One-Pot Synthesis of 5-(Het)Aryl 8-Aminoquinoline Amide Derivatives as Potential Antibacterial / Cytotoxic Agents

Author(s): Zanjam Spandana, Tadigiri M. Rekha, Mandava V.B. Rao*, Manojit Pal*

Journal Name: Current Bioactive Compounds

Volume 16 , Issue 2 , 2020

DOI : 10.2174/1573407214666180910130225

  Journal Home
Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: The 8-Aminoquinoline (8-AQ) framework has attracted particular attention in the discovery and development of antimalarial and anti-bacterial agents or drugs. However, the clinical uses of 8-AQ based drugs are often associated with toxic side effects such as methemoglobinemia and hemolytic anemia with deficiency in Glucose-6-Phosphate Dehydrogenase (G6PD) Activity. The 4-aryl- 8-amino(acetamido)quinoline derivatives, on the other hand, have shown antiproliferative activities against cancer cell lines. These reports prompted us to assess the antibacterial and cytotoxic activities of a series of compounds based on 5-aryl 8-aminoquinoline amide scaffold.

Methods: A series of compounds based on 5-(het)aryl 8-aminoquinoline amide scaffold was synthesized via a one-pot ultrasound-assisted method using a C-5 selective halogenation of quinoline derivatives followed by Pd/C-catalyzed Suzuki-Miyaura coupling with (het)aryl boronic acids. All these compounds were evaluated for their in vitro antibacterial activities against representative Gram-(+) and Gram-(-) strains including Escherichia coli, Pseudomonas aeruginosa, Klebsiella species and Staphylococcus aureus. Three compounds were further tested for cytotoxicities in vitro against breast adenocarcinoma (MCF7) and Hepatocellular Carcinoma (HepG2) along with non-cancerous human embryonic kidney (HEK293) cell lines.

Results: All these compounds demonstrated moderate to good antibacterial activities against the four organisms used. In vitro assay results revealed that three compounds showed good activities against Gram-(+) strains and Gram-(-) strains and one was comparable to ciprofloxacin and pefloxacin. These three compounds were further tested for their cytotoxic properties against MCF7 and HepG2 cell lines. One of them showed IC50 value comparable to doxorubicin when tested against HepG2 cell lines. However, none of these compounds showed any significant effects when tested against HEK293 cells indicating their selectivity towards the growth inhibition of cancer cells.

Conclusion: A series of compounds based on 5-(het)aryl 8-aminoquinoline amide scaffold was synthesized and evaluated for antibacterial and cytotoxic activities. Several of these compounds showed promising antibacterial and cytotoxic activities when tested in vitro suggesting that the present class of compounds may be of interest for the identification of new and potential antibacterial / cytotoxic agents.

Keywords: Quinolone, suzuki-miyaura coupling, Pd/C, antibacterial activity, cytotoxicity, methemoglobinemia.

