Synthesis, Transformations and Characterization of 8 Aminomethyl Substituted Umbelliferones as Probable Anti-Arrhythmic Agents

Author(s): Alla V. Lipeeva, Arkady O. Brysgalov, Tatyana G. Tolstikova, Elvira E. Shults*.

Journal Name: Current Bioactive Compounds

Volume 15 , Issue 1 , 2019

Submit Manuscript
Submit Proposal

Graphical Abstract:


Abstract:

Background: Coumarin and modified nitrogen heterocyclic nuclei show biological activity. Combining these into a hybrid molecule could lead to new pharmacological agents. A series of hybrid compounds combining coumarin and piperidine, piperazine, purine or tetrahydroisoquinoline moieties were synthesized and evaluated for anti-arrhythmic activity.

Methods: The Mannich reaction of coumarins (peurutenicin, peucenol and 6-cyanoumbelliferrone) with formaldehyde and various amines, including several alkaloids – anabasine, theophylline or tetrahydroisoquinolines, proceeds by heating under reflux in dioxane in the presence of 4-dimethylaminopyridine. The Suzuki reaction of 6,8-disubstituted umbelliferone triflate was used for the introduction of an aryl substituent in position 7 of the the coumarin framework.

Results: Twenty two novel coumarin-based Mannich bases were synthesized via introduction of functional aminomethyl group at position 8 of 6 substituted 7-hydroxy-2H-chromen-2-ones by Mannich reaction. The results illustrated that the C-6 and C-8 substituents’ effect was obvious in our designed system and there was a relationship between the structures and the anti-arrhythmic activity of the 6,7,8- trisubstituted coumarins. 8-(6,7-dimethoxy-1-(3,4,5-trimethoxyphenyl)-tetrahydroisoquinolinylmethyl)- substituted peucenol derivatives shown in vivo a pronounced and selective anti-arrhythmic activity on epinephrine arrhythmias in comparison with natural coumarin peucenol. The moderate toxicity of the new compound encouraged further design of therapeutically relevant analogues based on this novel type of coumarin- tetrahydroisoquinoline hybrids.

Conclusion: We have developed a mild reaction protocol to synthesize new mannich products on the basis of substituted coumarins. The anti-arrhythmic activity of coumarin-tetrahydroisoquinoline hybrids was revealed. We report for the first time that coumarin containing 8-(1-(3,4,5-trimethoxyphenyl) tetrahydroisoquinolinyl)methyl) substituent offer a suitable scaffold for the development of novel anti-arrhythmic agents.

Keywords: Coumarin, isoquinoline, anabasine, xanthine, Mannich reaction, anti-arrhythmic ativity.

