Publicado

2021-05-17

Hydrazones derived from natural aldehydes: in vitro cytotoxic evaluation and in silico pharmacokinetic predictions

Hidrazonas derivadas de aldehídos naturales: evaluación citotóxica in vitro y determinación del perfil farmacocinético in silico

Hidrazonas derivadas de aldeídos naturais: avaliação citotóxica in vitro e determinação de perfil farmacocinético in silico

DOI:

https://doi.org/10.15446/rcciquifa.v50n1.91232

Palabras clave:

Antineoplastic drugs, cancer, molecular hybridization, phenylhydrazones (en)
Fármacos antineoplásicos, cáncer, fenilhidrazonas, hibridación molecular (es)
Medicamentos antineoplásicos, câncer, hibridação molecular, fenil hidrazonas (pt)

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Autores/as

  • Victória Laysna dos Anjos Santos Postgraduate of Health and Biological Sciences Program, Federal University of San Francisco Valley, Petrolina, Pernambuco
  • Arlan de Assis Gonsalves Postgraduate of Health and Biological Sciences Program, Federal University of San Francisco Valley, Petrolina, Pernambuco
  • Maria Franciele Souza Silva Postgraduate of Physiology and Pharmacology Program, Federal University of Ceará, Fortaleza, Ceará
  • Fátima de Cássia Evangelista de Oliveira Postgraduate of Physiology and Pharmacology Program, Federal University of Ceará, Fortaleza, Ceará
  • Marcília Pinheiro da Costa Graduate of Pharmacy, Federal University of Piauí, Teresina, Piauí
  • Claudia O. Pessoa Postgraduate of Physiology and Pharmacology Program, Federal University of Ceará, Fortaleza, Ceará
  • Cleônia Roberta Melo Araújo Postgraduate of Health and Biological Sciences Program, Federal University of San Francisco Valley, Petrolina, Pernambuco https://orcid.org/0000-0003-0422-5541

Introduction: Recent research has reported the cytotoxic potential of hydrazones against various strains of cancer cells. Aim: To evaluate the anticancer activity in vitro and the pharmacokinetic profile of six synthesized hydrazonic compounds, identified as vanillin 1-phthalazinylhydrazone (VAN-1); 2,4-dinitrophenylhydrazone vanillin (VAN-2); phenylhydrazone cinnamaldehyde (CIN-1); isonicotinoyl hydrazone cinnamaldehyde (CIN-2); cinnamaldehyde 1 phthalazinylhydrazone (CIN-3); and 2,4 dinitrophenylhydrazone cinnamaldehyde (CIN-4). Thecytotoxic activity was evaluated against four strains of cancer cells. Methodology: Thepharmacokinetic parameters of absorption, distribution, metabolism, excretion, and toxicity (ADME/T) of the hydrazones were evaluated using the PreADMET program. Results: Hydrazones derived from cinnamaldehyde (CIN-1 and CIN-2) showed high cytotoxic activity against leukemic (HL-60) and glioblastomas (SF-295) cell lines. The pharmacokinetic profile of the hydrazones showed that, in general, the hydrazones presented satisfactory characteristics of ADME/T. In addition, it was observed that CIN-2 presented the most promising in silico profile, showing high intestinal absorption, desirable distribution profile related to plasma protein binding, adequate renal excretion, and low toxicity. The ADME/T profile of the CIN-1 compound highlighted its potential as a promising antineoplastic agent with action of the CNS, more specifically against glioblastomas.