[1]
Shi, A.; Nguyen, T.A.; Battina, S.K.; Rana, S.; Takemoto, D.J.; Chiang, P.K.; Hua, D.H. Synthesis and anti-breast cancer activities of substituted quinolines. Bioorg. Med. Chem. Lett., 2008, 18(11), 3364-3368.
[http://dx.doi.org/10.1016/j.bmcl.2008.04.024] [PMID: 18457950]
[2]
Dzimbeg, G.; Zorc, B.; Kralj, M.; Ester, K.; Pavelić, K.; Andrei, G.; Snoeck, R.; Balzarini, J.; De Clercq, E.; Mintas, M. The novel primaquine derivatives of N-alkyl, cycloalkyl or aryl urea: synthesis, cytostatic and antiviral activity evaluations. Eur. J. Med. Chem., 2008, 43(6), 1180-1187.
[http://dx.doi.org/10.1016/j.ejmech.2007.09.001] [PMID: 17961851]
[3]
Vale, N.; Moreira, R.; Gomes, P. Primaquine revisited six decades after its discovery. Eur. J. Med. Chem., 2009, 44(3), 937-953.
[http://dx.doi.org/10.1016/j.ejmech.2008.08.011] [PMID: 18930565]
[4]
Ganesh, T.; Min, J.; Thepchatri, P.; Du, Y.; Li, L.; Lewis, I.; Wilson, L.; Fu, H.; Chiosis, G.; Dingledine, R.; Liotta, D.; Snyder, J.P.; Sun, A. Discovery of aminoquinolines as a new class of potent inhibitors of heat shock protein 90 (Hsp90): Synthesis, biology, and molecular modeling. Bioorg. Med. Chem., 2008, 16(14), 6903-6910.
[http://dx.doi.org/10.1016/j.bmc.2008.05.047] [PMID: 18571929]
[5]
Beutler, E.; Duparc, S. Glucose-6-phosphate dehydrogenase deficiency and antimalarial drug development. Am. J. Trop. Med. Hyg., 2007, 77(4), 779-789.
[http://dx.doi.org/10.4269/ajtmh.2007.77.779] [PMID: 17978087]
[6]
Dern, R.J.; Beutler, E.; Alving, A.S. The hemolytic effect of primaquine. V. Primaquine sensitivity as a manifestation of a multiple drug sensitivity. J. Lab. Clin. Med., 1955, 45(1), 30-39.
[PMID: 13233625]
[7]
Brueckner, R.P.; Lasseter, K.C.; Lin, E.T.; Schuster, B.G. First-time-in-humans safety and pharmacokinetics of WR 238605, a new antimalarial. Am. J. Trop. Med. Hyg., 1998, 58(5), 645-649.
[http://dx.doi.org/10.4269/ajtmh.1998.58.645] [PMID: 9598455]
[8]
Practical Chemotherapy of Malaria; World Health Organization. Technical Report Series no. 805; World Health Organization: Geneva,. 1990, 128.
[9]
Shiraki, H.; Kozar, M.P.; Melendez, V.; Hudson, T.H.; Ohrt, C.; Magill, A.J.; Lin, A.J. Antimalarial activity of novel 5-aryl-8-aminoquinoline derivatives. J. Med. Chem., 2011, 54(1), 131-142.
[http://dx.doi.org/10.1021/jm100911f] [PMID: 21141892]
[10]
Koh, E.J.; El-Gamal, M.I.; Oh, C-H.; Lee, S.H.; Sim, T.; Kim, G.; Choi, H.S.; Hong, J.H.; Lee, S.G.; Yoo, K.H. New diarylamides and diarylureas possessing 8-amino(acetamido)quinoline scaffold: synthesis, antiproliferative activities against melanoma cell lines, kinase inhibition, and in silico studies. Eur. J. Med. Chem., 2013, 70, 10-21.
[http://dx.doi.org/10.1016/j.ejmech.2013.06.060] [PMID: 24128410]
[11]
Paul, M.; Gafter-Gvili, A.; Fraser, A.; Leibovici, L. The anti-cancer effects of quinolone antibiotics? Eur. J. Clin. Microbiol. Infect. Dis., 2007, 26(11), 825-831.
[http://dx.doi.org/10.1007/s10096-007-0375-4] [PMID: 17701431]
[12]
Wang, Y.; Wang, Y.; Jiang, K.; Zhang, Q.; Li, D. Transition-metal-free oxidative C5 C-H-halogenation of 8-aminoquinoline amides using sodium halides. Org. Biomol. Chem., 2016, 14(43), 10180-10184.
