Synthesis, Cytotoxic and Heparanase Inhibition Studies of 5-oxo-1-arylpyrrolidine-3- carboxamides of Hydrazides and 4-amino-5-aryl-4H-1,2,4-triazole-3-thiol

Author(s): Swetha Hari, Toreshettahally R. Swaroop, Habbanakuppe D. Preetham, Chakrabhavi D. Mohan, Umashakara Muddegowda, Salundi Basappa, Israel Vlodavsky, Gautam Sethi, Kanchugarakoppal S. Rangappa*

Journal Name: Current Organic Synthesis

Volume 17 , Issue 3 , 2020

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Abstract:

Design of chemically novel, biologically potent small heterocyclic molecules with anticancer activities, which targets the enzyme heparanase has gained prominent clinical interest. We have synthesized a novel class of carboxamide derivatives by coupling various substituted aromatic acid hydrazides and triazoleamine with pyrrolidine carboxylic acid by using coupling agents. The synthesized compounds are characterized by spectroscopic techniques such as FT-IR, HRMS and NMR. These compounds are investigated for cytotoxicity on different cancer cell lines and heparanase inhibitory activity. Most of them showed moderate heparanase inhibitory activity and good cytotoxicity.

Keywords: Hydrazides, triazole, carboxamides, cytotoxicity, heparanase, pyrrolidine.