Introducción: investigaciones recientes han informado del potencial citotóxicon de las hidrazonas contra varias líneas de células cancerosas. Objetivo: evaluar la actividad anticancerígena in vitro y el perfil farmacocinético de seis compuestos hidrazónicos sintetizados, identificados como vainillina 1-ftalazinilhidrazona (VAN-1); vainillina 2,4-dinitrofenilhidrazona (VAN-2); fenilhidrazona cinamaldehído (CIN-1); cinamaldehído de isonicotinoil hidrazona (CIN-2); cinamaldehído 1-ftalazinilhidrazona (CIN-3); y 2,4-dinitrofenilhidrazona cinamaldehído (CIN-4). Se evaluó la actividad citotóxica frente a cuatro líneas celulares cancerosas. Metodología: los parámetros farmacocinéticos de absorción, distribución, metabolismo, excreción y toxicidad (ADME/T) de las hidrazonas se evaluaron mediante el programa PreADMET. Resultados: las hidrazonas derivadas del cinamaldehído (CIN-1 y CIN-2) mostraron una alta actividad citotóxica contra las líneas celulares leucémicas (HL-60) y glioblastomas (SF-295). El perfil farmacocinético de las hidrazonas mostró que, en general, las hidrazonas mostraban características satisfactorias de ADME/T. Además, se observó que CIN-2 presentó el perfil in silico más prometedor, presentando alta absorción intestinal, perfil de distribución deseable relacionado con la unión a proteínas plasmáticas, excreción renal adecuada y baja toxicidad. El perfil ADME/T d el compuesto CIN-1 destacó su p otencial como agente antineoplásico prometedor con acción sobre el SNC, más específicamente contra los glioblastomas.

Introdução: Pesquisas recentes relataram o potencial citotóxico das hidrazonas contra várias linhagens de células cancerígenas. Objetivo: Validara atividade anticâncer in vitro e o perfil farmacocinético de seis compostos hidrazônicos sintetizados, identificados como vanilina 1-ftalazinil hidrazona (VAN-1); vanilina 2,4-dinitrofenil-hidrazona (VAN 2); cinnamaldeído de fenil-hidrazona (CIN-1); cinamaldeído isonicotinoil-hidrazona (CIN-2); 1-ftalazinil-hidrazona de cinnamaldeído (CIN-3); e cinamaldeído de 2,4-dinitrofenil hidrazona (CIN-4). A atividade citotóxica foi avaliada contra quatro linhagens de células cancerígenas. Metodologia: Os parâmetros farmacocinéticos de absorção, distribuição, metabolismo, excreção e toxicidade (ADME/T) das hidrazonas foram avaliados utilizando o programa PreADMET. Resulados: As hidrazonas derivadas do cinnamaldeído (CIN-1 e CIN-2) apresentaram alta atividade citotóxica contra as linhagens celulares leucêmicas (HL-60) e de glioblastomas (SF-295). O perfil farmacocinético das hidrazonas mostrou que, em geral, as hidrazonas apresentaram características satisfatórias de ADME/T. Além disso, observou-se que a CIN-2 apresentou o perfil in silico mais promissor, exibindo alta absorção intestinal, perfil de distribuição desejável relacionado à ligação às proteínas plasmáticas, excreção renal adequada e baixa toxicidade. O perfil ADME/T do composto CIN-1 destacou seu potencial como um agente antineoplásico promissor com ação do SNC, mais especificamente contra glioblastomas.

Referencias

J.A. Somarelli, H. Gardner, V.L. Cannataro, E.F. Gunady, A.M. Boddy, N.A. Johnson, J.N. Fisk, S.G. Gaffney, J.H. Chuang, S. Li, F.D. Ciccarelli, A.R. Panchenko, K. Megquier, S. Kumar, A. Dornburg, J. De Gregori, J.P. Townsend, Molecular Biology and Evolution of Cancer: From Discovery to Action. Mol. Biol. Evol. Cancer, 37, 320–326 (2019).

A. Billington, D. Dayicioglu, P. Smith, J. Kiluk, Review of Procedures for Reconstruction of Soft Tissue Chest Wall Defects Following Advanced Breast Malignancies. Cancer Control, 26, 1-7 (2019).

L. Falzone, S. Solomone, M. Libra, Evolution of Cancer Pharmacological Treatments at the Turn of the Third Millennium. Front. Pharmacol., 9, 1-26 (2018).

L.P. Figueiredo, A.L. Ibiapino, D.N. Amaral, L.S. Ferraz, T. Rodrigues, E.J. Barreiro, L.M. Lima, F.F. Ferreira, Structural characterization and cytotoxicity studies of different forms of a combretastatin A4 analogue. J. Mol. Struct., 1147, 226-234 (2017).

R. Fanciullino, J. Ciccolini, G. Milano, Challenges, expectations and limits for nanoparticles-based therapeutics in cancer: a focus on nano-albumin-bound drugs. Crit. Rev. Oncol. Hematol., 88, 504-513 (2013).