[http://dx.doi.org/10.1039/C6OB02079H] [PMID: 27753444]
[13]
Suess, A.M.; Ertem, M.Z.; Cramer, C.J.; Stahl, S.S. Divergence between organometallic and single-electron-transfer mechanisms in copper(II)-mediated aerobic C-H oxidation. J. Am. Chem. Soc., 2013, 135(26), 9797-9804.
[http://dx.doi.org/10.1021/ja4026424] [PMID: 23750607]
[14]
Guo, H.L.; Chen, M.M.; Jiang, P.; Chen, J.; Pan, L.X.; Wang, M.; Xie, C.S.; Zhang, Y.H. Copper and palladium mediated C–H chlorination on 8-acylaminoquinoline scaffolds. Tetrahedron, 2015, 71, 70-76.
[http://dx.doi.org/10.1016/j.tet.2014.11.037]
[15]
Wu, C.G.; Zhou, H.; Wu, Q.L.M.; He, N.; Li, P.; Su, Q.; Mu, Y. Copper-catalyzed regioselective C–H iodination of aromatic carboxamides. Synlett, 2016, 868-875.
[http://dx.doi.org/10.1055/s-0035-1561335]
[16]
Xu, J.; Zhu, X.; Zhou, G.; Ying, B.; Ye, P.; Su, L.; Shen, C.; Zhang, P. Copper(II)-catalyzed C5 and C7 halogenation of quinolines using sodium halides under mild conditions. Org. Biomol. Chem., 2016, 14(11), 3016-3021.
[http://dx.doi.org/10.1039/C6OB00169F] [PMID: 26891279]
[17]
Liu, X.X.; Wu, Z.Y.; Luo, X.L.; He, Y.Q.; Zhou, X.Q.; Fu, Y.X.; Huang, G.S.PhI. (OAc) 2 oxidative C5 halogenation of quinolines using copper halides under mild conditions. RSC Advances, 2016, 6, 71485-71488.
[http://dx.doi.org/10.1039/C6RA14863H]
[18]
Chen, J.; Wang, T.; Liu, Y.; Wang, T.; Lin, A.; Yaoa, H.; Xu, J. Metal-free C5-selective halogenation of quinolones under aqueous conditions. Org. Chem. Front., 2017, 4, 622-626.
[http://dx.doi.org/10.1039/C6QO00765A]
[19]
Marck, G.; Villiger, A.; Buchecker, R. Aryl couplings with heterogeneous palladium catalysts. Tetrahedron Lett., 1994, 35, 3277-3280.
[http://dx.doi.org/10.1016/S0040-4039(00)76884-5]
[20]
Gala, D.; Stamford, A.; Jenkins, J.; Kugelman, M. One-step synthesis of biphenylacetic acids via Pd/C-catalyzed arylation. Org. Process Res. Dev., 1997, 1, 163-164.
[http://dx.doi.org/10.1021/op960035c]
[21]
Ennis, D.S.; McManus, J.; Wood-Kaczmar, W.; Richardoson, J.; Smith, G.E.; Carstairs, A. Multikilogram-scale synthesis of a biphenyl carboxylic acid derivative using a Pd/C-mediated Suzuki coupling approach. Org. Process Res. Dev., 1999, 3, 248-252.
[http://dx.doi.org/10.1021/op980079g]
[22]
LeBlond, C.R.; Andrews, A.T.; Sun, Y.; Sowa, J.R., Jr Activation of aryl chlorides for Suzuki cross-coupling by ligandless, heterogenous palladium. Org. Lett., 2001, 3, 1555-1557.
[http://dx.doi.org/10.1021/ol015850d]
[23]
Felpin, F-X.; Ayad, T.; Mitra, S. Pd/C: An Old Catalyst for New Applications – Its use for the Suzuki–miyaura reaction. Eur. J. Org. Chem., 2006, 2006, 2679-2690.
[http://dx.doi.org/10.1002/ejoc.200501004]
[24]
Cella, R.; Stefani, H.A. Ultrasonic reactions. Green Techniques for Organic Synthesis and Medicinal Chemistry; Zhang, W; Cue, B.W., Ed.; John Wiley & Sons, Ltd: Chichester, UK, 2012.
[http://dx.doi.org/10.1002/9780470711828.ch13]
[25]
Polácková, V.; Hut’ka, M.; Toma, S. Ultrasound effect on Suzuki reactions. 1. Synthesis of unsymmetrical biaryls. Ultrason. Sonochem., 2005, 12(1-2), 99-102.
