Evaluation of N-benzoylthiourea derivatives as possible analgesic agents by predicting their physicochemical and pharmacokinetic properties, toxicity, and analgesic activity


Suko Hardjono(1*), Siswandono Siswandono(2), Rina Andayani(3)

(1) Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Airlangga University, Campus B Jalan Dharmawangsa Dalam, Surabaya 60282, Indonesia
(2) Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Airlangga University, Campus B Jalan Dharmawangsa Dalam, Surabaya 60282, Indonesia
(3) Department of Pharmacy, Faculty of Medicine, Hang Tuah University, Jalan Gadung No. 1, Komplek Barat RSAL dr. Ramelan, Surabaya 60111, Indonesia
(*) Corresponding Author


This study aimed to predict the physicochemical properties, pharmacokinetic properties (ADME), toxicity, and analgesic activity of 30 compounds of N-benzoylthiourea derivatives that are potential analgesic drugs. One of the mechanisms of action of N-benzoylthiourea derivatives is the inhibition of the cyclooxygenase-2 (COX-2) isoenzyme. An in silico test was performed by docking a compound that would predict its activity with the target COX-2 isoenzyme, PDB ID: 1PXX, using the MVD (Molegro Virtual Docker) program. The result of the docking was a form of energy bond indicated by the value of the rerank score (RS), where compounds that had lower RS values were predicted to have a higher activity. The pkCSM and Protox online tools were used to predict various physicochemical properties. Based on the RS values, the N-benzoylthiourea derivatives can be predicted to have lower analgesic activity than diclofenac, the reference ligand. Three of the N-benzoylthiourea derivatives—N-(2,4-bis-trifluoromethyl)-benzoylthiourea, N-(3,5-bis-trifluoromethyl)benzoylthiourea, and N-(3-trifluoromethoxy)-benzoylthiourea—had RS values of -90.82, -94.73, and -92.76,  respectively, suggesting that these compounds were predicted to have analgesic activity relatively similar to diclofenac (RS value = -95.16). Furthermore, the majority of the  N-benzoylthiourea derivatives were predicted to have good pharmacokinetic properties (ADME), and cause relatively low toxicity.


ADME; analgesic activity; molecular modeling; N-benzoylthiourea; toxicity

Full Text:



Brunton L, Chabner BA, Knollman B. 2011. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th edition. New York: McGraw Hill Professional.

Budiati T, Suzana, Surdijati S. 2010. Sintesis, uji aktivitas analgesik dan anti- inflamasi senyawa benzoiltiourea tersubstitusi [Synthesis, analgesic and anti-inflammatory activities of substituted benzoylthioureas]. Majalah Farmasi Indonesia 21:68--76.

Chander S, Tang C-R, Al-Maqtari HM, Jamalis J, Penta A, Hadda TB, Sirat HM, Zheng Y-T, Sankaranarayanan M. 2017. Synthesis and study of anti-HIV-1 RT activity of 5-benzoyl-4-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one derivatives. Bioorganic Chemistry 72:74--79. doi:10.1016/j.bioorg.2017.03.013.

Hardjono S. 2012. Modifikasi Struktur 1-(benzoiloksi)urea dan Hubungan Kuantitatif Struktur-Aktivitas Sitotoksiknya [Dissertation]. [Surabaya]: Airlangga University.

Hardjono S, Siswodihardjo S, Pramono P, Darmanto W. 2016. Quantitative structure-cytotoxic activity relationship 1-(benzoyloxy)urea and its derivative. Current Drug Discovery Technologies 13:101--108.

Hinchliffe A. 2008. Molecular Modelling for Beginners. 2nd edition. Chichester: John Wiley & Sons Ltd.

Jensen F. 2007. Introduction to Computational Chemistry. 2nd edition. Chichester: John Wiley & Sons Ltd.