D. Saini, M. Gupta, Hydrazones as potential anticancer agents: An update. Asian J. Pharm. Pharmacol., 4, 116-122. (2018).

L.N. Suvarapu, K.Y. Seo, S.-O. Baek, V.R. Ammireddy, Review on analytical and biological applications of hydrazones and their metal complexes. J. Chem., 9, 1288-1304 (2012).

K. Mokhnache, K. Hanane, E-K. Soltani, S. Madoui, A. Karbab, N. Charef, L. Arrar, Hydrazones: origin, reactivity and biological activity. Adv. Biores., 10, 1-9 (2019).

V. Alves, R.C. Braga, E.N. Muratov, C.H. Andrade, Quimioinformática: uma introdução. Quím. Nova, 41, 202 – 213 (2017).

M. González-Medina, J.J. Naveja, N. Sanchez-Cruz, J.L. Medina-Franco, Open chemoinformatic resources to explore the structure, properties and chemical space of molecules. RSC Adv., 7, 54153-54163 (2017).

L.L.G. Ferreira, A.D. Andricopulo, ADMET modeling approaches in drug discovery. Drug Discov. Today, 24, 1157- 1165 (2019).

D.C.M. Souza, V.C. Sousa, L.P.L. Cruz, S.M.P. Carneiro, M.M.M. Alves, F.A.A. Carvalho, M.P. Costa, C.M. Corrêa, A.A. Gonsalves, C.R.M. Araújo, Síntese, atividade antileshmania e citotóxica de hidrazonas derivadas de aldeídos naturais. Quím. Nova, 43, 50-57 (2020).

L.G.daS. Souza, M.C.S. Almeida, T.L.G. Lemos, P.R.V. Ribeiro, E.S. Brito, V.L.M. Silva, A.M.S. Silva, R. Braz-Filho, J.G.M. Costa, F.G. Rodrigues, F.S. Barreto, M.O. Moraes, Synthesis, antibacterial and cytotoxic activities of new biflorin-based hydrazones and oximes. Bioorg. Med. Chem. Lett., 26, 435-439 (2016).

I. Graça, E.J. Souza, P. Costa-Pinheiro, F.Q. Vieira, J. Torres-Ferreira, M.G. Martins, R. Henrique, C. Jerónimo, Anti-neoplastic properties of hydralazine in prostate cancer. Oncotarget, 5, 5950 (2014).

M.J. Ruiz-Magaña, R. Martínez-Aguilar, E. Lucendo, D. Campillo-Davo, K. Schulze-Osthoff, C. Ruiz-Ruiz, The antihypertensive drug hydralazine activates the intrinsic pathway of apoptosis and causes DNA damage in leukemic T cells. Oncotarget, 7, 21875 – 21886 (2016).

X.-P. Zou, B. Zhang, Y. Liu, More questions than answers about the potential anticancer agents: DNA methylation inhibitors. Chin. Med. J., 123, 1206-1209 (2010).

M. Candelaria, A. Herrera, J. Labardini, A. González-Fierro, C. Trejo-Becerril, L. Taja-Chayeb, E. Pérez-Cárdenas, E. Cruz-Hernández, D. Arias-Bofill, S. Vidal, E. Cervera, A. Dueñas-Gonzalez, Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome. Preliminary results of a phase-II trial. Ann. Hemat., 90, 379-387 (2011).

Q. Yao, J. Qi, Y. Zheng, K. Qian, L. Wei, M. Maimaitiyiming, Z. Cheng, Y. Wang, Synthesis, anticancer activity and mechanism of iron chelator derived from 2,6-diacetylpyridine bis(acylhydrazones). J. Inorg. Biochem., 193, 1–8 (2019).

M. Hout, L.Dos Santos, A. Hamai, M. Mehrpour, A promising new approach to cancer therapy: Targeting iron metabolism in cancer stem cells. Semin Cancer Biol., 53, 125-138 (2018).

V.F.S. Pape, S. Tóth, A. Furedi, K. Szebényi, A. Lovrics, P. Szabó, M. Wiese, G. Szakács, Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance. Eur. J. Med. Chem., 117, 335-354 (2016).

