Neurotransmitter and psychostimulant recognition by the dopamine transporter Nature 521 322

    Article  CAS  Google Scholar 

  34. Gore S, Baskaran S and König B 2012 Fischer indole synthesis in low melting mixtures Org. Lett. 14 4568

    Article  CAS  Google Scholar 

  35. Würtz S, Rakshit S, Neumann J J, Dröge T and Glorius F 2008 Palladium-catalyzed oxidative cyclization of N-aryl enamines: from anilines to indoles Angew. Chem. Int. Ed. 47 7230

    Article  Google Scholar 

  36. Iida H, Yuasa Y and Kibayashi 1980 Intramolecular cyclization of enaminones involving arylpalladium complexes synthesis of carbazoles J. Org. Chem. 45 2938

  37. Janreddy D, Kavala V, Bosco J W, Kuo Ch- and Yao Ch-F 2011 An easy access to carbazolones and 2,3-disubstituted indoles Eur. J. Org. Chem. 12 2360

    Article  Google Scholar 

  38. Bunce R A and Nammalwar B 2009 1,2,3,9-Tetrahydro-4H-carbazol-4-one and 8,9-dihydropyrido-[1,2-a]indol-6(7H)-one from 1H-indole-2-butanoic acid J. Heterocycl. Chem. 46 172

    Article  CAS  Google Scholar 

  39. Mishra S, Liu J and Aponick A 2017 Enantioselective Alkyne Conjugate Addition Enabled by Readily Tuned Atropisomeric P,N-Ligands J. Am. Chem. Soc. 139 3352

    Article  CAS  Google Scholar 

  40. Najda E, Zakaszewska A, Janikowska K and Makowiec S 2016 Practical method for the preparation of 2,2-dimethyl-5-[aryl(heteroaryl)methyl]-1,3-dioxane-4,6-diones - Synthesis and mechanistic study Synthesis 48 3589

  41. Najda-Mocarska E, Zakaszewska A, Janikowska K and Makowiec S 2018 New thiourea organocatalysts and their application for the synthesis of 5-(1H-indol-3-yl)methyl-2,2-dimethyl-1, 3-dioxane-4,6-diones a source of chiral 3-indoylmethyl ketenes Synth. Commun. 48 14

    Article  CAS  Google Scholar 

  42. Fillion E, Fishlock D, Wilsily A and Goll J M 2005 Meldrum’s acids as acylating agents in the catalytic intramolecular Friedel-Crafts reaction J. Org. Chem. 70 1316

    Article  CAS  Google Scholar 

  43. Fillion E and Fishlock D 2003 Convenient access to polysubstituted 1-indanones by Sc(OTf)\(_3\)-catalyzed intramolecular Friedel-Crafts acylation of benzyl Meldrum’s acid derivatives Org. Lett. 5 4653

    Article  CAS  Google Scholar 

  44. Prajakta N N, Nabil A H A and Radhika S K 2015 Beckmann rearrangement for the synthesis of derivatives of \(\upbeta \)- and \(\upgamma \)-carbolinones, dihydropyrrolopyridinone and tetrahydroisoquinolinone ARKIVOC 7 362

  45. Banwell J M G and Smith J A 2002 Exploiting multiple nucleophilic sites on pyrrole for the assembly of polyheterocyclic frameworks: application to a formal total synthesis of (\(\pm )\)-aspidospermidine Chem. Soc. Perkin Trans. 10 2613

  46. Pamukcu R and Piazza G A 2002 Method of inhibiting neoplastic cells with indole derivatives U.S. Patent 6358992 B1

  47. Maertens F, Toppet S, Hoornaert G J and Compernolle F 2005 Incorporation of an indole-containing diarylbutylamine pharmacophore into furo[2,3-a]carbazole ring systems Tetrahedron 61 1715

  48. Haddad M, Dorbais J and Larcheveque M 1997 Stereocontrolled reductive amination of 3-hydroxy ketones Tetrahedron Lett. 38 5981

    Article  CAS  Google Scholar 

  49. Cherukupally P, Vajrala V R, Adla V K, Rangineni S and Kanniah S 2011 Preparation of rasagiline salts therof U.S. Patent 20110218360 A1

  50. Kang S, Cooper G, Dunne S F, Luan C, Surmeier D J and Silverman R B 2013 Structure–activity relationship of N,N’-disubstituted pyrimidinetriones as Ca 1.3 calcium channel-selective antagonists for Parkinson’s disease J. Med. Chem. 56 4786

    Article  CAS  Google Scholar 

  51. Barluenga J, Jimenez-Aquino A, Aznar F and Valdes C 2009 Modular Synthesis of indoles from imines and o-Dihaloarenes or o-Chlorosulfonates by a Pd-catalyzed cascade process J. Am. Chem. Soc. 131 4031

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The project was carried-out within the PARENT-BRIDGE programme of the Foundation for Polish Science (POMOST/2013-8/6), co-financed from the European Union under the European Regional Development Fund. We warmly thank undergraduate and graduate students Mateusz Leśniewski and Marek Cichon for their contribution to the project.

Author information

Authors and Affiliations

  1. Department of Organic Chemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12, 80-233, Gdańsk, Poland

    Milena Szewczyk, Paweł Punda, Karolina Janikowska & Sławomir Makowiec

Authors
  1. Milena Szewczyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paweł Punda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Karolina Janikowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sławomir Makowiec
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sławomir Makowiec.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (pdf 4103 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Szewczyk, M., Punda, P., Janikowska, K. et al. Design, synthesis, and molecular docking of new 5-HT reuptake inhibitors based on modified 1,2-dihydrocyclopenta[b]indol-3(4H)-one scaffold. J Chem Sci 131, 45 (2019). https://doi.org/10.1007/s12039-019-1621-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12039-019-1621-x

Keywords

Search

Navigation