[1]
Fux, L.; Ilan, N.; Sanderson, R.D.; Vlodavsky, I. Heparanase: busy at the cell surface. Trends Biochem. Sci., 2009, 34(10), 511-519. Available from.
[http://dx.doi.org/10.1016/j.tibs.2009.06.005] [PMID: 19733083]
[2]
Vlodavsky, I.; Miao, H.Q.; Medalion, B.; Danagher, P.; Ron, D. Involvement of heparan sulfate and related molecules in sequestration and growth promoting activity of fibroblast growth factor. Cancer Metastasis Rev., 1996, 15(2), 177-186. Available from.
[http://dx.doi.org/10.1007/BF00437470] [PMID: 8842489]
[3]
Sasisekharan, R.; Shriver, Z.; Venkataraman, G.; Narayanasami, U. Roles of heparan-sulphate glycosaminoglycans in cancer. Nat. Rev. Cancer, 2002, 2(7), 521-528. Available from.
[http://dx.doi.org/10.1038/nrc842] [PMID: 12094238]
[4]
Rafael, G.; Silvia, M.; Leticia, O.; Rodriguez-Diaz, J.; Rodrigo, J.C.; Patricia, M.; Pineda-Lucena, A. Hit identification of novel heparanase inhibitors by structure- and ligand-based approaches. Bioorg. Med. Chem., 2013, 21, 1944-1951. Available from.
[http://dx.doi.org/10.1016/j.bmc.2013.01.033] [PMID: 23415087]
[5]
Keerthy, H.K.; Mohan, C.D.; Sivaraman, S.K.; Fuchs, J.E.; Rangappa, S.; Sundaram, M.S.; Li, F.; Girish, K.S.; Sethi, G. Novel synthetic biscoumarins target tumor necrosis factor-α in hepatocellular carcinoma in vitro and in vivo. J. Biol. Chem., 2014, 289(46), 31879-31890. Available from.
[http://dx.doi.org/10.1074/jbc.M114.593855] [PMID: 25231984]
[6]
Bharath, K.H.; Mohan, C.D.; Ananda, H.; Fuchs, J.E.; Li, F.; Rangappa, S.; Surender, M.; Bulusu, K.C.; Girish, K.S.; Sethi, G.; Bender, A. Microwave-assisted synthesis, characterization and cytotoxic studies of novel estrogen receptor α ligands towards human breast cancer cells. Bioorg. Med. Chem. Lett., 2015, 25(8), 1804-1807. Available from.
[http://dx.doi.org/10.1016/j.bmcl.2015.01.030] [PMID: 25797502]
[7]
Rakesh, K.S.; Jagadish, S.; Vinayaka, A.C.; Hemshekhar, M.; Paul, M.; Thushara, R.M.; Sundaram, M.S.; Swaroop, T.R.; Mohan, C.D. A new ibuprofen derivative inhibits platelet aggregation and ROS mediated platelet apoptosis. PLoS One, 2014, 9(9) 107182 Available from.
[http://dx.doi.org/10.1371/journal.pone.0107182] [PMID: 25238069]
[8]
Roopashree, R.; Mohan, C.D.; Swaroop, T.R.; Jagadish, S.; Raghava, B.; Balaji, K.S.; Jayarama, S. Bioorg. Med. Chem. Lett., 2015, 25(12), 2589-2593. Available from.
[http://dx.doi.org/10.1016/j.bmcl.2015.04.010] [PMID: 25920563]
[9]
Keerthy, H.K.; Garg, M.; Mohan, C.D.; Madan, V.; Kanojia, D.; Shobith, R.; Nanjundaswamy, S.; Mason, D.J.; Bender, A. Synthesis and characterization of novel 2-amino-chromene-nitriles that target Bcl-2 in acute myeloid leukemia cell lines. PLoS One, 2014, 9(9) 107118 Available from.
[http://dx.doi.org/10.1371/journal.pone.0107118] [PMID: 25268519]
[10]
Mohan, C.D.; Srinivasa, V.; Rangappa, S.; Mervin, L.; Mohan, S.; Paricharak, S.; Baday, S.; Li, F.; Shanmugam, M.K.; Chinnathambi, A.; Zayed, M.E.; Sulaiman, A.A.; Bender, A.; Sethi, G. Trisubstituted-imidazoles induce apoptosis in human breast cancer cells by targeting the oncogenic PI3K/Akt/mTOR signaling pathway. PLoS One, 2016, 11(4) 0153155 Available from.
[http://dx.doi.org/10.1371/journal.pone.0153155]
[11]
Baburajeev, C.P.; Mohan, C.D.; Patil, G.S.; Rangappa, S.; Pandey, V.; Sebastian, A.; Fuchs, J.E.; Bender, A.; Lobie, P.E. RSC Advances, 2016, 6(43), 36775-36785. Available from.
[http://dx.doi.org/10.1039/C6RA01906D]
[12]
Tariq, S.; Alam, O.; Amir, M. Synthesis, anti-inflammatory, p38α MAP kinase inhibitory activities and molecular docking studies of quinoxaline derivatives containing triazole moiety. Bioorg. Chem., 2018, 76, 343-358. Available from.
[http://dx.doi.org/10.1016/j.bioorg.2017.12.003] [PMID: 29227918]
[13]
