J. Pharm. Pharmacogn. Res., vol. 11, no. 5, pp. 902-925, Sep-Oct 2023.

DOI: https://doi.org/10.56499/jppres23.1657_11.5.902

Original Article

Synthesis and in vitro activity tests of N-benzoyl-N’-phenylthiourea derivatives as macrophage migration inhibitory factor

[Síntesis y pruebas de actividad in vitro de derivados de N-benzoil-N’-feniltiourea como factor inhibidor de la migración de macrófagos]

Dini Kesuma¹, Galih S. Putra^2*, Tegar A. Yuniarta¹,Farida Suhud¹, I G.A. Sumartha¹, Sawitri Boengas³, Melanny I. Sulistyowaty⁴, Tjie Kok⁵

¹Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Surabaya, Surabaya, Indonesia.

²Department of Chemistry, Faculty of Mathematics and Natural Sciences, State University of Malang, Malang Indonesia.

³Faculty of Medicine, University of Surabaya, Surabaya, Indonesia.

⁴Department of Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Airlangga, Surabaya 60115, Indonesia.

⁵ Faculty of Biotechnology, University of Surabaya, Surabaya, Indonesia.

*E-mail: galih.satrio.fmipa@um.ac.id

Abstract

Context: The COVID-19 pandemic in 2020 resulted in widespread mortalities due to cytokine storms in the affected patients. Macrophage migration inhibitory factor (MIF) is one of the most interesting targets in developing anti-COVID-19 drugs. Some thiourea compounds have been identified as having potential as MIF inhibitors.

Aims: To investigate MIF inhibitory activity of N-benzoyl-N’-phenylthiourea derivatives.

Methods: The study consists of in-silico activity prediction of designed compounds using a molecular docking approach against MIF protein (PDB ID: 1LJT). Afterwards, the designed compounds were synthesized and tested in vitro using the tautomerase activity approach.

Results: The molecular docking study showed that all designed compounds possess comparable docking scores to the native ligand of the protein. MIF Assay performed on compounds (1) and (2) indicated a decrease in tautomerase activity of the MIF target protein of only 10.1 and 6.2%, respectively, compared to the positive control.

Conclusions: In silico results predicted better bioactivity against MIF protein, but the result does not translate to the in vitro assay, where two of the designed compounds possess only low inhibitory activity.

Keywords: 1LJT; MIF assay; tautomerase activity; thiourea derivatives.

Resumen

Contexto: La pandemia de COVID-19 en 2020 provocó mortalidades generalizadas debido a las tormentas de citocinas en los pacientes afectados. El factor inhibidor de la migración de macrófagos (MIF) es una de las dianas más interesantes en el desarrollo de fármacos anti-COVID-19. Se han identificado algunos compuestos de tiourea con potencial como inhibidores de MIF.

Objetivos: Investigar la actividad inhibidora de MIF de derivados de N-benzoil-N’-feniltiourea.

Métodos: El estudio consiste en la predicción in silico de la actividad de los compuestos diseñados utilizando un enfoque de acoplamiento molecular frente a la proteína MIF (PDB ID: 1LJT). Posteriormente, los compuestos diseñados se sintetizaron y probaron in vitro mediante el método de actividad tautomerasa.

Resultados: El estudio de acoplamiento molecular mostró que todos los compuestos diseñados poseen puntuaciones de acoplamiento comparables al ligando nativo de la proteína. El ensayo MIF realizado con los compuestos (1) y (2) indicó una disminución de la actividad tautomerasa de la proteína diana MIF de sólo el 10,1 y el 6,2%, respectivamente, en comparación con el control positivo.

Conclusiones: Los resultados in silico predijeron una mejor bioactividad frente a la proteína MIF, pero el resultado no se traslada al ensayo in vitro, donde dos de los compuestos diseñados sólo poseen una baja actividad inhibitoria.

Palabras Clave: actividad tautomerasa; derivados tiourea; ensayo MIF; 1LJT.

Citation Format: Kesuma D, Putra GS, Yuniarta TA, Suhud F, Sumartha IGA, Boengas S, Sulistyowati MI, Kok T (2023) Synthesis and in vitro activity tests of N-benzoyl-N'-phenylthiourea derivatives as macrophage migration inhibitory factor. J Pharm Pharmacogn Res 11(5): 902–925. https://doi.org/10.56499/jppres23.1657_11.5.902

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