G.S.S. Firmino, S.C. André, Z. Hastenreiter, V.K. Campos, M.A.L. Abdel-Salam, E.M. Souza-Fagundes, J.A. Lessa, In vitro assessment of the cytotoxicity of Gallium (III) complexes with isoniazid-derived hydrazones: effects on clonogenic survival of HCT-116 cells. Inorg. Chim. Acta, 497, 119079-119086 (2019).

E.G. Figueiredo, J.W.V.F. Faria, M.J. Teixeira, Treatment of recurrent glioblastoma with intra-arterial BCNU [1, 3-bis (2-chloroethyl)-1-nitrosourea]. Arq. Neuro-Psiquiatr., 68, 778-782 (2010).

T. Reithmeier, E. Graf, T. Piroth, M. Trippel, M.O. Pinsker, G. Nikkhah, BCNU for recurrent glioblastoma multiforme: efficacy, toxicity and prognostic factors. BMC cancer, 10, 1-8 (2010).

S.-N. Zhang, X.-Z Li, X.-Y. Yang, Drug-likeness prediction of chemical constituents isolated from Chinese materia medica Ciwujia. J. Ethnopharmacol., 198, 131-138 (2017).

M.F. Dolabela, A.R.P. da Silva, L.H. Ohashi, M.L.C. Bastos, M.C.M. da Silva, V.V. Vale, Estudo in silico das atividades de triterpenos e iridoides isolados de Himatanthus articulatus (Vahl) Woodson. Revista Fitos, 12, 227-242 (2018).

R.E. Kartasasmita, A. Muhtadi, S. Ibrahim, Binding affinity of asiatic acid derivatives design against inducible nitric oxide synthase and ADMET prediction. J. Appl. Pharm. Sci., 4, 75-80 (2014).

S. Nandi, M.C. Bagchi, QSAR modeling of 4-anilinofuro [2, 3-b] quinolines: an approach to anticancer drug design. Med. Chem. Res., 23, 1672-1682 (2014).

H. Kumar, D. Malhotra, R. Sharma, E. Sausville, M. Malhotra, Synthesis, characterization and evaluation of isoniazid analogues as potent anticancer agents. Pharmacologyonline, 3, 337-343 (2011).

S.Z. Kovačević, L. Jevrić, S.O.P. Kuzmanović, E.S. Lonćar, Prediction of in silico ADME properties of 1, 2-O-isopropylidene aldohexose derivatives. Iran. J. Pharm. Res., 13, 899-907 (2014).

L. Xu-Zhao, S.-N. Zhang, X.-Y. Yang, Combination of cheminformatics and bioinformatics to explore the chemical basis of the rhizomes and aerial parts of Dioscorea nipponica Makino. J. Pharm. Pharmacol., 69, 1846-1857 (2017).

Nursamsiar, A.T. Toding, A. Awaluddin, In-silico study chalcone and pyrimidine analog derivatives as anti-inflammatory: prediction of absorption, distribution, and toxicity. Pharmacy, 13, 92-100 (2016).

D. Wang, Y. Guo, S.A. Wrighton, G.E. Cooke, W. Sadee, Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. The Pharmacogenomics Journal, 11, 274-286 (2011).

P. Wang, K. Pradhan, X. Zhong, X. Ma, Isoniazid metabolism and hepatotoxicity. Acta Pharm. Sin. B, 6, 384-392 (2016).

S.K. Paramashivam, K. Elayaperumal, B.B. Natarajan, M.D. Ramamoorthy, S. Balasubramanian, K.N. Dhiraviam, In silico pharmacokinetic and molecular docking studies of small molecules derived from Indigofera aspalathoides Vahl targeting receptor tyrosine kinases. Bioinformation, 11, 73- 84 (2015).

Y. Sicak, E.E. Oruç-Emre, M. Ozturk, T. Taskin-Tok, A. Karakucuk-Iyidogan, Novel fluorine-containing chiral hydrazide-hydrazones: design, synthesis, structural elucidation, antioxidant and anticholinesterase activity, and in silico studies. Chirality, 31, 603-615 (2019).

