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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Research Article

Chalcogenium-AZT Derivatives: A Plausible Strategy To Tackle The RT-Inhibitors-Related Oxidative Stress While Maintaining Their Anti- HIV Properties

Author(s): Joelma M. Sarturi, Luciano Dornelles, Natalia V. Segatto, Tiago Collares, Fabiana K. Seixas, Bruna Candia Piccoli, Fernanda D’Avila da Silva, Folorunsho Bright Omage, João Batista Teixeira da Rocha, Renata A. Balaguez, Diego Alves, Eder J. Lenardão, Eric F. Lopes, Anna Kula-Pacurar*, Krzysztof Pyrc, Luca Sancineto and Oscar E.D. Rodrigues*

Volume 30, Issue 21, 2023

Published on: 07 November, 2022

Page: [2449 - 2462] Pages: 14

DOI: 10.2174/0929867329666220906095438

Price: $65

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Abstract

Background: This study presents the synthesis and multi-target behavior of the new 5'-hydroxy-3-(chalcogenyl-triazoyl)-thymidine and the biological evaluation of these compounds as antioxidant and anti-HIV agents.

Objective: Antiretroviral therapy induces oxidative stress. Based on this, this manuscript's main objective is to prepare compounds that combine anti-HIV and antioxidant activities.

Methods: The compounds were prepared from commercially available AZT through a copper-catalyzed Huisgen 1,3-dipolar cycloaddition exploiting the AZT azide group and chalcogenyl alkynes.

Results: The chalcogenium-AZT derivatives were obtained in good yields via click chemistry. The compounds evaluated showed antioxidant and anti-HIV activity. Additionally, in vivo toxicity of this class of compounds was also evaluated. The representative nucleoside did not change the survival, behavior, biochemical hepatic, or renal markers compared to the control mice.

Conclusion: Data suggest the feasibility of modifying the AZT nucleus with simple organohalogen fragments, exploring the reactivity of the azide group via 1,3-dipolar Huisgen cycloaddition reaction. The design of these new compounds showed the initially desired biological activities.

Keywords: Chalcogenium-AZT, anti-HIV, low toxicity, antioxidant, click chemistry, in silico evaluation.