[1]
Barot, K.P.; Jain, S.V.; Kremer, L.; Singh, S.; Ghate, M.D. Recent advances and therapeutic journey of coumarins: current status and perspectives. Med. Chem. Res., 2015, 24, 2771-2798.
[2]
Ventura, T.L.B.; Silva, D.R.S.; Lassounskaia, E.; Edmulson, M.J.; Muzitano, M.F.; de Oliveira, R.R. Coumarine Analogues with Antimycobacterial and Immunomodulatory Activity. Curr. Bioact. Compd., 2015, 11, 109-115.
[3]
Pérez-Cruz, F.; Vazquez-Rodriguez, S.; Matos, M.J.; Herrera-Morales, A.; Villamena, F.A.; Das, A.; Gopalakrishnan, B.; Olea-Azar, C.; Santana, L.; Uriarte, E. Synthesis and electrochemical and biological studies of novel coumarin-chalcone hybrid compounds. J. Med. Chem., 2013, 56(15), 6136-6145.
[4]
Kaur, A.; Haghighatbin, M.A.; Hogan, C.F.; New, E.J. A FRET-based ratiometric redox probe for detecting oxidative stress by confocal microscopy, FLIM and flow cytometry. Chem. Commun. (Camb.), 2015, 51(52), 10510-10513.
[5]
Bhila, V.G.; Patel, C.V.; Patel, N.H.; Brahmbhatt, D.I. One pot synthesis of some novel coumarins containing 5-(substituted-2-hydroxybenzoyl) pyridine as a new class of antimicrobial and antituberculosis agents. Med. Chem. Res., 2013, 22, 4338-4346.
[6]
Krishna, C.; Bhargavi, M.V.; Rao, C.P.; Krupadanam, G.L.D. Synthesis and antimicrobial assessment of novel coumarins featuring 1,2,4-oxadiazole. Med. Chem. Res., 2015, 24, 3743-3751.
[7]
Yusufzai, S.K.; Osman, H.; Khan, M.S.; Mohamad, S.; Sulaiman, O.; Parumasivam, T.; Gansau, J.A.; Johansah, N. Noviany. Design, characterization, in vitro antibacterial, antitubercular evaluation and structure–activity relationships of new hydrazinyl thiazolyl coumarin derivatives. Med. Chem. Res., 2017, 26, 1139-1148.
[8]
Peng, X.M.; Damu, G.L.; Zhou, C. Current developments of coumarin compounds in medicinal chemistry. Curr. Pharm. Des., 2013, 19(21), 3884-3930.
[9]
Jameel, E.; Umar, T.; Kumar, J.; Hoda, N. Coumarin: A Privileged Scaffold for the Design and Development of Antineurodegenerative Agents. Chem. Biol. Drug Des., 2016, 87(1), 21-38.
[10]
Amin, K.M.; Abou-Seri, S.M.; Awadallah, F.M.; Eissa, A.A.M.; Hassan, G.S.; Abdulla, M.M. Synthesis and anticancer activity of some 8-substituted-7-methoxy-2H-chromen-2-one derivatives toward hepatocellular carcinoma HepG2 cells. Eur. J. Med. Chem., 2015, 90, 221-231.
[11]
Lab, H.B.; Giri, R.R.; Chovatiya, Y.L.; Brahmbhatt, D.I. Synthesis of modified pyridine and bipyridine substituted coumarins as potent antimicrobial agents. J. Serb. Chem. Soc., 2015, 80, 739-747.
[12]
Amin, K.M.; Awadalla, F.M.; Eissa, A.A.M.; Abou-Seri, S.M.; Hassan, G.S. Design, synthesis and vasorelaxant evaluation of novel coumarin-pyrimidine hybrids. Bioorg. Med. Chem., 2011, 19(20), 6087-6097.
[13]
Kontogiorgis, C.A.; Hadjipavlou-Litina, D.J. Synthesis and antiinflammatory activity of coumarin derivatives. J. Med. Chem., 2005, 48(20), 6400-6408.
[14]
Gupta, W.N.; Sharima, B.R.; Avora, R.B. Pharmacologically active coumarin derivatives. I. Mannich bases from umbelliferone and 4-methylumbelliferone. J. Sci. Ind. Res. (India), 1961, 20B, 300-301.
[15]
Molho, D.; Boschetti, E. (1962) 7-Hydroxy-8-(dialkylaminomethyl)-coumarins. Fr Pat 1,310,535, p 7. CA (Edinb.), 1963, (58), 12517f.
[16]
Sandhu, S.; Bansal, Y.; Silakari, O.; Bansal, G. Coumarin hybrids as novel therapeutic agents. Bioorg. Med. Chem., 2014, 22(15), 3806-3814.
[17]
Roman, G. Mannich bases in medicinal chemistry and drug design. Eur. J. Med. Chem., 2015, 89, 743-816.
[18]
Gaudino, E.C.; Tagliapietra, S.; Martina, K.; Palmisano, G.; Cravotto, G. Recent advances and perspectives in the synthesis of bioactive coumarins. RSC Advances, 2016, 6, 46394-46405.
[19]
