Publicado

2014-01-01

Assessment of the anticonvulsant activity of pyrazolo[1,5-a][1,3,5]triazines obtained by synthesis

Evaluación de la actividad anticonvulsiva de pirazolo [1,5-a] [1,3,5] triazinas obtenidos por síntesis

DOI:

https://doi.org/10.15446/rcciquifa.v43n1.45462

Palabras clave:

Pyrazolotriazines, Anticonvulsants, Evaluación Preclínica de Medicamentos, Electroshock, Structure-Activity Relationship (en)
Pirazolotriazinas, Anticonvulsivantes, Drug screening, Electrochoque, Relación Estructura Actividad (es)

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Autores/as

  • Henry Insuasty Universidad de Nariño
  • Edinson Castro Universidad de Nariño
  • Juan C. Escobar Universidad Nacional de Colombia
  • Vanesa Murillo Universidad Nacional de Colombia
  • Jeanette Rodriguez Universidad Nacional de Colombia
  • Luis E. Cuca Universidad Nacional de Colombia
  • Martin Estrada Universidad Nacional de Colombia
  • Braulio Insuasty Universidad del Valle
  • Mario F. Guerrero Universidad Nacional de Colombia
Giving that the pyrazolo[1,5-a][1,3,5]triazine system is a potential source of pharmacological agents for treatment of central nervous system disorders this work was aimed to asses anticonvulsant and acute neurotoxic effects of six molecules obtained by synthesis, using experimental models in mice. A series of six pyrazolo[1,5-a][1,3,5]triazines (EAC-21, EAC-31, EAC-33, MH4a, MH4b1 and MH4c) obtained by one-step reaction from S,S-diethyl aroyl-/hetaroylimidodithiocarbonates and 5-aminopyrazoles were screened in vivo (300 mg/kg, v.o.) for their anticonvulsant activity in the maximal electroshock (MES) test in ICR mice and for acute toxicity in the rota-rod and wiring test. The structures of the obtained compounds were unambiguously established by IR, 1H and 13C-NMR spectroscopic techniques, COSY 1H-1H, HSQC and HMBC experiments, mass spectrometry and elemental analyses. Results shown that only MH4b1 showed protection against MES (p<0.05) and was devoid of gross neurotoxicity signs. Therefore, MH4b1 was chosen for additional anticonvulsant screening against MES, pentilenetetrazole, picrotoxin, strychnine and 6 Hz psychomotor seizure model, in a dose dependent manner (50, 150, 300 mg/kg, v.o.). MH4b1 also protected against 6 Hz seizure test (>150 mg/kg, v.o.). These data suggest that MH4b1 could be a source for anticonvulsant pyrazolo[1,5-a][1,3,5]triazine analogs potentially useful against tonic clonic and refractory seizures.

Dado el interés que el sistema pirazolo[1,5-a][1,3,5]triazina tiene como fuente potencial para la obtención de agentes farmacológicos para el tratamiento de trastornos del sistema nervioso central, en este trabajo se efectuó el cribado anticonvulsivante y el efecto neurotóxico agudo de seis moléculas derivadas de este sistema, en ratones ICR. La serie de compuestos denominados EAC-21, EAC-31, EAC-33, MH4a, MH4b1 y MH4c, obtenidas por la reacción de S,S-dietil aroil-/heteroilimidoditiocarbonatos y 5-aminopirazoles se evaluó in vivo (300 mg/kg, v.o.) en la prueba de convulsiones inducidas por electrochoque y en las pruebas de actividad neurotóxica aguda del eje rodante y del alambre. La estructura de estos compuestos se determinó por técnicas de infrarrojo, espectroscopia de 1H, 13C-NMR, COSY 1H-1H, experimentos de HSQC y HMBC, espectrometría de masas y análisis elemental. Los resultados mostraron que el compuesto MH4b1 confirió protección frente a las convulsiones inducidas por electrochoque (p<0.05) sin producir signos de neurotoxicidad aguda. Por consiguiente, MH4b1 se escogió para las siguientes pruebas de actividad anticonvulsivante, dosis - respuesta (50, 150, 300 mg/kg, v.o.): electrochoque, pentilenetetrazol, picrotoxin, estricnina y el modelo de convulsión psicomotora de 6 Hz. MH4b1 mostró efectos protectores en función de la dosis frente a las pruebas de convulsión por electrochoque (>150 mg/kg) y convulsión de 6 Hz (300 mg/kg, v.o.). Estos resultados sugieren que MH4b1 podría constituirse en fuente anticonvulsivante del sistema pirazolo[1,5-a][1,3,5]triazina eventualmente útil para el tratamiento de las crisis tónicas clónicas generalizadas y las crisis refractarias.

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Cómo citar

APA

Insuasty, H., Castro, E., Escobar, J. C., Murillo, V., Rodriguez, J., Cuca, L. E., Estrada, M., Insuasty, B. y Guerrero, M. F. (2014). Assessment of the anticonvulsant activity of pyrazolo[1,5-a][1,3,5]triazines obtained by synthesis. Revista Colombiana de Ciencias Químico-Farmacéuticas, 43(1), 22–38. https://doi.org/10.15446/rcciquifa.v43n1.45462

ACM

[1]
Insuasty, H., Castro, E., Escobar, J.C., Murillo, V., Rodriguez, J., Cuca, L.E., Estrada, M., Insuasty, B. y Guerrero, M.F. 2014. Assessment of the anticonvulsant activity of pyrazolo[1,5-a][1,3,5]triazines obtained by synthesis. Revista Colombiana de Ciencias Químico-Farmacéuticas. 43, 1 (ene. 2014), 22–38. DOI:https://doi.org/10.15446/rcciquifa.v43n1.45462.

