Synthesis and Biological Evaluation of 3-cyano-4H-chromene Derivatives Bearing Carbamate Functionality

Author(s): Fatma Boukattaya, Amal Daoud, Fabien Boeda, Morwenna S.M. Pearson-Long, Néji Gharsallah, Adel Kadri, Philippe Bertus*, Houcine Ammar.

Journal Name: Medicinal Chemistry

Volume 15 , Issue 3 , 2019

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Graphical Abstract:


Background: 2-Aminochromene derivatives display important pharmacological properties, including mainly antibiotic and anticancer activities.

Objective: The study aims to synthesize new chromene derivatives via a new approach using Grignard reagents, for the evaluation of their antibiotic and antifungal properties.

Method: A series of novel 3-cyano-4-aminochromene derivatives bearing alkyl substituents at the 4-position was prepared for biological evaluation.

Results: These compounds were obtained by the addition of various Grignard reagents into Nethoxycarbonyl- 3-cyanoiminocoumarines in moderate to good yields (72-96%). The reaction is completely regioselective. The new chromene derivatives were screened for their in vitro antimicrobial activities against a panel of six bacterial and three fungal strains using agar dilution method.

Conclusion: The antibacterial activity of the chromene derivatives was more pronounced on Gram-positive bacteria than on Gram-negative bacteria with a significant activity observed against Staphylococcus aureus. An interesting antifungal activity against Fusarium sp. and Fusarium oxysporum was also noticed.

Keywords: Antibacterial activity, Antifungal activity, Carbamates, Chromenes, Coumarins, Grignard reagents.

