Generic placeholder image

Current Drug Delivery

Author(s): Esmeralda Sánchez-Pavón, Aracely López-Monteon, Delia Hernández-Romero, María de la Soledad Lagunes-Castro, Dxinegueela Yolanda Zanatta-García and Angel Ramos-Ligonio*

DOI: 10.2174/1567201817666200214110442

DownloadDownload PDF Flyer Cite As
Design and Synthesis of IMR-23, an Oxime Derived from Nitroimidazole as an Immunomodulatory Molecule

Page: [324 - 332] Pages: 9

  • * (Excluding Mailing and Handling)

Abstract

Background: Adjuvants have been obtained empirically by trial and error experiments and today, there is a tendency to the rational design of adjuvants candidates, which will increasingly achieve effective and safe products. The aim of this work was to design and evaluate the compound IMR-23 derived from nitroimidazole as an immunomodulatory molecule.

Materials and Methods: The IMR-23 molecule was obtained by a condensation reaction, cytotoxicity was tested by the sulforhodamine B assay. Adjuvanticity was evaluated in vivo and in vitro in J774A.1 cells and in the mouse model, respectively.

Results: IMR-23 that did not show cytotoxicity on HeLa, Vero cells and macrophages J774A.1, was able to induce the production of molecules involved in the inflammatory process, such as cytokines and chemokines determined by ELISA, to induce the production of antibodies and to generate antigenspecific cells to ovalbumin and against the antigen GST-L1b.

Conclusion: These results open the possibility of further studies to obtain a proper balance of immunogenicity- toxicity in the use of IMR-23 as an adjuvant molecule.

Keywords: Oxime, nitroimidazole, adjuvant, inflammation, immune response, antibody.

