Synthesis and evaluation of chromone derivatives as inhibitors of monoamine oxidase

  • Annah N. Mpitimpiti
  • Jacobus P. PetzerEmail author
  • Anél Petzer
  • Johannes H. L. Jordaan
  • Anna C. U. Lourens
Original Article


Based on reports that chromone compounds are good potency inhibitors of monoamine oxidase (MAO), the present study evaluates the effect of substitution with flexible side chains on the 3 position on MAO inhibition potency. Fifteen chromone derivatives were synthesised by reacting aromatic and aliphatic amines and alcohols with chromone 3-carboxylic acid in the presence of carbonyldiimidazole (CDI). This yielded chromane-2,4-dione and ester chromone derivatives. Generally, the esters exhibited weak MAO inhibition, while the chromane-2,4-dione derivatives showed promise as selective MAO-B inhibitors with IC50 values in the micromolar range. Compound 14b, 3-[(benzylamino)methylidene]-3,4-dihydro-2H-1-benzopyran-2,4-dione, was the most potent MAO-B inhibitor with an IC50 value of 638 µM. This compound was shown to be a reversible and competitive MAO-B inhibitor with a Ki of 94 µM. In conclusion, the effect of chain elongation and introduction of flexible substituents on position 3 of chromone were explored and the results showed that aminomethylidene substitution is preferable over ester substitution. Good potency MAO-B inhibitors may act as leads for the design and development of therapy for Parkinson’s disease where these agents reduce the central metabolism of dopamine.

Graphical abstract


Chromone Chromandione Monoamine oxidase MAO Inhibitor Competitive Parkinson’s disease 



The NMR and MS spectra were recorded by André Joubert and Johan Jordaan of the Laboratory for Analytical Services (LAS) in the focus area Chemical Resource Beneficiation, while HPLC analysis was carried out by Jan du Preez of the Analytical Technology Laboratory (ATL) at the North-West University (NWU). X-ray crystallography was carried out by Johan Jordaan.


The financial assistance of the National Research Foundation (NRF) of South Africa [Grant specific unique reference numbers (UID) 85642, 96180, 76308] towards this research is hereby acknowledged. The Grantholders acknowledge that opinions, findings and conclusions or recommendations expressed in any publication generated by the NRF supported research are that of the authors, and that the NRF accepts no liability whatsoever in this regard.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11030_2019_9917_MOESM1_ESM.pdf (3.6 mb)
Table S1 and Fig. S1: 1H NMR, 13C NMR, mass spectra and infra-red spectra for the synthesised compounds (PDF 3671 kb)