H. Woopen, R. Richter, F. Ismaeel, R. Chekerov, I.Roots, T. Siepmann, J. Sehouli, The influence of polypharmacy on grade III/IV toxicity, prior discontinuation of chemotherapy and overall survival in ovarian cancer. Gynecol. Oncol., 140, 554-558 (2016).

A. Buschini, D. Dayicioglu, P. Smith, J. Kiluk, Multicentre study for the evaluation of mutagenic/carcinogenic risk in nurses exposed to antineoplastic drugs: assessment of DNA damage. Occup. Environ. Med., 70, 789-794 (2013).

B.N. Ames, E.G. Gurney, J.A. Miller, H. Bartsch, Carcinogens as frameshift mutagens: metabolites and derivatives of 2-acetylaminofluorene and other aromatic amine carcinogens. Proc. Natl. Acad. Sci., 69, 3128-3132 (1972).

R.K.P Tripathi, S.R. Ayyannan, Evaluation of 2-amino-6-nitrobenzothiazole derived hydrazones as acetylcholinesterase inhibitors: in vitro assays, molecular docking and theoretical ADMET prediction. Med. Chem. Res., 27, 709-725 (2018).

K. Kümmerer, A. Haiβ, A. Schuster, A. Hein, I. Ebert, Antineoplastic compounds in the environment—substances of special concern. Environ. Sci. Pollut. Res., 23, 14791-14804 (2016).

B. Kopp, R. Schierl, D. Nowak, Evaluation of working practices and surface contamination with antineoplastic drugs in outpatient oncology health care settings. Int. Arch. Occup. Environ. Health, 86, 47-55 (2013).

M. Villarini, L. Dominici, R. Piccinini, C. Fatigoni, M. Ambrogi, G. Curti, P. Morucci, G.Muzi, S. Monarca, M. Moretti, Assessment of primary, oxidative and excision repaired DNA damage in hospital personnel handling antineoplastic drugs. Mutagenesis, 26, 359-369 (2010).

E. Senkus, J. Jassem, Cardiovascular effects of systemic cancer treatment. Cancer Treat. Rev., 37, 300-311 (2011).

Cómo citar

APA

dos Anjos Santos, V. L. ., de Assis Gonsalves, A. ., Souza Silva, M. F. ., Evangelista de Oliveira, F. de C., Pinheiro da Costa, M., Pessoa, C. O. . y Araújo, C. R. M. (2021). Hydrazones derived from natural aldehydes: in vitro cytotoxic evaluation and in silico pharmacokinetic predictions. Revista Colombiana de Ciencias Químico-Farmacéuticas, 50(1). https://doi.org/10.15446/rcciquifa.v50n1.91232

ACM

[1]
dos Anjos Santos, V.L. , de Assis Gonsalves, A. , Souza Silva, M.F. , Evangelista de Oliveira, F. de C., Pinheiro da Costa, M., Pessoa, C.O. y Araújo, C.R.M. 2021. Hydrazones derived from natural aldehydes: in vitro cytotoxic evaluation and in silico pharmacokinetic predictions. Revista Colombiana de Ciencias Químico-Farmacéuticas. 50, 1 (may 2021). DOI:https://doi.org/10.15446/rcciquifa.v50n1.91232.

ACS

(1)
dos Anjos Santos, V. L. .; de Assis Gonsalves, A. .; Souza Silva, M. F. .; Evangelista de Oliveira, F. de C.; Pinheiro da Costa, M.; Pessoa, C. O. .; Araújo, C. R. M. Hydrazones derived from natural aldehydes: in vitro cytotoxic evaluation and in silico pharmacokinetic predictions. Rev. Colomb. Cienc. Quím. Farm. 2021, 50.

ABNT

DOS ANJOS SANTOS, V. L. .; DE ASSIS GONSALVES, A. .; SOUZA SILVA, M. F. .; EVANGELISTA DE OLIVEIRA, F. de C.; PINHEIRO DA COSTA, M.; PESSOA, C. O. .; ARAÚJO, C. R. M. Hydrazones derived from natural aldehydes: in vitro cytotoxic evaluation and in silico pharmacokinetic predictions. Revista Colombiana de Ciencias Químico-Farmacéuticas, [S. l.], v. 50, n. 1, 2021. DOI: 10.15446/rcciquifa.v50n1.91232. Disponível em: https://revistas.unal.edu.co/index.php/rccquifa/article/view/91232. Acesso em: 29 abr. 2025.