Graphical Abstract

[1]
Edelman, R.; Hardegree, M.C.; Chedid, L. Summary of an international symposium on potentiation of the immune response to vaccines. J. Infect. Dis., 1980, 141(1), 103-112.
[http://dx.doi.org/10.1093/infdis/141.1.103] [PMID: 6767789]
[2]
Pérez, O.; Batista-Duharte, A.; González, E.; Zayas, C.; Balboa, J.; Cuello, M.; Cabrera, O.; Lastre, M.; Schijns, V.E. Human prophylactic vaccine adjuvants and their determinant role in new vaccine formulations. Braz. J. Med. Biol. Res., 2012, 45(8), 681-692.
[http://dx.doi.org/10.1590/S0100-879X2012007500067] [PMID: 22527130]
[3]
Heegaard, P.M.; Dedieu, L.; Johnson, N. Adjuvants and delivery systems in veterinary vaccinology: current state and future developments. Arch. Virol., 2011, 156(2), 183-202.
[http://dx.doi.org/10.1007/s00705-010-0863-1]
[4]
Aucouturier, J; Ascarateil, S; Dupuis, L The use of oil adjuvants in therapeutic vaccines. Vaccine, 2006, (6), S2/44-S2/45.
[http://dx.doi.org/10.1016/j.vaccine.2005.01.116]
[5]
Billiau, A.; Matthys, P. Modes of action of Freund’s adjuvants in experimental models of autoimmune diseases. J. Leukoc. Biol., 2001, 70(6), 849-860.
[PMID: 11739546]
[6]
Toomer, O.T.; Ferguson, M.; Pereira, M. Maternal and postnatal dietary probiotic supplementation enhances splenic regulatory T helper cell population and reduces ovalbumin allergen-induced hypersensitivity responses in mice. Immunobiology, 2014, 219(5), 367-376.
[http://dx.doi.org/10.1016/j.imbio.2014.01.003]
[7]
Schijns, V.E. Immunological concepts of vaccine adjuvant activity. Curr. Opin. Immunol., 2000, 12(4), 456-463.
[http://dx.doi.org/10.1016/S0952-7915(00)00120-5] [PMID: 10899018]
[8]
O’Hagan, D.T.; Valiante, N.M. Recent advances in the discovery and delivery of vaccine adjuvants., 2003.
[http://dx.doi.org/10.1038/nrd1176]
[9]
Pérez, O.; Lastre, M.; Cabrera, O.; del Campo, J.; Bracho, G.; Cuello, M.; Balboa, J.; Acevedo, R.; Zayas, C.; Gil, D.; Mora, N.; González, D.; Pérez, R.; González, E.; Barberá, R.; Fajardo, E.M.; Sierra, G.; Solís, R.L.; Campa, C. New vaccines require potent adjuvants like AFPL1 and AFCo1. Scand. J. Immunol., 2007, 66(2-3), 271-277.
[http://dx.doi.org/10.1111/j.1365-3083.2007.01981.x] [PMID: 17635804]
[10]
Celik, A.; Aras Ateş, N. The frequency of sister chromatid exchanges in cultured human peripheral blood lymphocyte treated with metronidazole in vitro. Drug Chem. Toxicol., 2006, 29(1), 85-94.
[11]
Boyer, J.H. Nitroazoles: The C- Nitro Derivates of Five Membered N- and N, O- Heterocycles (Organic Nitro Chemistry); VCH Publishers, Inc.: Deerfield Beach, FL, 1986.
[12]
Adams, G.E. Failla Memorial Lecture. Redox, radiation, and reductive bioactivation. Radiat. Res., 1992, 132(2), 129-139.
[http://dx.doi.org/10.2307/3578516] [PMID: 1438693]
[13]
Kapoor, V.K.; Chadha, R.; Venisetty, P.K.; Prasanth, S. Medicinal significance of nitroimidazoles: Some recent advances. J. Sci. Ind. Res. (India), 2003, 62, 659-665.
[14]
Günay, N.S.; Capan, G.; Ulusoy, N.; Ergenç, N.; Otük, G.; Kaya, D. 5-Nitroimidazole derivatives as possible antibacterial and antifungal agents. Farmaco, 1999, 54(11-12), 826-831.
[http://dx.doi.org/10.1016/S0014-827X(99)00109-3] [PMID: 10668184]
[15]
