Generic placeholder image

Medicinal Chemistry

Author(s): Vikrant Patil, Siddappa A. Patil*, Renukadevi Patil, Alejandro Bugarin, Kenneth Beaman and Shivaputra A. Patil*

DOI: 10.2174/1573406414666180524074648

DownloadDownload PDF Flyer Cite As
Exploration of (hetero)aryl Derived Thienylchalcones for Antiviral and Anticancer Activities

Page: [150 - 161] Pages: 12

  • * (Excluding Mailing and Handling)

Abstract

Background: Search for new antiviral and anticancer agents are essential because of the emergence of drug resistance in recent years. In continuation of our efforts in identifying the new small molecule antiviral and anticancer agents, we identified chalcones as potent antiviral and anticancer agents.

Objective: With the aim of identifying the broad acting antiviral and anticancer agents, we discovered substituted aryl/heteroaryl derived thienyl chalcones as antiviral and anticancer agents.

Method: A focused set of thienyl chalcone derivaties II-VI was screened for selected viruses Hepatitis B virus (HBV), Herpes simplex virus 1 (HSV-1), Human cytomegalovirus (HCMV), Dengue virus 2 (DENV2), Influenza A (H1N1) virus, MERS coronavirus, Poliovirus 1 (PV 1), Rift Valley fever (RVF), Tacaribe virus (TCRV), Venezuelan equine encephalitis virus (VEE) and Zika virus (ZIKV) using the National Institute of Allergy and Infectious Diseases (NIAID)’s Division of Microbiology and Infectious Diseases (DMID) antiviral screening program. Additionally, a cyclopropylquinoline derivative IV has been screened for 60 human cancer cell lines using the Development Therapeutics Program (DTP) of NCI.

Results: All thienyl chalcone derivatives II-VI displayed moderate to excellent antiviral activity towards several viruses tested. Compounds V and VI were turned out be active compounds towards human cytomegalovirus for both normal strain (AD169) as well as resistant isolate (GDGr K17). Particularly, cyano derivative V showed very high potency (EC50: <0.05 µM) towards AD169 strain of HCMV compared to standard drug Ganciclovir (EC50: 0.12 µM). Additionally, it showed moderate activity in the secondary assay (AD169; EC50: 2.30 µM). The cyclopropylquinoline derivative IV displayed high potency towards Rift Valley fever virus (RVFV) and Tacaribe virus (TCRV) towards Rift Valley fever virus (RVFV). The cyclopropylquinoline derivative IV is nearly 28 times more potent in our initial in vitro visual assay (EC50: 0.39 µg/ml) and nearly 17 times more potent in neutral red assay (EC50: 0.71 μg/ml) compared to the standard drug Ribavirin (EC50: 11 µg/ml; visual assay and EC50: 12 µg/ml; neutral red assay). It is nearly 12 times more potent in our initial in vitro visual assay (EC50: >1 µg/ml) and nearly 8 times more potent in neutral red assay (EC50: >1.3 µg/ml) compared to the standard drug Ribavirin (EC50: 12 µg/ml; visual assay and EC50: 9.9 µg/ml; neutral red assay) towards Tacaribe virus (TCRV). Additionally, cyclopropylquinoline derivative IV has shown strong growth inhibitory activity towards three major cancers (colon, breast, and leukemia) cell lines and moderate growth inhibition shown towards other cancer cell lines screened.

Conclusion: Compounds V and VI were demonstrated viral inhibition towards Human cytomegalovirus, whereas cyclopropylquinoline derivative IV towards Rift Valley fever virus and Tacaribe virus. Additionally, cyclopropylquinoline derivative IV has displayed very good cytotoxicity against colon, breast and leukemia cell lines in vitro.

Keywords: Anticancer, antiviral, colon, thienyl chalcone, aryl/heteroaryl, structure-activity relationship.