Küçükgüzel, I.; Güniz Küçükgüzel, S.; Rollas, S.; Otük-Saniş, G.; Ozdemir, O.; Bayrak, I.; Altuğ, T.; Stables, J.P. Synthesis of some 3-(arylalkylthio)-4-alkyl/aryl-5-(4-aminophenyl)-4H-1,2,4-triazole derivatives and their anticonvulsant activity. Farmaco, 2004, 59(11), 893-901. Available from.
[http://dx.doi.org/10.1016/j.farmac.2004.07.005] [PMID: 15544794]
[14]
Montes, G.C.; Monteiro-da Silva, B.N.; Rezende, B.; Sudo, R.T.; Ferreira, V.F.; de Carvalho -da, S.F.; Pinto, A.C.; Vasconcellos-da, S.B.; Zapata-Sudo, G. Molecules, 2017, 22, 800. Available from.
[http://dx.doi.org/10.3390/molecules22050800]
[15]
Kaur, R.; Dwivedi, A.R.; Kumar, B. Recent developments on 1,2,4-triazole nucleus in anticancer compounds:A review. Anticancer. Agents Med. Chem., 2016, 16, 465-489. Available from.
[http://dx.doi.org/10.2174/1871520615666150819121106] [PMID: 26286663]
[16]
Al-Soud, Y.A.; Al-Dweri, M.N.; Al-Masoudi, N.A. Synthesis, antitumor and antiviral properties of some 1,2,4-triazole derivatives. Farmaco, 2004, 59(10), 775-783. Available from.
[http://dx.doi.org/10.1016/j.farmac.2004.05.006] [PMID: 15474054]
[17]
Holla, B.S.; Kalluraya, B.; Sridhar, K.R. Synthesis and antibacterial activities of 5-subsituted-4-amino-1,2,4-triazole-3-thiols. Curr. Sci., 1987, 56, 236-243.
[18]
Park, H.I.; Pham, N.T.A. 1,2,3-triazole derivatives as antidiabetic agent, and methods for the preparation thereof. Korean Patent 2017045941 A20170428. 2017.
[19]
Foroumadi, A.; Kiani, Z.; Soltani, F. Antituberculosis agents VIII. Synthesis and in vitro antimycobacterial activity of alkyl alpha-[5-(5-nitro-2-thienyl)-1,3,4-thiadiazole-2-ylthio]acetates. Farmaco, 2003, 58(11), 1073-1076. Available from.
[http://dx.doi.org/10.1016/S0014-827X(03)00158-7] [PMID: 14572857]
[20]
Kumar, P.V.; Rao, V.R. Synthesis and Antitubercular, Antiviral and Anticancer Activity of 3-(3-Mercaptoalkyl-7H-[1,2,4]triazolo[3,4b] [1,3,4] thiadiazin-6-yl)chromen-2-one and Its Derivatives. Indian J Chem., 2008, 47(B), 106-111. Available from.
[http://dx.doi.org/10.1002/chin.200817162]
[21]
Ashok, D.; Gundu, S.; Aamate, V.K.; Devulappaly, M.G.; Bathini, R.; Manga, V. Dimers of coumarin-1,2,3-triazole hybrids bearing alkyl spacer: Design, microwave-assisted synthesis, molecular docking and evaluation as antimycobacterial and antimicrobial agents. J. Mol. Struct., 2018, 1157, 312-321. Available from.
[http://dx.doi.org/10.1016/j.molstruc.2017.12.080]
[22]
Cao, X.; Wang, W.; Wang, S.; Bao, L. Asymmetric synthesis of novel triazole derivatives and their in vitro antiviral activity and mechanism of action. Eur. J. Med. Chem., 2017, 139, 718-725. Available from.
[http://dx.doi.org/10.1016/j.ejmech.2017.08.057] [PMID: 28858766]
[23]
Keivanloo, A.; Bakherad, M.; Abbasi, F.; Besharati-Sedani, T.; Amin, A.H. Efficient synthesis of novel 1,2,3-triazole-linked quinoxaline scaffold via copper-catalyzed click reactions. RSC Advances, 2016, 6, 105433-105441. Available from.
[http://dx.doi.org/10.1039/C6RA22603E]
[24]
Kumar, S.S.; Kavitha, H.P. Synthesis and biological applications of triazole derivatives – A review. Mini Rev. Org. Chem., 2013, 10, 40-65. Available from.
[http://dx.doi.org/10.2174/1570193X11310010004]
[25]
Nett, J.E.; Andes, D.R. Antifungal agents: Spectrum of activity, pharmacology, and clinical indications. Infect. Dis. Clin. North Am., 2016, 30, 51-83. Available from.
[http://dx.doi.org/10.1016/j.idc.2015.10.012]
[26]
Chang, K.; Shi, Y.; Chen, J.; He, Z.; Xu, Z.; Zhao, Z.; Zhu, W.; Li, H.; Xu, Y.; Li, B.; Qian, X. The discovery of new plant activators and scaffolds with potential induced systemic resistance: From jasmonic acid to pyrrolidone. MedChemComm, 2016, 7(9), 1849-1857. Available from.
[http://dx.doi.org/10.1039/C6MD00261G]
[27]
