Abstract
A series of new bifunctional 7-benzyloxy-2, 3-dimethyl-4-oxo-4H-chromene-8-carboxamides 5a-5 l were synthesized from 7-hydroxy 2,3 dimethyl chromone via key intermediate 7-benzyloxy 2,3 dimethyl-8-carboxylic acid using Jones oxidation and HBTU/HOBt (Hexafluorophosphate Benzotriazole Tetramethyl Uronium/Hydroxybenzotriazole) as selective amide coupling agent. All the amide derivatives 5a-5 l were screened for their in vitro human monoamine oxidase, hMAO-A and hMAO-B inhibitory activity. Two compounds 5c and 5e, identified as more potent MAO-B inhibitors (IC50 values within nanomolar range) compared to the standard MAO-B inhibitor, Selegiline. Five compounds 5b, 5c, 5e, 5 g and 5 k exhibited high MAO-B inhibition selectivity with selectivity index (SI) value > 50. The most potent compound 5e has also showed reversibility of MAO-B inhibition in dialysis method with relative recovery percentage up to 69.9%. Furthermore, the MAO-B selective binding affinities of these newly synthesized chromone amides and structure activity relationships were scrutinized with the help of quantified scoring function values from Genetic Optimization of Ligand Docking (GOLD). The docking results have conclusively lain out that these chromone carboxamides show positive interactions with hMAO-B and repulsive interactions with hMAO-A which affirm its selectivity towards MAO-B.
Graphic abstract
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abdelmoty I, Albericio F, Carpino LA, Foxman BM, Kates SA (1994) Structural studies of reagents for peptide bond formation: Crystal and molecular structures of HBTU and HATU. Lett Pept Sci 1:57–67. https://doi.org/10.1007/BF00126274
Alam S, Sarkar Z, Islam A (2004) Synthesis and studies of antibacterial activity of pongaglabol. J Chem Sci 116:29–32. https://doi.org/10.1007/BF02708210
Amaral S, Mira L, Nogueira JM, da Silva AP, Helena Florêncio M (2009) Plant extracts with anti-inflammatory properties–a new approach for characterization of their bioactive compounds and establishment of structure-antioxidant activity relationships. Bioorg Med Chem 17(5):1876–1883. https://doi.org/10.1016/j.bmc.2009.01.045
Anjum NF, Aleem A, Nayeem N, Asdaq SM (2011) Synthesis and antibacterial activity of substituted 2-phenyl-4-chromones. Der Pharm Chem 3(5):56–62
Atli O, Özkay Y (2017) Synthesis and MAO inhibitory activity of thiazole-hydrazones. Turk J Chem 41:685–699. https://doi.org/10.3906/kim-1612-78
Baek SC, Ryu HW, Kang MG, Lee H, Park D, Cho ML, Oh SR, Kim H (2018) Selective inhibition of monoamine oxidase A by chelerythrine, an isoquinoline alkaloid. Bioorg Med Chem Lett 28(14):2403–2407. https://doi.org/10.1016/j.bmcl.2018.06.023
Bennett CJ, Caldwell ST, McPhail DB, Morrice PC, Duthie GG, Hartley RC (2004) Potential therapeutic antioxidants that combine the radical scavenging ability of myricetin and the lipophilic chain of vitamin E to effectively inhibit microsomal lipid peroxidation. Bioorg Med Chem 12(9):2079–2098. https://doi.org/10.1016/j.bmc.2004.02.031
Binda C, Newton-Vinson P, Hubalek F, Edmondson DE, Mattevi A (2001) structure of human monoamine oxidase B, A drug target for the treatment of neurological disorders. Nat Struct Mol Biol 9:22–26. https://doi.org/10.1038/nsb732
BioVision (2017a) Fluorometric Monoamine Oxidase A (MAO-A) Inhibitor Screening Kit, Catalog No: K796–100, Data Sheet; BioVision: Milpitas, CA, USA. https://www.biovision.com/documentation/datasheets/K796.pdf
BioVision (2017b) Fluorometric Monoamine Oxidase B (MAO-B) Inhibitor Screening Kit, Catalog No: K797–100, Data Sheet; BioVision: Milpitas, CA, USA. https://www.biovision.com/documentation/datasheets/K797.pdf
Burda S, Oleszek W (2001) Antioxidant and antiradical activities of flavonoids. J Agric Food Chem 49(6):2774–2779. https://doi.org/10.1021/jf001413m