Silvestri, R.; Artico, M.; De Martino, G.; Ragno, R.; Massa, S.; Loddo, R.; Murgioni, C.; Loi, A.G.; La Colla, P.; Pani, A. Synthesis, biological evaluation, and binding mode of novel 1-[2-(diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles targeted at the HIV-1 reverse transcriptase. J. Med. Chem., 2002, 45(8), 1567-1576.
[http://dx.doi.org/10.1021/jm010904a] [PMID: 11931611]
[16]
Silvestri, R.; Artico, M.; Massa, S.; Marceddu, T.; De Montis, F.; La Colla, P. 1-[2-(Diphenylmethoxy)ethyl]-2-methyl-5-nitroimidazole: a potent lead for the design of novel NNRTIs. Bioorg. Med. Chem. Lett., 2000, 10(3), 253-256.
[http://dx.doi.org/10.1016/S0960-894X(99)00664-2] [PMID: 10698447]
[17]
Hodgkiss, R.J. Use of 2-nitroimidazoles as bioreductive markers for tumour hypoxia. Anticancer Drug Des., 1998, 13(6), 687-702.
[PMID: 9755725]
[18]
Kasai, S.; Nagasawa, H.; Yamashita, M.; Masui, M.; Kuwasaka, H.; Oshodani, T.; Uto, Y.; Inomata, T.; Oka, S.; Inayama, S.; Hori, H. New antimetastatic hypoxic cell radiosensitizers: design, synthesis, and biological activities of 2-nitroimidazole-acetamide, TX-1877, and its analogues. Bioorg. Med. Chem., 2001, 9(2), 453-464.
[http://dx.doi.org/10.1016/S0968-0896(00)00265-0] [PMID: 11249137]
[19]
Petray, P.B.; Morilla, M.J.; Corral, R.S.; Romero, E.L. In vitro activity of Etanidazole against the protozoan parasite Trypanosoma cruzi. Mem. Inst. Oswaldo Cruz, 2004, 99(2), 233-235.
[http://dx.doi.org/10.1590/S0074-02762004000200021] [PMID: 15250482]
[20]
Elizondo, G.; Gonsebatt, M.E.; Salazar, A.M.; Lares, I.; Santiago, P.; Herrera, J.; Hong, E.; Ostrosky-Wegman, P. Genotoxic effects of metronidazole. Mutat. Res., 1996, 370(2), 75-80.
[http://dx.doi.org/10.1016/0165-1218(96)00022-5] [PMID: 8879264]
[21]
Mikhaleva, A.; Zaitsev, A.B.; Trofimov, B.A. 6) Oximes as reagents. Russ. Chem. Rev., 2006, 75, 797-823.
[http://dx.doi.org/10.1070/RC2006v075n09ABEH003594]
[22]
Sikharulidze, M.I.; Nadaraia, N.S.; Kakhabrishvili, M.L.; Barbakadze, N.N.; Mulkidzhanyan, K.G. Synthesis and biological activity of several steroidal oximes., 2010.
[http://dx.doi.org/10.1007/s10600-010-9657-7]
[23]
Abele, E.; Abele, R.; Golomba, L. Oximes of six-membered heterocyclic compounds with two and three heteroatoms: II. reactions and biological activity. Chem. Heterocycl. Compd., 2010, 46, 1123-1153.
[http://dx.doi.org/10.1007/s10593-010-0602-2]
[24]
Abele, E.; Abele, R.; Rubina, K.; Lukevics, E. Quinoline Oximes: Synthesis, reactions, and biological activity. Chem. Heterocycl. Compd., 2015, 41, 163-190.
[http://dx.doi.org/10.1007/s10593-005-0119-2]
[25]
Haabeth, O.A.; Bogen, B.; Corthay, A. A model for cancer-suppressive inflammation. OncoImmunology, 2012, 1(7), 1146-1155.
[http://dx.doi.org/10.4161/onci.21542] [PMID: 23170261]
[26]
Kruisbeek, A.M.; Shevach, E.M. Proliferative assays for T cell Function; In Current Protocols in Immunology In: Current Protocols in Immunology; Coligan, J.E.; Kruisbeek, A.M.; Margulies, D.H., Eds.. Greene Publishing and Wiley-Interscience: New York, 1991, pp. 3.12.1-3.12.14.
[27]
Ramos-Ligonio, A.; Ramírez-Sánchez, M.E.; González-Hernández, J.C.; Rosales-Encina, J.L.; López-Monteon, A. [Prevalence of antibodies against Trypanosoma cruzi in blood bank donors from the IMSS General Hospital in Orizaba, Veracruz, Mexico]. Salud Publica Mex., 2006, 48(1), 13-21.
[PMID: 16555530]
[28]