Graphical Abstract

[1]
Irwin, K.K.; Renzette, N.; Kowalik, T.F.; Jensen, J.D. Antiviral drug resistance as an adaptive process. Virus Evol., 2016, 2(1), vew014.
[2]
Patil, S.A.; Patil, V.; Patil, R.; Beaman, K.; Patil, S.A. Identification of novel 5,6-dimethoxyindan-1-one derivatives as antiviral agents. Med. Chem., 2017, 13(8), 787-795.
[3]
Patil, R.; Ghosh, A.Sun; Cao, P.; Sommer, R.D.; Grice, K.A.; Waris, G.; Patil, S. Novel 5-arylthio-5H-chromenopyridines as a new class of anti-fibrotic agents. Bioorg. Med. Chem. Lett., 2017, 27(5), 1129-1135.
[4]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2016. CA Cancer J. Clin., 2016, 66(1), 7-30.
[5]
Available at. www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2016
[6]
Baselga, J. Targeting tyrosine kinases in cancer: The second wave. Science, 2006, 312, 1175-1178.
[7]
Croom, K.F.; Perry, C.M. Imatinibmesylate: in the treatment of gastrointestinal stromal tumors. Drugs, 2003, 63, 513-522.
[8]
Druker, B.J.; Talpaz, M.; Resta, D.J.; Peng, B.; Buchdunger, E.; Ford, J.M.; Lydon, N.B.; Kantarjian, H.; Capdeville, R.; Ohno-Jones, S.; Sawyers, C.L. Efficacy and safety of a specific inhibitor of the BCRABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med., 2001, 344, 1031-1037.
[9]
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.
[10]
Patil, S.A.; Pfeffer, S.R.; Seibel, W.L.; Pfeffer, L.M.; Miller, D.D. Identification of imidazoquinoline derivatives as potent antiglioma agents. Med. Chem., 2015, 11(4), 400-406.
[11]
Maria, K.; Dimitra, H.L.; Maria, G. Synthesis and anti-inflammatory activity of chalcones and related Mannich bases. Med. Chem., 2008, 4(6), 586-596.
[12]
Wu, J.; Li, J.; Cai, Y.; Pan, Y.; Ye, F.; Zhang, Y.; Zhao, Y.; Yang, S.; Li, X.; Liang, G. Evaluation and discovery of novel synthetic chalcone derivatives as anti-inflammatory agents. J. Med. Chem., 2011, 54(23), 8110-8123.
[13]
Nowakowska, Z. A review of anti-infective and anti-inflammator chalcones. Eur. J. Med. Chem., 2007, 42(2), 125-137.
[14]
Miranda, C.L.; Stevens, J.F.; Ivanov, V.; McCall, M.; Frei, B.; Deinzer, M.L.; Buhler, D.R. Antioxidant and prooxidant actions of prenylated and nonprenylated chalcones and flavanones in vitro. J. Agric. Food Chem., 2000, 48(9), 3876-3884.
[15]
Chiaradia, L.D.; Mascarello, A.; Purificação, M.; Vernal, J.; Cordeiro, M.N.S.; Zenteno, M.E.; Villarino, A.; Nunes, R.J.; Yunes, R.A.; Terenzi, H. Synthetic chalcones as efficient inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase PtpA. Bioorg. Med. Chem. Lett., 2008, 18(23), 6227-6230.
[16]
Wu, J.H.; Wang, X.H.; Yi, Y.H.; Lee, K.H. Anti-AIDS agents 54. A potent anti-HIV chalcone and flavonoids from genus Desmos. Bioorg. Med. Chem. Lett., 2003, 13(10), 1813-1815.
[17]
Domínguez, J.N.; Charris, J.E.; Lobo, G.; Gamboa de Domínguez, N.; Moreno, M.M.; Riggione, F.; Sanchez, E.; Olson, J.; Rosenthal, P.J. Synthesis of quinolinylchalcones and evaluation of their antimalarial activity. Eur. J. Med. Chem., 2001, 36(6), 555-560.
[18]
Dimmock, J.R.; Elias, D.W.; Beazely, M.A.; Kandepu, N.M. Bioactivities of chalcones. Curr. Med. Chem., 1999, 6(12), 1125-1149.
[19]
Patil, V.; Barragan, E.; Patil, S.A.; Patil, S.A.; Bugarin, A. Direct synthesis and antimicrobial evaluation of structurally complex chalcones. Chem. Select., 2016, 1(13), 3647.
[20]