[http://dx.doi.org/10.1016/j.ultsonch.2004.05.011] [PMID: 15474960]
[26]
Wang, X.; Qiu, R.; Yan, C.; Reddy, V.P.; Zhu, L.; Xu, X.; Yin, S-F. Nickel-catalyzed direct thiolation of C(sp(3))-H bonds in aliphatic amides. Org. Lett., 2015, 17(8), 1970-1973.
[http://dx.doi.org/10.1021/acs.orglett.5b00706] [PMID: 25822847]
[27]
Wu, X.; Zhao, Y.; Ge, H. Nickel-catalyzed site-selective alkylation of unactivated C(sp3)-H bonds. J. Am. Chem. Soc., 2014, 136(5), 1789-1792.
[http://dx.doi.org/10.1021/ja413131m] [PMID: 24446698]
[28]
Aihara, Y.; Chatani, N. Nickel-catalyzed direct arylation of C(sp3)-H bonds in aliphatic amides via bidentate-chelation assistance. J. Am. Chem. Soc., 2014, 136(3), 898-901.
[http://dx.doi.org/10.1021/ja411715v] [PMID: 24377655]
[29]
Performance standards for antimicrobial susceptibility testing: 9th informational supplement. National Committee for Clinical Laboratory Standard (NCCLS), 2008. Document No. M100-S9, Wayne, PA
[30]
Banothu, V.; Neelagiri, C.; Adepally, U.; Lingam, J.; Bommareddy, K. Phytochemical screening and evaluation of in vitro antioxidant and antimicrobial activities of the indigenous medicinal plant Albizia odoratissima. Pharm. Biol., 2017, 55(1), 1155-1161.
[http://dx.doi.org/10.1080/13880209.2017.1291694] [PMID: 28219296]
[31]
Chen, J-S.; Vasiliev, A.N.; Panarello, A.P.; Khinast, J.G. Pd-leaching and Pd-removal in Pd/C-catalyzed Suzuki couplings. Appl. Catal. A Gen., 2007, 325, 76-86.
[http://dx.doi.org/10.1016/j.apcata.2007.03.010]
[32]
Amatore, C.; Jutand, A.; Le Duc, G. Kinetic data for the transmetalation/reductive elimination in palladium-catalyzed Suzuki-Miyaura reactions: unexpected triple role of hydroxide ions used as base. Chemistry, 2011, 17(8), 2492-2503.
[http://dx.doi.org/10.1002/chem.201001911] [PMID: 21319240]
[33]
Beslija, S. The Role of anthracyclines / anthraquinones in metastatic breast cancer. Breast Cancer Res. Treat., 2003, 81, 25-32.
[http://dx.doi.org/10.1023/A:1026308604784]
[34]
Lown, J.W. Anthracycline and anthraquinone anticancer agents: current status and recent developments. Pharmacol. Ther., 1993, 60(2), 185-214.
[http://dx.doi.org/10.1016/0163-7258(93)90006-Y] [PMID: 8022857]
[35]
Cox, O.; Velez, C.; Kumar, V.; Malhotra, S.V.; Rivera, L.A.; Hernandez, W.J.; Martinez, J.R.; Cordero, M.; Zayas, B. Synthesis of and Biological Study of 7-Benzyl-3-aminobenzimidazo[3,2-a]quinolinium Chloride (ABQ-48: NSC D-763307) and 7-benzyl-3-nitrobenzimidazo[3,2-a]quinolinium Chloride (NBQ 48: NSC D-763303). Curr. Bioact. Compd., 2014, 10, 286-291.
[http://dx.doi.org/10.2174/1573407210666141126204355]
[36]
Aoyama, H.; Baba, M.; Hashimoto, Y. Nitrogen-containing fused-heteroaromatic compounds as Anti-Bovine Viral Diarrhea Virus (BVDV) agents. Curr. Bioact. Compd., 2010, 6, 118-128.
[http://dx.doi.org/10.2174/157340710791184868]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 2
Year: 2020
Page: [142 - 151]
Pages: 10
DOI: 10.2174/1573407214666180910130225
Price: $65

Article Metrics

PDF: 17
HTML: 1
EPUB: 1
PRC: 1



Most Downloaded Article(s)