Hauguel, T.M.; Hackett, C.J. Rationally-designed vaccine adjuvants: separating efficacy from toxicity. Front. Biosci., 2008, 13, 2806-2813.
[http://dx.doi.org/10.2741/2887] [PMID: 17981755]
[29]
Batista-Duharte, A.; Lastre, M.; Pérez, O. Adyuvantes inmunológicos. Determinantes en el balance eficacia-toxicidad de las vacunas contemporáneas. Enferm. Infecc. Microbiol. Clin., 2014, 32(2), 106-114.
[http://dx.doi.org/10.1016/j.eimc.2012.11.012] [PMID: 23332294]
[30]
Menéndez, D.; Rojas, E.; Herrera, L.A.; López, M.C.; Sordo, M.; Elizondo, G.; Ostrosky-Wegman, P. DNA breakage due to metronidazole treatment. Mutat. Res., 2001, 478(1-2), 153-158.
[http://dx.doi.org/10.1016/S0027-5107(01)00136-1] [PMID: 11406179]
[31]
López Nigro, M.M.; Gadano, A.B.; Carballo, M.A. Evaluation of genetic damage induced by a nitroimidazole derivative in human lymphocytes: Tinidazole (TNZ). Toxicol. In Vitro, 2001, 15(3), 209-213.
[http://dx.doi.org/10.1016/S0887-2333(01)00010-8] [PMID: 11377093]
[32]
D’Auria, M.; D’Onofrio, F.; Suwinski, J.; Swierczek, K. Synthesis and photochemical behaviour of 4-nitroimidazoles. Tetrahedron, 1993, 49, 3899-3906.
[http://dx.doi.org/10.1016/S0040-4020(01)90240-6]
[33]
Suwinski, J.; Szczepankiewicz, W.; Widel, M. Nitroimidazoles, XIV: Synthesis of 4-nitroimidazoles with 1-substituents containing acid, ester or phenol functions, and radiosensitizing efficiency of some of these compounds. Arch. Pharm. (Weinheim), 1992, 325(6), 317-324.
[http://dx.doi.org/10.1002/ardp.19923250602] [PMID: 1444756]
[34]
Luo, Y.; Song, R.; Li, Y. Design, synthesis, and biological evaluation of chalcone oxime derivatives as potential immunosuppressive agents. Bioorg. Med. Chem. Lett., 2012, 22, 3039-3043.
[http://dx.doi.org/10.1016/j.bmcl.2012.03.080]
[35]
Batista-Duharte, A.; Lindblad, E.B.; Oviedo-Orta, E. Progress in understanding adjuvant immunotoxicity mechanisms. Toxicol. Lett., 2011, 203(2), 97-105.
[http://dx.doi.org/10.1016/j.toxlet.2011.03.001] [PMID: 21392560]
[36]
Suffredini, A.F.; Fantuzzi, G.; Badolato, R.; Oppenheim, J.J.; O’Grady, N.P. New insights into the biology of the acute phase response. J. Clin. Immunol., 1999, 19(4), 203-214.
[http://dx.doi.org/10.1023/A:1020563913045] [PMID: 10471974]
[37]
Luster, A. Mechanisms of Disease:. Chemokines--chemotactic cytokines that mediate inflammation. N. Engl. J. Med., 1998, 338, 436-445.
[http://dx.doi.org/10.1056/NEJM199802123380706]
[38]
Warren, H.; Vogel, F.; Chedid, L.A. Current status of immunological adyuvants. Annu. Rev. Immunol., 1986, 4, 369-388.
[39]
Sun, C.Y.; Bai, J.; Hu, T.Y. CD4+ T cell responses in Balb/c mice with food allergy induced by trinitrobenzene sulfonic acid and ovalbumin. Mol. Med. Rep., 2016, 13, 5349-5357.
[http://dx.doi.org/10.3892/mmr.2016.5153]
[40]
Awate, S.; Babiuk, L.A.; Mutwiri, G. Mechanisms of action of adjuvants. Front. Immunol., 2013, 4, 114.
[http://dx.doi.org/10.3389/fimmu.2013.00114] [PMID: 23720661]
[41]
Apostólico, J de S.; Lunardelli, V.A.; Coirada, F.C.; Boscardin, S.B.; Rosa, D.S. Adjuvants: Classification, modus operandi, and licensing. J. Immunol. Res., 2016, 20161459394
[http://dx.doi.org/10.1155/2016/1459394] [PMID: 27274998]
[42]
O’Hagan, D.T.; Valiante, N.M. Recent advances in the discovery and delivery of vaccine adjuvants. Nat. Rev. Drug Discov., 2003, 2(9), 727-735.
[http://dx.doi.org/10.1038/nrd1176] [PMID: 12951579]