[1]
Byanyima, W. Global AIDS update; UNAIDS, Programme on HIV/AIDS, Joint United Nations, 2021.
[2]
WHO. Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach., 2021. Available from: https://www.who.int/publications/i/item/9789240031593
[3]
Pierson, T.; McArthur, J.; Siliciano, R.F. Reservoirs for HIV-1: Mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy. Annu. Rev. Immunol., 2000, 18, 665-708.
[4]
Brojan, L.E.F.; Marca, L.M.; Dias, F.A.; Rattmann, Y.D. Antiretroviral drug use by individuals living with HIV/AIDS and compliance with the Clinical Protocol and Therapy Guidelines. Einstein (Sao Paulo), 2020, 18, 1-7.
[5]
Vidal, F.; Gutiérrez, F.; Gutiérrez, M.; Olona, M.; Sánchez, V.; Mateo, G.; Peraire, J.; Viladés, C.; Veloso, S.; López-Dupla, M. Pharmacogenetics of adverse effects due to antiretroviral drugs. AIDS Rev., 2010, 12(1), 15-30.
[6]
Mandas, A.; Iorio, E.L.; Congiu, M.G.; Balestrieri, C.; Mereu, A.; Cau, D.; Dessì, S.; Curreli, N. Oxidative imbalance in HIV-1 infected patients treated with antiretroviral therapy. J. Biomed. Biotechnol., 2009, 2009, 1-7.
[7]
Sharma, B. Oxidative stress in HIV patients receiving antiretroviral therapy. Curr. HIV Res., 2014, 12, 13-21.
[8]
Ngondi, J.L.; Oben, J.; Forkah, D.M.; Etame, L.H.; Mbanya, D. The effect of different combination therapies on oxidative stress markers in HIV infected patients in cameroon. AIDS Res. Ther., 2006, 3, 19.
[9]
Shahar, E.; Pollack, S.; Kedem, E.; Hassoun, G.; Nagler, R. Effect of HAART on salivary composition and oxidative profile in HIV infected patients. Curr. HIV Res., 2008, 6, 447-451.
[10]
Sundaram, M.; Saghayam, S.; Priya, B.; Venkatesh, K.K.; Balakrishnan, P.; Shankar, E.M.; Murugavel, K.G.; Solomon, S.; Kumarasamy, N. Changes in antioxidant profile among HIV-infected individuals on generic highly active antiretroviral therapy in southern India. Int. J. Infect. Dis., 2008, 12, e61-e66.
[11]
García de la Asunción, J.; del Olmo, L.; Gómez-Cambronero, L.G.; Sastre, J.; Pallardó, F.V.; Viña, J. AZT induces oxidative damage to cardiac mitochondria: Protective effect of vitamins C and E. Life Sci., 2004, 76, 47-56.
[12]
Halliwell, B. Free radicals, antioxidants, and human disease: Curiosity, cause, or consequence? Lancet, 1994, 344, 721-724.
[13]
Schreck, R.; Rieber, P.; Baeuerle, P.A. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J., 1991, 10, 2247-2258.
[14]
Kruman, I.I.; Nath, A.; Mattson, M.P. HIV-1 protein tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress. Exp. Neurol., 1998, 154, 276-288.
[15]
Martin, J.A. Hepatic γ-cystathionase deficiency in patients with AIDS. JAMA, 2001, 285, 1444-1445.
[16]
Wang, S.; Ukhtary, M.S.; Saito, R. Strain effect on circularly polarized electroluminescence in transition metal dichalcogenides. Phys. Rev. Res., 2020, 2, 033340.
[17]
Wang, S.; Ren, S.; Tian, H.; Yu, J.; Sun, M. MoS2/ZnO van der Waals heterostructure as a high-efficiency water splitting photocatalyst: A first-principles study. Phys. Chem. Chem. Phys., 2018, 20, 13394-13399.
[18]
Wang, S.; Tian, H.; Ren, C. Electronic and optical properties of heterostructures based on transition metal dichalcogenides and graphene-like zinc oxide. Sci. Rep., 2018, 8, 12009.
[19]
Pacuła, A.J.; Mangiavacchi, F.; Sancineto, L.; Lenardão, J.; Ścianowski, J.; Santi, C. An update on “Selenium containing compounds from poison to drug candidates: A review on the GPx-like activity”. Curr. Chem. Biol., 2016, 9, 97-112.
[20]
Soares, L.C.; Alberto, E.E.; Schwab, R.S.; Taube, P.S.; Nascimento, V.; Rodrigues, O.E.D.; Braga, A.L. Ephedrine-based diselenide: A promiscuous catalyst suitable to mimic the enzyme glutathione peroxidase (GPx) and to promote enantioselective C–C coupling reactions. Org. Biomol. Chem., 2012, 10, 6595-6599.
[21]
Santi, C.; Scimmi, C.; Sancineto, L. Ebselen and analogues: Pharmacological properties and synthetic strategies for their preparation. Molecules, 2021, 26, 4230-4255.
[22]
Baba, M. Cellular factors as alternative targets for inhibition of HIV-1. Antiviral Res., 1997, 33, 141-152.
[23]
Zhan, P.; Liu, X.; Fang, Z.; Pannecouque, C.; De Clercq, E. 1,2,3-Selenadiazole thioacetanilides: Synthesis and anti-HIV activity evaluation. Bioorg. Med. Chem., 2009, 17, 6374-6379.
[24]
Sancineto, L.; Mariotti, A.; Bagnoli, L.; Marini, F.; Desantis, J.; Iraci, N.; Santi, C.; Pannecouque, C.; Tabarrini, O. Design and synthesis of diselenobisbenzamides (DISeBAs) as nucleocapsid protein 7 (NCp7) inhibitors with anti-HIV activity. J. Med. Chem., 2015, 58, 9601-9614.
[25]
Sancineto, L.; Iraci, N.; Tabarrini, O.; Santi, C. NCp7: Targeting a multitasking protein for next-generation anti-HIV drug development part 1: Covalent inhibitors. Drug Discov. Today, 2018, 23, 260-271.
[26]