Cottiglia F, Dhanapal B, Sticher O, Heilmann J (2004) New chromanone acids with antibacterial activity from Calophyllum brasiliense. J Nat Prod 67(4):537–541. https://doi.org/10.1021/np030438n
Dengle RV, Deshmukh RN (2013) Synthesis and antimicrobial evaluation of chromones bearing 1, 5-benzo thiazepinyl moiety. Inter J Pharml Sci Res 4:1495–1498 (10.13040/IJPSR.0975-8232.4(4).1495-98)
Gasper A, Reis J, Fonseca A, Milhazes N, Viňa D, Uriarte E, Borges F (2011) Chromone 3-phenylcarboxamides as potent and selective MAO-B inhibitors. Bioorg Med Chem Lett 21(2):707–709. https://doi.org/10.1016/j.bmcl.2010.11.128
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 43:4747–4758. https://doi.org/10.1021/jm001028o
Göker H, Ozden S, Yildiz S, Boykin DW (2005) Synthesis and potent antibacterial activity against MRSA of some novel 1,2-disubstituted-1H-benzimidazole-N-alkylated-5-carboxamidines. Eur J Med Chem 40(10):1062–1069. https://doi.org/10.1016/j.ejmech.2005.05.002
Heim KE, Tagliaferro AR, Bobilya DJ (2002) Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J Nutr Biochem 13(10):572–584. https://doi.org/10.1016/s0955-2863(02)00208-5
Huang W, Liu MZ, Li Y, Tan Y, Yang GF (2007) Design, syntheses, and antitumor activity of novel chromone and aurone derivatives. Bioorg Med Chem 15:5191–5197. https://doi.org/10.1016/j.bmc.2007.05.022
Huang W, Ding Y, Miao Y, Liu MZ, Li Y, Yang GF (2009) Synthesis and antitumor activity of novel dithiocarbamate substituted chromones. Eur J Med Chem 44:3687–3696. https://doi.org/10.1016/j.ejmech.2009.04.004
Kavitha P, Saritha M, Reddy KL (2013) Synthesis, structural characterization, fluorescence, antimicrobial, antioxidant and DNA cleavage studies of Cu(II) complexes of formyl chromone Schiff bases. Mol Biomol Spect 102C:159–168. https://doi.org/10.1016/j.saa.2012.10.037
Kaya B, Sağlık BN, Levent S, Ozkay Y, Kaplancikh ZA (2016) Synthesis of some novel 2-substituted benzothiazole derivatives containing benzylamine moiety as monoamine oxidase inhibitory agents. J Enzyme Inhib Med Chem 31:1654–1661. https://doi.org/10.3109/14756366.2016.1161621
Lee H, Lee K, Jung JK, Cho J, Theodorakis EA (2005) Synthesis and evaluation of 6-hydroxy-7-methoxy-4-chromanone- and chroman-2-carboxamides as antioxidants. Bioorg Med Chem Lett 15(11):2745–2748. https://doi.org/10.1016/j.bmcl.2005.03.118
Legoabe LJ, Petzer A, Jacobus PP (2012) Selected C7-substituted chromone derivatives as monoamine oxidase inhibitors. Bioorg Med Chem Lett 45:1–11. https://doi.org/10.1016/j.bioorg.2012.08.003
Legoabe LJ, Petzer A, Petzer JP (2012) Selected chromone derivatives as inhibitors of monoamine oxidase. Bioorg Med Chem Lett 22:5480–5484. https://doi.org/10.1016/j.bmcl.2012.07.025
Liang J, Edelsbrunner H, Woodward C (1998) Anatomy of protein pockets and cavities: measurement of binding site geometry and implications for ligand design. Protein Sci 7:1884–1897. https://doi.org/10.1002/pro.5560070905
Mathew GE, Oh JM, Mohan K, Tengli A, Mathew B, Kim H (2020) Development of methylthiosemicarbazones as new reversible monoamine oxidase-B inhibitors for the treatment of Parkinson’s disease. J Biomol Struct Dyn. https://doi.org/10.1080/07391102.2020.1782266
Mays JR, Hill SA, Moyers JT, Blagg BS (2010) The synthesis and evaluation of flavone and isoflavone chimeras of novobiocin and derrubone. J Bioorg Med Chem 18:249–266. https://doi.org/10.1016/j.bmc.2009.10.061
Montalbetti AGN, Falque V (2005) Amide bond formation and peptide coupling. Tetrahedron 61:10827–10852. https://doi.org/10.1016/j.tet.2005.08.031
Nagatsu T, Sawada M (2006) Molecular mechanism of the relation of monoamine oxidase B and its inhibitors to Parkinson’s disease: possible implications of glial cells. J Neural Transm Suppl 71:53–65. https://doi.org/10.1007/978-3-211-33328-0_7
