Synthesis and Biological Activity of N-(arylsulfonyl) Valine Hydrazones and Assistance of NMR Spectroscopy for Definitive 3D Structure

Author(s): Sevil Şenkardeş, Esra Tatar, Ridvan Nepravishta*, Dorisa Cela, Maurizio Paci, Özlem Bingöl Özakpınar, Turgut Şekerler, Erik De Clercq, Christophe Pannecouque, Ş. Güniz Küçükgüzel*, İlkay Küçükgüzel.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 9 , 2019

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Graphical Abstract:


Background: Hydrazide-hydrazones constitute an important class of compounds for new drug development. In this study, a series of 39 new acylhydrazones (3-41), derived from (2S)-3-methyl- 2-[[(4-methylphenyl)sulfonyl]amino]butanoic acid hydrazide were synthesized with further aim to achieve biologically active acylhydrazones carrying an amino acid side chain.

Methods: Compounds 3-41 were synthesized by microwave-assisted method. All synthesized compounds have been tested for their anti-HIV activity compound 21 was subjected to a new set of 2DNMR analysis for the characterization of the isomers in solution and determination of its 3D structure.

Results: The IC50 values for compounds 2-40 were found between >125-10.90 µg/ml against HIV- 1(IIIB) and HIV-2(ROD) strains in MT-4 cells. Compounds 3, 6, 10, 12, 23, 24, 27, 32, and 37 with CC50 values between 10.90-14.50 µg/ml were selected to evaluate for their antileukemia activity. IC50 values for these mentioned compounds were found as >100μM on human chronic myelogenous leukemia, K562 cell line.

Conclusion: Some compounds with IC50 values between 10.90-14.50 μg/ml will be of benefit in the development of novel leads.

Keywords: Acylhydrazones, anti-HIV activity, antileukemia activity, 2D-NMR spectroscopy, 3D structure, L-valine, microwave assisted synthesis.