Xianfeng, L.; Wenming, C.; Qiu, Z. Lin, X.; Chen, W.; Qiu, Z.; Guo, L.; Zhu, W.; Li, W.; Wang, Z.; Zhang, W.; Zhang, Z.; Rong, Y.; Zhang, Lingjie Yu, M.; Zhong, S.; Zhao, R.; Wu, X.; Wong, J.C.; Tang, G. Design and Synthesis of Orally Bio Available Aminopyrrolidinone Histone Deacetylase 6 Inhibitors. J. Med. Chem., 2015, 58, 2809-2820. Available from.
[http://dx.doi.org/10.1021/jm502011f]
[28]
George, S.; Thengungal, K.R. Oxadiazolo pyrrolidine carboxamides as enoyl-ACP reductase inhibitors: Design, synthesis and antitubercular activity screening. Med. Chem. Res., 2013, 22, 3428-3433. Available from.
[http://dx.doi.org/10.1007/s00044-012-0340-3]
[29]
Packiarajan, M.; Mazza Ferreira, C.G.; Hong, S.P.; White, A.D.; Chandrasena, G.; Pu, X.; Brodbeck, R.M.; Robichaud, A.J. N-Aryl pyrrolidinonyl oxadiazoles as potent mGluR5 positive allosteric modulators. Bioorg. Med. Chem. Lett., 2012, 22, 5658-5662. Available from.
[http://dx.doi.org/10.1016/j.bmcl.2012.06.094] [PMID: 22832311]
[30]
Bharathkumar, H.; Mohan, C.D.; Rangappa, S.; Kang, T.; Keerthy, H.K.; Fuchs, J.E.; Kwon, N.H.; Bender, A.; Kim, S. Screening of quinoline, 1,3-benzoxazine, and 1,3-oxazine-based small molecules against isolated methionyl-tRNA synthetase and A549 and HCT116 cancer cells including an in silico binding mode analysis. Org. Biomol. Chem., 2015, 13, 9381-9387. Available from.
[http://dx.doi.org/10.1039/C5OB00791G] [PMID: 26159576]
[31]
Baburajeev, C.P.; Mohan, C.D.; Shobith, R.; Daniel, J.M.; Julian, E. Identification of novel class of triazolo-thiadiazoles as potent inhibitors of human heparanase and their anticancer activity. BMC Cancer, 2017, 17, 235. Available from.
[http://dx.doi.org/10.1186/s12885-017-3214-8] [PMID: 28359266]
[32]
Khan, S.I.; Badshah, A.; Chaudhry, A.H.; Aslam, M.; Akhtar, M.S.; Ashfaq, K.M.; Malik, T.A. Synthesis and antibacterial activities of 5-subsituted-4- amino-1,2,4-triazole-3-thiols. Med. Chem. Drug Discov., 2012, 3(2), 116-121. Available from. https://dx.doi.org/10.4103%2F2231-4040.161515
[PMID: 26317080]
[33]
Xin, H.; Akram, A.; Robert, S.; Paul, R. Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis. J. Med. Chem., 2006, 49(21), 6308-6323. Available from.
[http://dx.doi.org/10.1021/jm060715y] [PMID: 17034137]
[34]
Mohan, C.D.; Anilkumar, N.C.; Rangappa, S.; Shanmugam, M.K.; Mishra, S. Novel 1,3,4-oxadiazole induces anticancer activity by targeting nf-κb in hepatocellular carcinoma cells. Front. Oncol., 2018, 8, 42. Available from. https://dx.doi.org/10.3389%2Ffonc.2018.00042
[PMID: 29616186]
[35]
Mohan, C.D.; Bharathkumar, H. Dukanya, Shobith. N-Substituted Pyrido-1,4-Oxazin-3-ones induce apoptosis of hepatocellular carcinoma cells by targeting nf-κb signaling pathway. Front. Pharmacol., 2018, 9, 1125. Available from. https://dx.doi.org/10.3389%2Ffphar.2018.01125
[PMID: 30455641]
[36]
Rakesh, K.S.; Jagadish, S.; Swaroop, T.R.; Mohan, C.D.; Ashwini, N.; Harsha, K.B.; Zameer, F.; Kesturu, S. Med. Chem., 2015, 11, 462-472. Available from.
[http://dx.doi.org/10.2174/1573406411666141210141918] [PMID: 25494807]
[37]
Chaithanya, S.; Mahesh, H.; Sharath Kumar, K.S.; Ananad, H.; Srivastava, M.; Harsha, K.B.; Mohan, C.D.; Kavya, A. Synthesis and biological evaluation of novel thiazol-2yl-amine derivatives as potential anticancer agents. Lett. Org. Chem., 2018, 15, 270-281. Available from.
[http://dx.doi.org/10.2174/1570178614666170907122026]
[38]
Hammond, E.; Li, C.P.; Ferro, V. Development of a colorimetric assay for heparanase activity suitable for kinetic analysis and inhibitor screening. Anal. Biochem., 2010, 396(1), 112-116. Available from.
[http://dx.doi.org/10.1016/j.ab.2009.09.007] [PMID: 19748475]


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VOLUME: 17
ISSUE: 3
Year: 2020
Page: [243 - 250]
Pages: 8
DOI: 10.2174/1570179417666200225123329
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