Pratap, R.; Ram, V.J. Natural and synthetic chromenes, fused chromenes and versatility of dihydrobenzo[h] chromemes in organic synthesis. Chem. Rev., 2014, 114(20), 10476-10526.
Ellis, G.P.; Lockhart, I.M. In: The Chemistry of Heterocyclic Compounds: Chromenes, Chromanones, and Chromones; Ellis, G.P., Ed.; Wiley-VCH: New York, 2009, Vol. 31, pp. 1-1196.
Subbareddy, C.V.; Sundarrajan, S.; Mohanapriya, A.; Subashini, R.; Sumathi, S. Synthesis, antioxidant, antibacterial, solvatochromism and molecular docking studies of indolyl-4H-chromene-phenylprop-2-en-1-one derivatives. J. Mol. Liq., 2018, 251, 296-307.
Chitreddy, S.V.; Shanmugam, S. Solvent free-synthesis of highly functionalized 4H-chromene-3-carboxamide derivatives using cerium ammonium nitrate and their antioxidant, antibacterial and solvatochromism studies. J. Mol. Liq., 2017, 243, 494-502.
Jain, N.; Xu, J.; Kanojia, R.M.; Du, F.; Jian-Zhong, G.; Pacia, E.; Lai, M.T.; Musto, A.; Allan, G.; Reuman, M.; Li, X.; Hahn, D.; Cousineau, M.; Peng, S.; Ritchie, D.; Russell, R.; Lundeen, S.; Sui, Z. Identification and structure-activity relationships of chromene-derived selective estrogen receptor modulators for treatment of postmenopausal symptoms. J. Med. Chem., 2009, 52(23), 7544-7569.
Mori, J.; Iwashima, M.; Takeuchi, M.; Saito, H. A synthetic study on antiviral and antioxidative chromene derivative. Chem. Pharm. Bull., 2006, 54(3), 391-396.
Park, J.H.; Lee, S.U.; Kim, S.H.; Shin, S.Y.; Lee, J.Y.; Shin, C.G.; Yoo, K.H.; Lee, Y.S. Chromone and chromanone derivatives as strand transfer inhibitors of HIV-1 integrase. Arch. Pharm. Res., 2008, 31(1), 1-5.
Cheng, J.F.; Ishikawa, A.; Ono, Y.; Arrhenius, T.; Nadzan, A. Novel chromene derivatives as TNF-alpha inhibitors. Bioorg. Med. Chem. Lett., 2003, 13(21), 3647-3650.
De Simone, R.W.; Currie, K.S.; Mitchell, S.A.; Darrow, J.W.; Pippin, D.A. Privileged structures: applications in drug discovery. Comb. Chem. High Throughput Screen., 2004, 7(5), 473-493.
Costantino, L.; Barlocco, D. Privileged structures as leads in medicinal chemistry. Curr. Med. Chem., 2006, 13(1), 65-85.
Zhang, G.; Zhang, Y.; Yan, J.; Chen, R.; Wang, S.; Ma, Y.; Wang, R. One-pot enantioselective synthesis of functionalized pyranocoumarins and 2-amino-4H-chromenes: discovery of a type of potent antibacterial agent. J. Org. Chem., 2012, 77(2), 878-888.
Afifi, T.H.; Okasha, R.M.; Ahmed, H.E.A.; Ilaš, J.; Saleh, T.; Abd-El-Aziz, A.S. Structure-activity relationships and molecular docking studies of chromene and chromene based azo chromophores: A novel series of potent antimicrobial and anticancer agents. EXCLI J., 2017, 16, 868-902.
Khafagy, M.M.; Abd El-Wahab, A.H.F.; Eid, F.A.; El-Agrody, A.M. Synthesis of halogen derivatives of benzo[h]chromene and benzo[a]anthracene with promising antimicrobial activities. Farmaco, 2002, 57, 715-722.
Suresh, L.; Kumar, P.S.V.; Chandramouli, G.V.P. An efficient one-pot synthesis, characterization and antibacterial activity o novel chromeno-pyrimidine derivatives. J. Mol. Struct., 2017, 1134, 51-58.
Kidwai, M.; Saxena, S.; Khan, M.K.R.; Thukral, S.S. Aqua mediated synthesis of substituted 2-amino-4H-chromenes and in vitro study as antibacterial agents. Bioorg. Med. Chem. Lett., 2005, 15(19), 4295-4298.
Thumar, N.J.; Patel, M.P. Synthesis and in vitro antimicrobial evaluation of 4H-pyrazolopyran, -benzopyran and naphthopyran derivatives of 1H-pyrazole. ARKIVOC, 2009, xiii, 363-380.
El-Bakhshawangy, N.M.; El-Nassan, H.B.; Kassab, A.E.; Taher, A.T. Design, synthesis and biological evaluation of chromenopyrimidines as potential cytotoxic agents. Future Med. Chem., 2018, 10(12), 1465-1481.
Patil, S.A.; Patil, R.; Pfeffer, L.M.; Miller, D.D. Chromenes: Potential new chemotherapeutic agents for cancer. Future Med. Chem., 2013, 5(14), 1647-1660.
Patil, S.A.; Wang, J.; Li, X.S.; Chen, J.; Jones, T.S.; Hosni-Ahmed, A.; Patil, R.; Seibel, W.L.; Li, W.; Miller, D.D. New substituted 4H-chromenes as anticancer agents. Bioorg. Med. Chem. Lett., 2012, 22(13), 4458-4461.
Drewe, J.A.; Cai, S.X.; Wang, Y. Substituted 4H-chromene and analogs as activator of caspases and inducers of apoptosis and the use thereof. WO patent 01/34591 A2, May 17, 2001.