Rollas, S.; Küçükgüzel, Ş.G. Biological activities of hydrazone derivatives. Molecules, 2007, 12, 1910-1939.
Maia-Rdo, C.; Tesch, R.; Fraga, C.A. Acylhydrazone derivatives: A patent review. Expert Opin. Ther. Pat., 2014, 24, 1161-1170.
Abdel-Aziz, H.A.; Eldehna, W.M.; Fares, M.; Elsaman, T.; Abdel-Aziz, M.M.; Soliman, D.H. Synthesis, in vitro and in silico studies of some novel 5-nitrofuran-2-yl hydrazones as antimicrobial and antitubercular agents. Biol. Pharm. Bull., 2015, 38, 1617-1630.
Zhang, Y.; Kolesar, J.M. Eltrombopag: An oral thrombopoietin receptor agonist for the treatment of idiopathic thrombocytopenic purpura. Clin. Ther., 2011, 33, 1560-1576.
Krause, T.; Gerbershagen, M.U.; Fiege, M.; Weisshorn, R.; Wappler, F. Dantrolene-a review of its pharmacology, therapeutic use and new developments. Anaesthesia, 2004, 59, 364-373.
Pierrakos, C.; Velissaris, D.; Franchi, F.; Muzzi, L.; Karanikolas, M.; Scolletta, S. Levosimendan in critical illness: A literature review. J. Clin. Med. Res., 2014, 6, 75-85.
Tian, B.; He, M.; Tang, S.; Hewlett, I.; Tan, Z.; Li, J.; Jin, Y.; Yang, M. Synthesis and antiviral activities of novel acylhydrazone derivatives targeting HIV-1 capsid protein. Bioorg. Med. Chem. Lett., 2009, 19, 2162-2167.
Jin, Y.; Tan, Z.; He, M.; Tian, B.; Tang, S.; Hewlett, I.; Yang, M. SAR and molecular mechanism study of novel acylhydrazone compounds targeting HIV-1 CA. Bioorg. Med. Chem., 2010, 18, 2135-2140.
Tian, B.; He, M.; Tan, Z.; Tang, S.; Hewlett, I.; Chen, S.; Jin, Y.; Yang, M. Synthesis and antiviral evaluation of new N-acylhydrazones containing glycine residue. Chem. Biol. Drug Des., 2011, 77, 189-198.
Pinheiro, A.C.; Kaiser, C.R.; Nogueira, T.C.; Carvalho, S.A.; da Silva, E.F.; Feitosa Lde, O.; Henriques, Md.; Candéa, A.L.; Lourenço, M.C.; de Souza, M.V. Synthesis and antitubercular activity of new L-serinyl hydrazone derivatives. Med. Chem., 2011, 7, 611-623.
Da Costa, C.F.; Pinheiro, A.C.; De Almeida, M.V.; Lourenço, M.C.; De Souza, M.V. Synthesis and antitubercular activity of novel amino acid derivatives. Chem. Biol. Drug Des., 2012, 79, 216-222.
Tatar, E.; Küçükgüzel, I.; Daelemans, D.; Talele, T.T.; Kaushik-Basu, N.; De Clercq, E.; Pannecouque, C. Some hydrazones of 2-aroylamino-3-methylbutanohydrazide: Synthesis, molecular modeling studies, and identification as stereoselective inhibitors of HIV-1. Arch. Pharm. (Weinheim), 2013, 346, 140-153.
Lacerda, R.B.; Sales, N.M.; da Silva, L.L.; Tesch, R.; Miranda, A.L.; Barreiro, E.J.; Fernandes, P.D.; Fraga, C.A. Novel potent imidazo[1,2-a]pyridine-N-Glycinyl-hydrazone inhibitors of TNF-α production: In vitro and in vivo studies. PLoS One, 2014, 9e91660
Tatar, E.; Şenkardeş, S.; Sellitepe, H.E.; Küçükgüzel, Ş.G.; Alpay Karaoğlu, Ş.; Bozdeveci, A.; De Clercq, E.; Pannecouque, C.; Ben Hadda, T.; Küçükgüzel, I. Synthesis and prediction of molecular properties and antimicrobial activity of some acylhydrazones derived from N-arylsulfonyl methionine. Turk. J. Chem., 2016, 40, 510-534.
Kulabaş, N.; Tatar, E.; Bingöl Özakpınar, Ö.; Özsavcı, D.
Pannecouque, C.; De Clercq, E.; Küçükgüzel, I. Synthesis and antiproliferative evaluation of novel 2-(4H-1,2,4-triazole-3-yl-thioacetamide derivatives as inducers of apoptosis in cancer cells. Eur. J. Med. Chem., 2016, 121, 58-70.
Kulabaş, N.; Bingöl Özakpınar, Ö.; Özsavcı, D.; Leyssen, P.; Neyts, J.; Küçükgüzel, I. Synthesis, characterization and biological evaluation of thioureas, acylthioureas and 4-thiazolidinones as anticancer and antiviral agents. Marmara Pharm. J., 2017, 21, 371-384.
Karrer, P.; van der Sluys-Veer, F.C. Zur konfiguration des natürlichen valins. Helv. Chim. Acta, 1932, 15, 746-750.