Prichard, M.N.; Williams, J.D.; Komazin-Meredith, G.; Khan, A.R.; Price, N.B.; Jefferson, G.M.; Harden, E.A.; Hartline, C.B.; Peet, N.P.; Bowlin, T.L. Synthesis and antiviral activities of methylenecyclopropane analogs with 6-alkoxy and 6-alkylthio substitutions that exhibit broad-spectrum antiviral activity against human herpesviruses. Antimicrob. Agents Chemother., 2013, 57(8), 3518-3527.
[21]
Smee, D.F.; Huffman, J.H.; Morrison, A.C.; Barnard, D.L.; Sidwell, R.W. Cyclopentane neuraminidase inhibitors with potent in vitro anti-influenza virus activities. Antimicrob. Agents Chemother., 2001, 45(3), 743-748.
[22]
Smee, D.F.; Evans, W.J.; Nicolaou, K.C.; Tarbet, E.B.; Day, C.W. Susceptibilities of enterovirus D68, enterovirus 71, and rhinovirus 87 strains to various antiviral compounds. Antiviral Res., 2016, 131, 61-65.
[23]
Korba, B.E.; Gerin, J.L. Use of a standardized cell culture assay to assess activities of nucleoside analogs against hepatitis B virus replication. Antiviral Res., 1992, 19(1), 55-70.
[24]
Korba, B.E.; Milman, G. A cell culture assay for compounds which inhibit hepatitis B virus replication. Antiviral Res., 1991, 15(3), 217-228.
[25]
Boyd, M.R.; Paull, K.D. Some practical considerations and applications of the National Cancer Institute in vitro anticancer drug discovery screen. Drug Dev. Res., 1995, 34, 91-109.
[26]
Holbeck, S.L.; Collins, J.M.; Doroshow, J.H. Analysis of Food and Drug Administration-approved anticancer agents in the NCI60 panel of human tumor cell lines. Mol. Cancer Ther., 2010, 9(5), 1451-1460.
[27]
Covell, D.G.; Huang, R.; Wallqvist, A. Anticancer medicines in development: assessment of bioactivity profiles within the National Cancer Institute anticancer screening data. Mol. Cancer Ther., 2007, 6(8), 2261-2270.
[28]
Skehan, P.; Streng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J.T.; Bokesch, H.; Kenney, S.; Boyd, M. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst., 1990, 82, 1107-1112.
[29]
Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.; Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A.; Gray-Goodrich, M.; Campbell, H.; Mayo, J.; Boyd, M. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell Lines. J. Natl. Cancer Inst., 1991, 11, 757-766.
[30]
Lok, A.S. Hepatitis B infection: pathogenesis and management. J. Hepatol., 2000, 32, 89-97.
[31]
Shepard, C.W.; Simard, E.P.; Finelli, L.; Fiore, E.; Bell, B.P. Hepatitis B virus infection: epidemiology and vaccination. Epidemiol. Rev., 2006, 28, 112-125.
[32]
Sharma, A.; Chakravarti, B.; Gupta, M.P.; Siddiqui, J.A.; Konwar, R.; Tripathi, R.P. Synthesis and anti breast cancer activity of biphenyl based chalcones. Bioorg. Med. Chem., 2010, 18(13), 4711-4720.
[33]
Lee, J.M.; Lee, M.S.; Koh, D.; Lee, Y.H.; Lim, Y.; Shin, S.Y. A new synthetic 2′-hydroxy-2,4,6-trimethoxy-5′,6′-naphthochalcone induces G2/M cell cycle arrest and apoptosis by disrupting the microtubular network of human colon cancer cells. Cancer Lett., 2014, 354(2), 348-354.
[34]
Mai, C.W.; Yaeghoobi, M.; Abd-Rahman, N.; Kang, Y.B.; Pichika, M.R. Chalcones with electron-withdrawing and electron-donating substituents: anticancer activity against TRAIL resistant cancer cells, structure-activity relationship analysis and regulation of apoptotic proteins. Eur. J. Med. Chem., 2014, 77, 378-387.