Iraci, N.; Tabarrini, O.; Santi, C.; Sancineto, L. NCp7: Targeting a multitask protein for next-generation anti-HIV drug development part 2. Noncovalent inhibitors and nucleic acid binders. Drug Discov. Today, 2018, 23, 687-695.
[27]
Sancineto, L.; Iraci, N.; Barreca, M.L.; Massari, S.; Manfroni, G.; Corazza, G.; Cecchetti, V.; Marcello, A.; Daelemans, D.; Pannecouque, C. Exploiting the anti-HIV 6-desfluoroquinolones to design multiple ligands. Bioorg. Med. Chem., 2014, 22, 4658-4666.
[28]
Sancineto, L.; Iraci, N.; Massari, S.; Attanasio, V.; Corazza, G.; Barreca, M.L.; Sabatini, S.; Manfroni, G.; Avanzi, N.R.; Cecchetti, V. Computer-aided design, synthesis and validation of 2-phenylquinazolinone fragments as CDK9 inhibitors with anti-HIV-1 tat-mediated transcription activity. ChemMedChem, 2013, 8, 1941-1953.
[29]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. Autodock4 and AutoDockTools4: Automated docking with selective receptor flexiblity. J. Comput. Chem., 2009, 16, 2785-2791.
[30]
Stewart, J.J.P. MOPAC: A semiempirical molecular orbital program. J. Comput. Aided Mol. Des., 1990, 4, 1-103.
[31]
DeLano, W.L. The PyMOL Molecular Graphics System; Version 2.3; Schrödinger LLC, 2020.
[32]
Salentin, S.; Schreiber, S.; Haupt, V.J.; Adasme, M.F.; Schroeder, M. PLIP: Fully automated protein-ligand interaction profiler. Nucleic Acids Res., 2015, 43, W443-W447.
[33]
Mitsuya, H.; Weinhold, K.J.; Furman, P.A.; St Clair, M.H.; Lehrman, S.N.; Gallo, R.C.; Bolognesi, D.; Barry, D.W.; Broder, S. 3′-Azido-3′-deoxythymidine (BW A509U): An antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc. Natl. Acad. Sci. USA, 1985, 82, 7096-7100.
[34]
Battivelli, E.; Dahabieh, M.S.; Abdel-Mohsen, M.; Svensson, J.P.; Da Silva, T.J.; Cohn, L.B.; Gramatica, A.; Deeks, S.; Greene, W.C.; Pillai, S.K.; Verdin, E. Distinct chromatin functional states correlate with HIV latency reactivation in infected primary CD4+ T cells. eLife, 2018, 7, e34655.
[35]
Quoos, N.; Dornelles, L.; Buss, J.; Begnini, K.R.; Collares, T.; Seixas, F.K.; Garcia, F.D.; Rodrigues, O.E.D. Synthesis and antiproliferative evaluation of 5′-Arylchalcogenyl-3-(phenylselanyl-triazoyl)-thymidine. ChemistrySelect, 2020, 5, 324-329.
[36]
Lopes, E.F.; Dalberto, B.T.; Perin, G.; Alves, D.; Barcellos, T.; Lenardão, E.J. Synthesis of terminal Ethynyl Aryl Selenides and Sulfides based on the Retro-Favorskii reaction of Hydroxypropargyl precursors. Chemistry, 2017, 23, 13760-13765.
[37]
Alves, D.; Goldani, B.; Lenardão, E.J.; Perin, G.; Schumacher, R.F.; Paixão, M.W. Copper catalysis and organocatalysis showing the way: Synthesis of selenium-containing highly functionalized 1,2,3-Triazoles. Chem. Rec., 2018, 18, 527-542.
[38]
Gao, P.; Sun, L.; Zhou, J.; Li, X.; Zhan, P.; Liu, X. Discovery of novel anti-HIV agents via Cu(I)-catalyzed azidealkyne cycloaddition (CuAAC) click chemistry-based approach. Expert Opin. Drug Discov., 2016, 11, 857-871.
[39]
Breugst, M.; Reissig, H.U. The Huisgen Reaction: Milestones of, the 1,3-Dipolar Cycloaddition. Angew. Chem. Int. Ed. Engl., 2020, 59, 12293-12307.
[40]
Wang, X.; Huang, B.; Liu, X.; Zhan, P. Discovery of bioactive molecules from CuAAC click-chemistry-based combinatorial libraries. Drug Discov. Today, 2016, 21, 118-132.
[41]
Ohkawa, H.; Ohishi, N.; Yagi, K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem., 1979, 95, 351-358.
[42]
Barbosa, N.V.; Nogueira, C.W.; Nogara, P.A.; de Bem, A.F.; Aschner, M.; Rocha, J.B.T. Organoselenium compounds as mimics of selenoproteins and thiol modifier agents. Metallomics, 2017, 9, 1703-1734.
[43]
Nogueira, C.W.; Zeni, G.; Rocha, J.B.T. Organoselenium and organotellurium compounds: Toxicology and pharmacology. Chem. Rev., 2004, 104, 6255-6286.
[44]
Esposito, F.; Corona, A.; Tramontano, E. HIV-1 reverse transcriptase still remains a new drug target: Structure, function, classical inhibitors, and new inhibitors with innovative mechanisms of actions. Mol. Biol. Int., 2012, 2012, 1-23.
[45]
Hang, J.; Rajendran, S.; Yang, Y.; Li, Y.; In, P.W.; Overton, H.; Parkes, K.E.; Cammack, N.; Martin, J.A.; Klumpp, K. Activity of the isolated HIV RNase H domain and specific inhibition by N-hydroxyimides. Biochem. Biophys. Res. Commun., 2004, 317(2), 321-329.
[46]
Kirschberg, T.A.; Balakrishnan, M.; Squires, N.H.; Barnes, T.; Brendza, K.M.; Chen, X.; Eisenberg, E.J.; Jin, W.; Kutty, N.; Leavitt, S. RNase H active site inhibitors of human immunodeficiency Virus Type 1 Reverse Transcriptase: Design, biochemical activity, and structural information. J. Med. Chem., 2009, 52, 5781-5784.
[47]
Varga, Z.V.; Ferdinandy, P.; Liaudet, L.; Pacher, P. Drug induced mitochondrial dysfunction and cardiotoxicity. Am. J. Physiol. Heart Circ. Physiol., 2015, 309(9), H1453-H1467.

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