Lee Jeewoo, Kang S-U, Choi H-K, Lee Jiyoun, Lim J-O, Kil M-J, Jin M-K, Kim K-P, Sung J-H, Chung S-J, et al. 2004. Analysis of structure-activity relationships for the “B-region” of N-(3-acyloxy-2-benzylpropyl)-N(’)-[4-(methylsulfonylamino)benzyl]thiourea analogues as vanilloid receptor antagonists: discovery of an N-hydroxythiourea analogue with potent analgesic activity. Bioorganic & Medicinal Chemistry Letters 14:2291--2297. doi:10.1016/j.bmcl.2004.02.002.

Lee Jeewoo, Lee Jiyoun, Kang M-S, Kim K-P, Chung S-J, Blumberg PM, Yi J-B, Park YH. 2002. Phenolic modification as an approach to improve the pharmacology of the 3-acyloxy-2-benzylpropyl homovanillic amides and thioureas, a promising class of vanilloid receptor agonists and analgesics. Bioorganic & Medicinal Chemistry 10:1171--1179.

Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. 2001. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews 46:3–26.

Park H, Park M, Choi J, Choi S, Lee Jihye, Park B, Kim MG, Suh Y, Cho H, Oh U, et al. 2003. Synthesis of N,N’,N"-trisubstituted thiourea derivatives and their antagonist effect on the vanilloid receptor. Bioorganic & Medicinal Chemistry Letters 13:601–604.

Pires DEV, Blundell TL, Ascher DB. 2015. pkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. Journal of Medicinal Chemistry 58:4066–4072. doi:10.1021/acs.jmedchem.5b00104.

Rowlinson SW, Kiefer JR, Prusakiewicz JJ, Pawlitz JL, Kozak KR, Kalgutkar AS, Stallings WC, Kurumbail RG, Marnett LJ. 2003. A novel mechanism of cyclooxygenase-2 inhibition involving interactions with Ser-530 and Tyr-385. Journal of Biological Chemistry 278:45763–45769. doi:10.1074/jbc.M305481200.

Ruswanto, Siswandono, Richa M, Tita N, Tresna L. 2017. Molecular docking of 1-benzoyl-3-methylthiourea as anti cancer candidate and its absorption, distribution, and toxicity prediction. Journal of Pharmaceutical Science and Research 9:680--684.

Saeed A, Rehman S, Channar PA, Larik FA, Abbas Q, Hassan M, Raza H, Flörke U, Seo S-Y. 2017. Long chain 1-acyl-3-arylthioureas as jack bean urease inhibitors, synthesis, kinetic mechanism and molecular docking studies. Journal of the Taiwan Institute of Chemical Engineers 77:54–63. doi:10.1016/j.jtice.2017.04.044.

Schlick T. 2010. Molecular modeling and simulation: an interdisciplinary guide. 2nd edition. New York: Springer.

Shalas AF, Siswandono, Rudyanto M. 2016. Synthesis and structure-activity relationship of 1-allyl-3-(2-chlorobenzoyl) thiourea as analgesic. International Journal of Pharmacy and Pharmaceutical Sciences 8:297--298.

Siswandono. 2014. Pengembangan Obat Baru [Development of New Drugs]. 1st edition. Surabaya: Airlangga University Press.

Siswandono, editor. 2016. Kimia Medisinal I [Medicinal Chemistry I]. 2nd edition. Surabaya: Airlangga University Press.

Thomsen R, Christensen MH. 2006. MolDock: a new technique for high-accuracy molecular docking. Journal of Medicinal Chemistry 49:3315–3321. doi:10.1021/jm051197e.

United Nations. 2005. A guide tothe globally harmonized system of classification and labeling of chemicals {(GHS)}.


DOI: https://doi.org/10.22146/ijbiotech.27171

Article Metrics

Abstract views : 689 | views : 204


  • There are currently no refbacks.

Copyright (c) 2017 The Author(s)

Creative Commons License
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.

Past issues

The Indonesian Journal of Biotechnology (print ISSN 0853-8654; online ISSN 2089-2241) is published by the Research Center for Biotechnology in collaboration with the Graduate School of Universitas Gadjah Mada. The content of this website is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License, and attributable to Siti Nurleily Marliana and Joaquim Baeta. Built on the Public Knowledge Project's OJS and designed by Joaquim Baeta. Web
Analytics View website statistics.

IJBiotech is indexed in