Lipeeva, A.V.; Khvostov, M.V.; Baev, D.S.; Shakirov, M.M.; Tolstikova, T.G.; Shults, E.E. Synthesis, in vivo anticoagulant evaluation and molecular docking studies of new groups of bicoumarins obtained from furocoumarin peucedanin. Med. Chem., 2016, 12(7), 674-683.
[20]
Najmanová, I.; Doseděl, M.; Hrdina, R.; Anzenbacher, P.; Filipský, T.; Říha, M.; Mladěnka, P. Cardiovascular effects of coumarins besides their antioxidant activity. Curr. Top. Med. Chem., 2015, 15(9), 830-849.
[21]
Fusi, F.; Sgaragli, G.; Ha, M.; Cuong, N.M.; Saponara, S. Mechanism of osthole inhibition of vascular Ca(v)1.2 current. Eur. J. Pharmacol., 2012, 680(1-3), 22-27.
[22]
Cuong, N.M.; Khanh, P.N.; Duc, H.V.; Huong, T.T.; Tai, B.H.; Binh, N.Q.; Durante, M.; Fusi, F. Vasorelaxing activity of two coumarins from Murraya paniculata leaves. Biol. Pharm. Bull., 2014, 37(4), 694-697.
[23]
Zawadowski, T.; Kossakowski, J. Synthesis of aminoalkanols derivatives of 6,7-dimethoxy-2H-1-benzopyran-2-one with antiarrhythmic activity. Acta Pol. Pharm., 1993, 50(6), 453-455.
[24]
Watanuki, S.; Matsuura, K.; Tomura, Y.; Okada, M.; Okazaki, T.; Ohta, M.; Tsukamoto, S. Synthesis and pharmacological evaluation of 1-isopropyl-1,2,3,4-tetrahydroisoquinoline derivatives as novel antihypertensive agents. Chem. Pharm. Bull. (Tokyo), 2011, 59(8), 1029-1037.
[25]
Ogiyama, T.; Yonezawa, K.; Inoue, M.; Watanabe, T.; Sugano, Y.; Gotoh, T.; Kiso, T.; Koakutsu, A.; Kakimoto, S.; Shishikura, J. Discovery of a 1-isopropyltetrahydroisoquinoline derivative as an orally active N-type calcium channel blocker for neuropathic pain. Bioorg. Med. Chem., 2015, 23(15), 4624-4637.
[26]
Tibbs, G.R.; Posson, D.J.; Goldstein, P.A. Voltage-Gated Ion Channels in the PNS: Novel Therapies for Neuropathic Pain? Trends Pharmacol. Sci., 2016, 37(7), 522-542.
[27]
Osadchii, S.A.; Shul’ts, E.E.; Shakirov, M.M.; Tolstikov, G.A. Study of Plant Coumarins. 1. Transformations of peucedanin. Russ. Chem. Bull., 2006, 55, 375-379.
[28]
Shults, E.E.; Petrova, T.N.; Shakirov, M.M.; Chernyak, E.I.; Pokrovskii, L.M.; Nekhoroshev, S.A.; Tolstikov, G.A. Coumarins from the roots of Peucedanum morisonii Bess. Chem. Sust. Dev., 2003, 11, 683-691.
[29]
Bagryanskaya, I.Y.; Gatilov, Y.V.; Osadchii, S.A.; Martynov, A.A.; Shakirov, M.M.; Shul’ts, E.E.; Tolstikov, G.A. Plant Coumarins. 2. Beckmann rearrangement of oreoselone E- and Z-oximes. Chem. Nat. Compd., 2005, 41, 657-662.
[30]
Zhurakulov, S.N.; Vinogradova, V.I.; Levkovich, M.G. Synthesis of 1-aryltetrahydroisoquinoline alkaloids and their analogs. Chem. Nat. Compd., 2013, 49, 70-74.
[31]
Ábrányi-Balogh, P.; Földesi, T.; Milen, M. Total synthesis of racemic 1-aryl-tetrahydroisoquinoline alkaloids. Monatsh. Chem., 2015, 146, 1907-1912.
[32]
Khabriev, R.U. Preclinical researches of effectiveness of the pharmaceuticals intended for treatment of cardiovascular system diseases. In: Handbook of experimental research to clinical substances; Medicine: Moscow, 2005; pp. 393-476.
[33]
Tramontini, M. Advances in the Chemistry of Mannich Bases Synthesis, 1973, 12, 703-775.
[34]
Tramontini, M.; Angiolini, L. Further advances in the chemistry of Mannich bases. Tetrahedron, 1990, 46, 1791-1837.
[35]
Khilya, O.V.; Shablykina, O.V.; Frasinyuk, M.S.; Ishchenko, V.V.; Khilya, V.P. 3-(2-Pyridyl)coumarins. Chem. Nat. Compd., 2005, 41, 523-528.
[36]
Bondarenko, S.P.; Frasinyuk, M.S.; Vinogradova, V.I.; Khilya, V.P. Synthesis of flavonoid derivatives of cytisine. 1. Aminomethylation of 7-hydroxy-3-arylcoumarins. Chem. Nat. Compd., 2010, 46, 771-773.
[37]
Lipeeva, A.V.; Shul’ts, E.E.; Shakirov, M.M.; Tolstikov, G.A. Plant coumarins: Suzuki reaction in the synthesis of 3-aryl(hetaryl)furocoumarins. Russ. J. Org. Chem., 2011, 47, 1404-1409.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 15
ISSUE: 1
Year: 2019
Page: [71 - 82]
Pages: 12
DOI: 10.2174/1573407213666171030152601
Price: $58

Article Metrics

PDF: 14
HTML: 1