ACS

(1)
Insuasty, H.; Castro, E.; Escobar, J. C.; Murillo, V.; Rodriguez, J.; Cuca, L. E.; Estrada, M.; Insuasty, B.; Guerrero, M. F. Assessment of the anticonvulsant activity of pyrazolo[1,5-a][1,3,5]triazines obtained by synthesis. Rev. Colomb. Cienc. Quím. Farm. 2014, 43, 22-38.

ABNT

INSUASTY, H.; CASTRO, E.; ESCOBAR, J. C.; MURILLO, V.; RODRIGUEZ, J.; CUCA, L. E.; ESTRADA, M.; INSUASTY, B.; GUERRERO, M. F. Assessment of the anticonvulsant activity of pyrazolo[1,5-a][1,3,5]triazines obtained by synthesis. Revista Colombiana de Ciencias Químico-Farmacéuticas, [S. l.], v. 43, n. 1, p. 22–38, 2014. DOI: 10.15446/rcciquifa.v43n1.45462. Disponível em: https://revistas.unal.edu.co/index.php/rccquifa/article/view/45462. Acesso em: 28 mar. 2024.

Chicago

Insuasty, Henry, Edinson Castro, Juan C. Escobar, Vanesa Murillo, Jeanette Rodriguez, Luis E. Cuca, Martin Estrada, Braulio Insuasty, y Mario F. Guerrero. 2014. «Assessment of the anticonvulsant activity of pyrazolo[1,5-a][1,3,5]triazines obtained by synthesis». Revista Colombiana De Ciencias Químico-Farmacéuticas 43 (1):22-38. https://doi.org/10.15446/rcciquifa.v43n1.45462.

Harvard

Insuasty, H., Castro, E., Escobar, J. C., Murillo, V., Rodriguez, J., Cuca, L. E., Estrada, M., Insuasty, B. y Guerrero, M. F. (2014) «Assessment of the anticonvulsant activity of pyrazolo[1,5-a][1,3,5]triazines obtained by synthesis», Revista Colombiana de Ciencias Químico-Farmacéuticas, 43(1), pp. 22–38. doi: 10.15446/rcciquifa.v43n1.45462.

IEEE

[1]
H. Insuasty, «Assessment of the anticonvulsant activity of pyrazolo[1,5-a][1,3,5]triazines obtained by synthesis», Rev. Colomb. Cienc. Quím. Farm., vol. 43, n.º 1, pp. 22–38, ene. 2014.

MLA

Insuasty, H., E. Castro, J. C. Escobar, V. Murillo, J. Rodriguez, L. E. Cuca, M. Estrada, B. Insuasty, y M. F. Guerrero. «Assessment of the anticonvulsant activity of pyrazolo[1,5-a][1,3,5]triazines obtained by synthesis». Revista Colombiana de Ciencias Químico-Farmacéuticas, vol. 43, n.º 1, enero de 2014, pp. 22-38, doi:10.15446/rcciquifa.v43n1.45462.

Turabian

Insuasty, Henry, Edinson Castro, Juan C. Escobar, Vanesa Murillo, Jeanette Rodriguez, Luis E. Cuca, Martin Estrada, Braulio Insuasty, y Mario F. Guerrero. «Assessment of the anticonvulsant activity of pyrazolo[1,5-a][1,3,5]triazines obtained by synthesis». Revista Colombiana de Ciencias Químico-Farmacéuticas 43, no. 1 (enero 1, 2014): 22–38. Accedido marzo 28, 2024. https://revistas.unal.edu.co/index.php/rccquifa/article/view/45462.

Vancouver

1.
Insuasty H, Castro E, Escobar JC, Murillo V, Rodriguez J, Cuca LE, Estrada M, Insuasty B, Guerrero MF. Assessment of the anticonvulsant activity of pyrazolo[1,5-a][1,3,5]triazines obtained by synthesis. Rev. Colomb. Cienc. Quím. Farm. [Internet]. 1 de enero de 2014 [citado 28 de marzo de 2024];43(1):22-38. Disponible en: https://revistas.unal.edu.co/index.php/rccquifa/article/view/45462

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CrossRef citations4

1. Samson Sahile Salile, Hamin John Lee, Paul Sewes Frederick Alberts, Teferra Abula, Joseph Valentino Raimondo, Gary Ivan Stafford. (2023). In vitro and in vivo anti-seizure activity of hydromethanolic extract and fractions of Pterolobium stellatum. Journal of Ethnopharmacology, 304, p.116073. https://doi.org/10.1016/j.jep.2022.116073.

2. Ranjana Aggarwal, Suresh Kumar. (2018). 5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines. Beilstein Journal of Organic Chemistry, 14, p.203. https://doi.org/10.3762/bjoc.14.15.

3. Oguz Özbek, Meliha Burcu Gürdere. (2020). A review on the synthesis and applications of molecules as anticonvulsant drug agent candidates. Medicinal Chemistry Research, 29(9), p.1553. https://doi.org/10.1007/s00044-020-02595-4.

4. Shikha Kumari, Chandra Bhushan Mishra, Manisha Tiwari. (2016). Pharmacological evaluation of novel 1-[4-(4-benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-phenyl]-3-phenyl-urea as potent anticonvulsant and antidepressant agent. Pharmacological Reports, 68(2), p.250. https://doi.org/10.1016/j.pharep.2015.08.013.

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