Constable, D.J.C.; Curzon, A.D.; Cunningham, V.L. Metrics to ‘green’ chemistry-which are the best? Green Chem., 2002, 4, 521-527.
Tatar, E.; Küçükgüzel, I.; De Clercq, E.; Şahin, F.; Güllüce, M. Synthesis, characterization and screening of antimicrobial, antituberculosis, antiviral and anticancer activity of novel 1,3-thiazolidine-4-ones derived from 1-[2-(benzoylamino)-4-(methylthio)butyryl]-4-alkyl/arylalkyl thiosemicarbazides. ARKIVOC, 2008, 14, 191-210.
Küçükgüzel, Ş.G.; Koç, D.; Çıkla-Süzgün, P.; Özsavcı, D.; Bingöl-Özakpınar, Ö.; Mega-Tiber, P.; Orun, O.; Erzincan, P.; Sağ-Erdem, S.; Şahin, F. Synthesis of tolmetin hydrazide-hydrazones and discovery of a potent apoptosis inducer in colon cancer cells. Arch. Pharm. (Weinheim), 2015, 348, 730-742.
Çıkla, P.; Özsavcı, D.; Bingöl-Özakpınar, Ö.; Şener, A.; Çevik, Ö.; Özbaş-Turan, S.; Akbuğa, J.; Şahin, F.; Küçükgüzel, Ş.G. Synthesis, cytotoxicity, and pro-apoptosis activity of etodolac hydrazide derivatives as anticancer agents. Arch. Pharm. (Weinheim), 2013, 346, 367-379.
Lopes, A.B.; Miguez, E.; Kümmerle, A.E.; Rumjanek, V.M.; Fraga, C.A.; Barreiro, E.J. Characterization of amide bond conformers for a novel heterocyclic template of N-acylhydrazone derivatives. Molecules, 2013, 18, 11683-11704.
Easmon, J.; Pürstinger, G.; Thies, K.S.; Heinisch, G.; Hofmann, J. Synthesis, structure-activity relationships, and antitumor studies of 2-benzoxazolyl hydrazones derived from alpha-(N)-acyl heteroaromatics. J. Med. Chem., 2006, 49, 6343-6350.
Wüthrich, K. NMR of Proteins And Nucleic Acids; John Wiley & Sons: New York, USA, 1986.
Pardi, A.; Billeter, M.; Wüthrich, K. Calibration of the angular dependence of the amide proton-C alpha proton coupling constants, 3JHN alpha, in a globular protein. Use of 3JHN alpha for identification of helical secondary structure. J. Mol. Biol., 1984, 180, 741-751.
Saggioro, D.; Panozzo, M.; Chieco-Bianchi, L. Human T-lymphotropic virus type I transcriptional regulation by methylation. Cancer Res., 1990, 50, 4968-4973.
Chow, W.A.; Jiang, C.; Guan, M. Anti-HIV drugs for cancer therapeutics: Back to the future? Lancet Oncol., 2009, 10, 61-71.
Timeus, F.; Crescenzio, N.; Ricotti, E.; Doria, A.; Bertin, D.; Saglio, G.; Tovo, P.A. The effects of saquinavir on imatinib-resistant chronic myelogenous leukemia cell lines. Haematologica, 2006, 91, 711-712.
Tintori, C.; Laurenzana, I.; La Rocca, F.; Falchi, F.; Carraro, F.; Ruiz, A.; Esté, J.A.; Kissova, M.; Crespan, E.; Maga, G.; Biava, M.; Brullo, C.; Schenone, S.; Botta, M. Identification of Hck inhibitors as hits for the development of antileukemia and anti-HIV agents. ChemMedChem, 2013, 8, 1353-1360.
Musumeci, F.; Schenone, S.; Brullo, C.; Desogus, A.; Botta, L.; Tintori, C. Hck inhibitors as potential therapeutic agents in cancer and HIV infection. Curr. Med. Chem., 2015, 22, 1540-1564.
Bermejo, M.; López-Huertas, M.R.; García-Pérez, J.; Climent, N.; Descours, B.; Ambrosioni, J.; Mateos, E.; Rodríguez-Mora, S.; Rus-Bercial, L.; Benkirane, M.; Miró, J.M.; Plana, M.; Alcamí, J.; Coiras, M. Dasatinib inhibits HIV-1 replication through the interference of SAMHD1phosphorylation in CD4+ T cells. Biochem. Pharmacol., 2016, 106, 30-45.
Yang, W.; Sun, Z.; Hua, C.; Wang, Q.; Xu, W.; Deng, Q.; Pan, Y.; Lu, L.; Jiang, S. Chidamide, a histone deacetylase inhibitor-based anticancer drug, effectively reactivates latent HIV-1 provirus. Microbes Infect., 2018, 20, 626-634.

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Article Details

Year: 2019
Page: [974 - 983]
Pages: 10
DOI: 10.2174/1570180815666180810120609
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