  1. 1.
    Brichta L, Greengard P, Flajolet M (2013) Advances in the pharmacological treatment of Parkinson’s disease: targeting neurotransmitter systems. Trends Neurosci 36:543–554. CrossRefGoogle Scholar
  2. 2.
    Wood-Kaczmar A, Gandhi S, Wood NW (2006) Understanding the molecular causes of Parkinson’s disease. Trends Mol Med 12:521–528. CrossRefGoogle Scholar
  3. 3.
    Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag AE, Lang AE (2017) Parkinson disease. Nat Rev Dis Primers 3:17013. CrossRefGoogle Scholar
  4. 4.
    Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909CrossRefGoogle Scholar
  5. 5.
    Schwarzschild MA, Agnati L, Fuxe K, Chen JF, Morelli M (2006) Targeting adenosine A2A receptors in Parkinson’s disease. Trends Neurosci 29:647–654. CrossRefGoogle Scholar
  6. 6.
    Lees AJ, Hardy J, Revesz T (2009) Parkinson’s disease. Lancet 373:2055–2066. CrossRefGoogle Scholar
  7. 7.
    Stocchi F (2014) Therapy for Parkinson’s disease: what is in the pipeline? Neurotherapeutics 11:24–33. CrossRefGoogle Scholar
  8. 8.
    LeWitt PA, Taylor DC (2008) Protection against Parkinson’s disease progression: clinical experience. Neurotherapeutics 5:210–225. CrossRefGoogle Scholar
  9. 9.
    Youdim MB, Edmondson D, Tipton KF (2006) The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci 7:295–309. CrossRefGoogle Scholar
  10. 10.
    Shih JC, Chen K, Ridd MJ (1999) Monoamine oxidase: from genes to behavior. Annu Rev Neurosci 22:197–217. CrossRefGoogle Scholar
  11. 11.
    Binda C, Newton-Vinson P, Hubalek F, Edmondson DE, Mattevi A (2002) Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders. Nat Struct Biol 9:22–26. CrossRefGoogle Scholar
  12. 12.
    Son SY, Ma J, Kondou Y, Yoshimura M, Yamashita E, Tsukihara T (2008) Structure of human monoamine oxidase A at 2.2-A resolution: the control of opening the entry for substrates/inhibitors. Proc Natl Acad Sci USA 105:5739–5744. CrossRefGoogle Scholar
  13. 13.
    Henchcliffe C, Schumacher HC, Burgut FT (2005) Recent advances in Parkinson’s disease therapy: use of monoamine oxidase inhibitors. Expert Rev Neurother 5:811–821. CrossRefGoogle Scholar
  14. 14.
    Youdim MB, Bakhle YS (2006) Monoamine oxidase: isoforms and inhibitors in Parkinson’s disease and depressive illness. Br J Pharmacol 147(Suppl 1):S287–S296. Google Scholar
  15. 15.
    Carradori S, Silvestri R (2015) New frontiers in selective human MAO-B inhibitors. J Med Chem 58:6717–6732. CrossRefGoogle Scholar
  16. 16.
    Carradori S, Petzer JP (2015) Novel monoamine oxidase inhibitors: a patent review (2012–2014). Expert Opin Ther Pat 25:91–110. CrossRefGoogle Scholar
  17. 17.
    Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR (2004) Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 5:863–873. CrossRefGoogle Scholar
  18. 18.
    Fowler JS, Volkow ND, Wang GJ, Logan J, Pappas N, Shea C, MacGregor R (1997) Age-related increases in brain monoamine oxidase B in living healthy human subjects. Neurobiol Aging 18:431–435CrossRefGoogle Scholar
  19. 19.
    deSouza RM, Schapira A (2017) Safinamide for the treatment of Parkinson’s disease. Expert Opin Pharmacother 18:937–943. CrossRefGoogle Scholar
  20. 20.
    Da Prada M, Zurcher G, Wuthrich I, Haefely WE (1988) On tyramine, food, beverages and the reversible MAO inhibitor moclobemide. J Neural Transm Suppl 26:31–56Google Scholar
  21. 21.
    Flockhart DA (2012) Dietary restrictions and drug interactions with monoamine oxidase inhibitors: an update. J Clin Psychiatry 73(Suppl 1):17–24. CrossRefGoogle Scholar
  22. 22.
    Gnerre C, Catto M, Leonetti F, Weber P, Carrupt PA, Altomare C, Carotti A, Testa B (2000) Inhibition of monoamine oxidases by functionalized coumarin derivatives: biological activities, QSARs, and 3D-QSARs. J Med Chem 43:4747–4758CrossRefGoogle Scholar
  23. 23.