Chicago

dos Anjos Santos, Victória Laysna, Arlan de Assis Gonsalves, Maria Franciele Souza Silva, Fátima de Cássia Evangelista de Oliveira, Marcília Pinheiro da Costa, Claudia O. Pessoa, y Cleônia Roberta Melo Araújo. 2021. «Hydrazones derived from natural aldehydes: in vitro cytotoxic evaluation and in silico pharmacokinetic predictions». Revista Colombiana De Ciencias Químico-Farmacéuticas 50 (1). https://doi.org/10.15446/rcciquifa.v50n1.91232.

Harvard

dos Anjos Santos, V. L. ., de Assis Gonsalves, A. ., Souza Silva, M. F. ., Evangelista de Oliveira, F. de C., Pinheiro da Costa, M., Pessoa, C. O. . y Araújo, C. R. M. (2021) «Hydrazones derived from natural aldehydes: in vitro cytotoxic evaluation and in silico pharmacokinetic predictions», Revista Colombiana de Ciencias Químico-Farmacéuticas, 50(1). doi: 10.15446/rcciquifa.v50n1.91232.

IEEE

[1]
V. L. . dos Anjos Santos, «Hydrazones derived from natural aldehydes: in vitro cytotoxic evaluation and in silico pharmacokinetic predictions», Rev. Colomb. Cienc. Quím. Farm., vol. 50, n.º 1, may 2021.

MLA

dos Anjos Santos, V. L. ., A. . de Assis Gonsalves, M. F. . Souza Silva, F. de C. Evangelista de Oliveira, M. Pinheiro da Costa, C. O. . Pessoa, y C. R. M. Araújo. «Hydrazones derived from natural aldehydes: in vitro cytotoxic evaluation and in silico pharmacokinetic predictions». Revista Colombiana de Ciencias Químico-Farmacéuticas, vol. 50, n.º 1, mayo de 2021, doi:10.15446/rcciquifa.v50n1.91232.

Turabian

dos Anjos Santos, Victória Laysna, Arlan de Assis Gonsalves, Maria Franciele Souza Silva, Fátima de Cássia Evangelista de Oliveira, Marcília Pinheiro da Costa, Claudia O. Pessoa, y Cleônia Roberta Melo Araújo. «Hydrazones derived from natural aldehydes: in vitro cytotoxic evaluation and in silico pharmacokinetic predictions». Revista Colombiana de Ciencias Químico-Farmacéuticas 50, no. 1 (mayo 17, 2021). Accedido abril 29, 2025. https://revistas.unal.edu.co/index.php/rccquifa/article/view/91232.

Vancouver

1.
dos Anjos Santos VL, de Assis Gonsalves A, Souza Silva MF, Evangelista de Oliveira F de C, Pinheiro da Costa M, Pessoa CO, Araújo CRM. Hydrazones derived from natural aldehydes: in vitro cytotoxic evaluation and in silico pharmacokinetic predictions. Rev. Colomb. Cienc. Quím. Farm. [Internet]. 17 de mayo de 2021 [citado 29 de abril de 2025];50(1). Disponible en: https://revistas.unal.edu.co/index.php/rccquifa/article/view/91232

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CrossRef citations2

1. Dawid Janasik, Krzysztof Jasiński, Julia Szreder, Władysław P. Węglarz, Tomasz Krawczyk. (2023). Hydrazone Molecular Switches with Paramagnetic Center as 19F Magnetic Resonance Imaging Relaxation Enhancement Agents for pH Imaging. ACS Sensors, 8(5), p.1971. https://doi.org/10.1021/acssensors.3c00080.

2. Neetu Singh, Surender Singh Yadav. (2024). Antimicrobial and anticancer insights of cinnamaldehyde Schiff bases and metal complexes. Inorganic Chemistry Communications, 167, p.112724. https://doi.org/10.1016/j.inoche.2024.112724.

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