Kemnitzer, W.; Kasibhatla, S.; Jiang, S.; Zhang, H.; Zhao, J.; Jia, S.; Xu, L.; Crogan-Grundy, C.; Denis, R.; Barriault, N.; Vaillancourt, L.; Charron, S.; Dodd, J.; Attardo, G.; Labrecque, D.; Lamothe, S.; Gourdeau, H.; Tseng, B.; Drewe, J.; Cai, S.X. Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 2. Structure-activity relationships of the 7- and 5-, 6-, 8-positions. Bioorg. Med. Chem. Lett., 2005, 15(21), 4745-4751.
Kemnitzer, W.; Drewe, J.; Jiang, S.; Zhang, H.; Zhao, J.; Crogan-Grundy, C.; Xu, L.; Lamothe, S.; Gourdeau, H.; Denis, R.; Tseng, B.; Kasibhatla, S.; Cai, S.X. Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 3. Structure−activity relationships of fused rings at the 7,8-Positions. J. Med. Chem., 2007, 50(12), 2858-2864.
Cai, S.X.; Drewe, J.; Kemnitzer, W. Discovery of 4-aryl-4H-chromenes as potent apoptosis inducers using a cell-and caspase-based anti-cancer screening apoptosis program (ASAP): SAR studies and the identification of novel vascular disrupting agents. Anticancer. Agents Med. Chem., 2009, 9(4), 437-456.
Nicolaou, K.C.; Pfefferkorn, J.A.; Roecker, A.J.; Cao, G.Q.; Barluenga, S.; Mitchell, H.J. Natural product-like combinatorial libraries based on privileged structures. 1. General principles and solid-phase synthesis of benzopyrans. J. Am. Chem. Soc., 2000, 122(41), 9939-9953.
Dammak, L.; Kammoun, M.; Allouche, N.; Ammar, H.; Abid, S. Synthesis and antibacterial activity of 2-amino chromenes arising cyanoiminocoumarins and β-naphthol. Org. Commun., 2017, 10(1), 32-39.
Ammar, H.; Abid, S.; Le Bigot, Y.; El Gharbi, R. Novel synthesis of bis-iminocoumarins. Synth. Commun., 2012, 42(6), 799-810.
Kammoun, M.; Turki, H.; El Gharbi, R.; Fery-Forgues, S. Reactivity of 3-cyano-N-ethoxycarbonyl-iminocoumarin with hydrazides as N-nucleophiles. J. Heterocycl. Chem., 2009, 46(1), 28-32.
Ghosh, A.K.; Brindisi, M. Organic carbamates in drug design and medicinal chemistry. J. Med. Chem., 2015, 58(7), 2895-2940.
Kamdar, N.R.; Haveliwala, D.D.; Mistry, P.T.; Patel, S.K. Synthesis and evaluation of in vitro antitubercular activity and antimicrobial activity of some novel 4H-chromeno [2,3-d]pyrimidine via 2-amino-4-phenyl-4H-chromene-3-carbonitriles. Med. Chem. Res., 2011, 20(7), 854-864.
Ballini, R.; Bosica, G.; Conforti, M.L.; Maggi, R.; Mazzacani, A.; Righi, P.; Sartori, G. Three-component process for the synthesis of 2-amino-2-chromenes in aqueous media. Tetrahedron, 2001, 57(7), 1395-1398.
Bardasov, I.N.; Alekseeva, A.U.; Ershov, O.V.; Grishanov, D.A. One-pot synthesis of 4-alkyl-2-amino-4H-chromene derivatives. Heterocycl. Commun., 2015, 21(3), 175-177.
Turki, H.; Abid, S.; Le Bigot, Y.; Fery-Forges, S.; El Gharbi, R. Novel synthesis of 2‐oxo‐2H‐benzopyrano [2,3‐d] pyrimidines. Synth. Commun., 2004, 34(19), 3553-3563.
Shanthi, G.; Perumal, P.T. Indium-mediated one-pot synthesis of new 4-allyl-2-amino-4H-chromenes in water. Synlett, 2008, 18, 2791-2794.
Al-Abdullah, E.S.; Al-Tuwaijri, H.M.; Hassan, H.M.; Al-Alshaikh, M.A.; Habib, E.E.; El-Emam, A.A. Synthesis, antimicrobial and hypoglycemic activities of novel N-(1-adamantyl) carbothioamide derivatives. Molecules, 2015, 20(5), 8125-8143.
Silhavy, T.J.; Kahne, D.; Walker, S. The bacterial cell envelop. Cold Spring Harb. Perspect. Biol., 2010, 2(5), a000414.
Renau, T.E.; Sanchez, J.P.; Gage, J.W.; Dever, J.A.; Shapiro, M.A. Structure−activity relationships of the quinolone antibacterials against mycobacteria: effect of structural changes at N-1 and C-7. J. Med. Chem., 1996, 39(3), 729-735.
Daoud, A.; Drira, M.; Bakari, S.; Hfaiedh, N.; Mnafgui, K.; Kadri, A.; Gharsallah, N. Assessment of polyphenol composition, antioxidant and antimicrobial properties of various extracts of Date Palm Pollen (DPP) from two Tunisian cultivars. Arab. J. Chem., 2015.
Gulluce, M.; Sahin, F.; Sokmen, M.; Ozer, H.; Daferea, D.; Sokmen, A.; Polissiou, M.; Adiguzel, A.; Ozkan, H. Antimicrobial and antioxidant properties of the essential oils and methanol extract from Mentha longifolia L. ssp. Longifolia. Food Chem., 2007, 103(4), 1449-1456.

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Article Details

Year: 2019
Page: [257 - 264]
Pages: 8
DOI: 10.2174/1573406414666181009124449
Price: $58

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