    Chimenti F, Fioravanti R, Bolasco A, Chimenti P, Secci D, Rossi F, Yanez M, Orallo F, Ortuso F, Alcaro S (2009) Chalcones: a valid scaffold for monoamine oxidases inhibitors. J Med Chem 52:2818–2824. CrossRefGoogle Scholar
  24. 24.
    Gamal-Eldeen AM, Djemgou PC, Tchuendem M, Ngadjui BT, Tane P, Toshifumi H (2007) Anti-cancer and immunostimulatory activity of chromones and other constituents from Cassia petersiana. Z Naturforsch C 62:331–338CrossRefGoogle Scholar
  25. 25.
    Djemgou PC, Gatsing D, Tchuendem M, Ngadjui BT, Tane P, Ahmed AA, Gamal-Eldeen AM, Adoga GI, Hirata T, Mabry TJ (2006) Antitumor and immunostimulatory activity of two Chromones and other constituents from Cassia petersiana. Nat Prod Commun 1:961–968Google Scholar
  26. 26.
    Kuroda M, Uchida S, Watanabe K, Mimaki Y (2009) Chromones from the tubers of Eranthis cilicica and their antioxidant activity. Phytochemistry 70:288–293. CrossRefGoogle Scholar
  27. 27.
    Zhou T, Shi Q, Lee KH (2010) Efficient microwave-assisted one-pot preparation of angular 2,2-dimethyl-2H-chromone containing compounds. Tetrahedron Lett 51:4382–4386. CrossRefGoogle Scholar
  28. 28.
    Martens S, Mithofer A (2005) Flavones and flavone synthases. Phytochemistry 66:2399–2407. CrossRefGoogle Scholar
  29. 29.
    Binbuga N, Ruhs C, Hasty JK, Henry WP, Schultz TP (2008) Developing environmentally benign and effective organic wood preservatives by understanding the biocidal and non-biocidal properties of extractives in naturally durable heartwood. Holzforschung 62:264–269. CrossRefGoogle Scholar
  30. 30.
    Sumiyoshi M, Kimura Y (2010) Enhancing effects of a chromone glycoside, eucryphin, isolated from Astilbe rhizomes on burn wound repair and its mechanism. Phytomedicine 17:820–829. CrossRefGoogle Scholar
  31. 31.
    Jovanovic SV, Steenken S, Tosic M, Marjanovic B, Simic MG (1994) Flavonoids as antioxidants. J Am Chem Soc 116:4846–4851. CrossRefGoogle Scholar
  32. 32.
    Machado NFL, Marques MPM (2010) Bioactive chromone derivatives—structural diversity. Curr Bioact Compd 6:76–89CrossRefGoogle Scholar
  33. 33.
    Legoabe LJ, Petzer A, Petzer JP (2012) Inhibition of monoamine oxidase by selected C6-substituted chromone derivatives. Eur J Med Chem 49:343–353. CrossRefGoogle Scholar
  34. 34.
    Legoabe LJ, Petzer A, Petzer JP (2012) Selected C7-substituted chromone derivatives as monoamine oxidase inhibitors. Bioorg Chem 45:1–11. CrossRefGoogle Scholar
  35. 35.
    Legoabe LJ, Petzer A, Petzer JP (2012) Selected chromone derivatives as inhibitors of monoamine oxidase. Bioorg Med Chem Lett 22:5480–5484. CrossRefGoogle Scholar
  36. 36.
    Alcaro S, Gaspar A, Ortuso F, Milhazes N, Orallo F, Uriarte E, Yanez M, Borges F (2010) Chromone-2- and -3-carboxylic acids inhibit differently monoamine oxidases A and B. Bioorg Med Chem Lett 20:2709–2712. CrossRefGoogle Scholar
  37. 37.
    Gaspar A, Silva T, Yanez M, Vina D, Orallo F, Ortuso F, Uriarte E, Alcaro S, Borges F (2011) Chromone, a privileged scaffold for the development of monoamine oxidase inhibitors. J Med Chem 54:5165–5173. CrossRefGoogle Scholar
  38. 38.
    Gaspar A, Reis J, Fonseca A, Milhazes N, Vina D, Uriarte E, Borges F (2011) Chromone 3-phenylcarboxamides as potent and selective MAO-B inhibitors. Bioorg Med Chem Lett 21:707–709. CrossRefGoogle Scholar
  39. 39.
    Cagide F, Silva T, Reis J, Gaspar A, Borges F, Gomes LR, Low JN (2015) Discovery of two new classes of potent monoamine oxidase-B inhibitors by tricky chemistry. Chem Commun 51:2832–2835. CrossRefGoogle Scholar
  40. 40.
    Staab HA (1962) New methods of preparative organic chemistry IV. Synthesis using heterocyclic amides (azolides). Angew Chem Int Edit 1:351–367CrossRefGoogle Scholar
  41. 41.
    Traven VF, Ivanov IV, Lebedev VS, Chibisova TA, Milevskii BG, Solov’eva NP, Polshakov VI, Alexandrov GG, Kazheva ON, Dyachenko OA (2010) E/Z(C = C)-Isomerization of enamines of 3-formyl-4-hydroxycoumarin induced by organic solvents. Russ Chem B 59:1605–1611. CrossRefGoogle Scholar
  42. 42.