Nam DH, Lee KY, Moon CS, Lee YS (2010) Synthesis and anticancer activity of chromone-based analogs of lavendustin A. Eur J Med Chem 45:4288–4292. https://doi.org/10.1016/j.ejmech.2010.06.030
Piao LZ, Park HR, Park YK, Lee SK, Park JH, Park MK (2002) Mushroom tyrosinase inhibition activity of some chromones. Chem Pharm Bull 50:309–311. https://doi.org/10.1248/cpb.50.309
Raju CB, Rao RN, Suman P, Yogeeswari P, Sriram D, Shaik TB, Kalivendi SV (2011) Synthesis, structure-activity relationship of novel substituted 4H-chromen-1,2,3,4-tetrahydropyrimidine-5-carboxylates as potential anti-mycobacterial and anticancer agents. Bioorg Med Chem Lett 21:2855–2859. https://doi.org/10.1016/j.bmcl.2011.03.079
Rao YJ, Krupadanam GLD (2000) A facile synthesis of 7,8/6,7 fused pyrano[4,3-b]pyridinochromones and evaluation of antibacterial activity. Indian J Chem 39B:610–630
Shih JC, Chen K, Ridd MJ (1999) Monoamine oxidase: from genes to behavior. Annu Rev Neurosci 22:197–217. https://doi.org/10.1146/annurev.neuro.22.1.197
Singh P, Kaur M, Holzer W (2010) Synthesis and evaluation of indole, pyrazole, chromone and pyrimidine based conjugates for tumor growth inhibitory activities–development of highly efficacious cytotoxic agents. Eur J Med Chem 45:4968–4982. https://doi.org/10.1016/j.ejmech.2010.08.004
Suresh J, Baek SC, Ramakrishnan SP, Kim H, Mathew B (2018) Discovery of potent and reversible MAO-B inhibitors as furanochalcones. Int J Biol Macromol 108:660–664. https://doi.org/10.1016/j.ijbiomac.2017.11.159
Ungwitayatorn J, Wiwat C, Samee W, Nunthanavanit P, Phosrithong N (2011) Synthesis, in vitro evaluation, and docking studies of novel chromone derivatives as HIV-1 protease inhibitor. J Mol Struct 1001:152–161. https://doi.org/10.1016/j.molstruc.2011.06.035
Verdonk ML, Chessari G, Cole JC, Hartshorn MJ, Murray CW, Nissink JWM, Taylor RD, Taylor R (2005) Modeling Water Molecules in Protein-Ligand Docking Using GOLD. J Med Chem 48:6504–6515. https://doi.org/10.1021/jm050543p
Wouters J, Leonard N, Lambert C, Depiereux E (2001) Human monoamine oxidase type A (truncated). RCSB-PDB. https://doi.org/10.5452/ma-c5dqf
Yadav PP, Gupta P, Chaturvedi AK, Shukla PK, Maurya R (2005) Synthesis of 4-hydroxy-1-methylindole and benzo[b]thiophen-4-ol based unnatural flavonoids as new class of antimicrobial agents. Bioorg Med Chem 13(5):1497–1505. https://doi.org/10.1016/j.bmc.2004.12.032
Youdim MBH, Edmondson D, Tipton KF (2006) The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neuroscience 7:295–309. https://doi.org/10.1038/nrn1883
Zhang S, Ma J, Bao Y, Yang P, Zou L, Li K, Sun X (2008) Nitrogen-containing flavonoid analogues as CDK1/cyclin B inhibitors: synthesis, SAR analysis, and biological activity. Bioorg Med Chem 16:7127–7132. https://doi.org/10.1016/j.bmc.2008.06.055
Acknowledgements
The authors gratefully acknowledge Department of Organic chemistry, Telangana Univeristy for technical support. The authors also thankful to Synteny Life sciences Pvt.Ltd., Hyderabad, India and Ciencia Life sciences, Hyderabad, India for conducting biological studies and Qstatix Pvt.Ltd., Hyderabad, India for performing molecular docking studies.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no competing financial interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Rao, Y.J., Abhijit, K., Mallikarjun, G. et al. Design and synthesis of novel benzyloxy-tethered-chromone-carboxamide derivatives as potent and selective human monoamine oxidase-b inhibitors. Chem. Pap. 75, 703–716 (2021). https://doi.org/10.1007/s11696-020-01332-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11696-020-01332-w