    Okumura K, Kondo K, Oine T, Inoue I (1974) The synthesis of chromone-3-carboxanilides. Chem Pharm Bull 22:331–336CrossRefGoogle Scholar
  43. 43.
    Ibrahim MA (2009) Ring transformation of chromone-3-carboxamide. Tetrahedron 65:7687–7690. CrossRefGoogle Scholar
  44. 44.
    Milevskii BG, Chibisova TA, Solov’eva NP, Anisimova OS, Lebedev VS, Ivanov IV, Traven VF (2013) Synthesis and structure of Schiff bases derived from 3-formyl-4-hydroxycoumarin and diamines. Chem Heterocycl Compd 48:1781–1792. CrossRefGoogle Scholar
  45. 45.
    Ishar MPS, Kumar K, Singh R (1998) Thermal rearrangements of C-(4-oxo-4H[1]benzopyran-3-yl)-N-phenylnitrone-a route to novel quinolino[2,3-b]chroman-12-ones. Tetrahedron Lett 39:6547–6550. CrossRefGoogle Scholar
  46. 46.
    Alberola A, Calvo L, Gonzalez-Ortega A, Encabo AP, Sanudo MC (2001) Synthesis of [1]benzopyrano [4,3-b] pyrrol-4(1H)-ones from 4-chloro-3-formylcoumarin. Synthesis-Stuttgart 2001:1941–1948CrossRefGoogle Scholar
  47. 47.
    Strakova I, Petrova M, Belyakov S, Strakovs A (2006) Reactions of 4-chloro-3-formylcoumarine with primary amines. Khim Geterotsikl 5:660–668Google Scholar
  48. 48.
    Novaroli L, Reist M, Favre E, Carotti A, Catto M, Carrupt PA (2005) Human recombinant monoamine oxidase B as reliable and efficient enzyme source for inhibitor screening. Bioorg Med Chem 13:6212–6217. CrossRefGoogle Scholar
  49. 49.
    Mostert S, Petzer A, Petzer JP (2015) Indanones as high-potency reversible inhibitors of monoamine oxidase. ChemMedChem 10:862–873. CrossRefGoogle Scholar
  50. 50.
    Petzer A, Pienaar A, Petzer JP (2013) The inhibition of monoamine oxidase by esomeprazole. Drug Res (Stuttg) 63:462–467. CrossRefGoogle Scholar
  51. 51.
    Costas-Lago MC, Besada P, Rodriguez-Enriquez F, Vina D, Vilar S, Uriarte E, Borges F, Teran C (2017) Synthesis and structure-activity relationship study of novel 3-heteroarylcoumarins based on pyridazine scaffold as selective MAO-B inhibitors. Eur J Med Chem 139:1–11. CrossRefGoogle Scholar
  52. 52.
    Ahmad S, Zaib S, Jalil S, Shafiq M, Ahmad M, Sultan S, Iqbal M, Aslam S, Iqbal J (2018) Synthesis, characterization, monoamine oxidase inhibition, molecular docking and dynamic simulations of novel 2,1-benzothiazine-2,2-dioxide derivatives. Bioorg Chem 80:498–510. CrossRefGoogle Scholar
  53. 53.
    Is YS, Durdagi S, Aksoydan B, Yurtsever M (2018) Proposing novel MAO-B hit inhibitors using multidimensional molecular modeling approaches and application of binary QSAR models for prediction of their therapeutic activity, pharmacokinetic and toxicity properties. ACS Chem Neurosci 9:1768–1782. CrossRefGoogle Scholar
  54. 54.
    Binda C, Wang J, Pisani L, Caccia C, Carotti A, Salvati P, Edmondson DE, Mattevi A (2007) Structures of human monoamine oxidase B complexes with selective noncovalent inhibitors: safinamide and coumarin analogs. J Med Chem 50:5848–5852. CrossRefGoogle Scholar
  55. 55.
    Bandyopadhyay C, Sur KR, Patra R, Sen A (2000) Synthesis of coumarin derivatives from 4-oxo-4H-1-benzopyran-3-carboxaldehyde via 3-(arylaminomethylene)chroman-2,4-dione. Tetrahedron 56:3583–3587. CrossRefGoogle Scholar
  56. 56.
    Fitton AO, Frost JR, Houghton PG, Suschitzky H (1997) Reactions of formylchromone derivatives. Part 2. Addition reactions of 3-(aryliminomethyl)chromones. J Chem Soc Perkin Trans 10:1691–1694Google Scholar
  57. 57.
    Petzer A, Harvey BH, Wegener G, Petzer JP (2012) Azure B, a metabolite of methylene blue, is a high-potency, reversible inhibitor of monoamine oxidase. Toxicol Appl Pharmacol 258:403–409. CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Centre of Excellence for Pharmaceutical SciencesNorth-West UniversityPotchefstroomSouth Africa
  2. 2.Pharmaceutical Chemistry, School of PharmacyNorth-West UniversityPotchefstroomSouth Africa
  3. 3.Research Focus Area for Chemical Resource BeneficiationNorth-West UniversityPotchefstroomSouth Africa

Personalised recommendations