Molecular Docking Study of Substituted Benzamide Derivatives as Analgesic Candidates
Article Sidebar
-
Benzamide, Drug Design, Inflammatory, Synthesis, Urea
Abstract
Thiourea derivatives represent a diverse class of compounds exhibiting a range of pharmacological activities, including antitubercular, analgesic, antiviral, and anticancer effects. Of particular interest is N-allyl-N'-(benzoylcarbamothioyl)benzamide, which is hypothesized to possess analgesic properties. A comprehensive in silico molecular docking study was undertaken to evaluate this potential. In silico assays, leveraging computer simulations, are invaluable tools for predicting outcomes, generating hypotheses, and accelerating drug discovery. Molecular docking, a prominent in silico application, facilitates structure-based screening by computationally assessing the binding affinity of compounds to target proteins. This research specifically aimed to predict the analgesic activity of N-allyl-N'-(benzoylcarbamothioyl)benzamide derivatives. To achieve this, various substituents, including methyl, methoxy, tert-butyl, dimethylamino, and halogens, were strategically incorporated at the ortho, meta, and para positions of the benzoylcarbamothioyl ring, generating a library of novel analgesic drug candidates. Compound activity was primarily evaluated using the rerank score. Additionally, ProTox-3.0 and pkCSM were utilized to predict these synthesized compounds' toxicity and physicochemical properties. Initial findings were encouraging, with 18 derivatives of N-allyl-N'-(benzoylcarbamothioyl)benzamide demonstrating enhanced predicted analgesic activity. Among these, six compounds exhibited promising analgesic properties without predicted toxicity. In conclusion, these in silico results suggest that certain N-allyl-N'-(benzoylcarbamothioyl)benzamide derivatives hold significant promise as potential analgesic agents, warranting further validation through subsequent laboratory and in vivo investigations.
Full text article
References
2. van Rensburg R, Reuter H. An overview of analgesics: NSAIDs, paracetamol, and topical analgesics Part 1. S Afr Fam Pract. 2019;61(sup1):S4-S10. DOI: 10.1080/20786190.2019.1610228
3. Sharma S, Sharma SC. An update on eicosanoids and inhibitors of cyclooxygenase enzyme systems. Indian J Exp Biol. 1997;35(10):1025-31. PMID: 9475035
4. Dvorakova M, Langhansova L, Temml V, Pavicic A, Vanek T, Landa P. Synthesis, Inhibitory Activity, and In Silico Modeling of Selective COX-1 Inhibitors with a Quinazoline Core. ACS Med Chem Lett. 2021;12(4):610-6. DOI: 10.1021/acsmedchemlett.1c00004; PMCID: PMC8040043; PMID: 33854702
5. Rouzer CA, Marnett LJ. Cyclooxygenases: structural and functional insights. J Lipid Res. 2009;50 Suppl(Suppl):S29-S34. DOI: 10.1194/jlr.r800042-jlr200; PMCID: PMC2674713; PMID: 18952571
6. Rouzer CA, Marnett LJ. Structural and Chemical Biology of the Interaction of Cyclooxygenase with Substrates and Non-Steroidal Anti-Inflammatory Drugs. Chem Rev. 2020;120(15):7592-641. DOI: 10.1021/acs.chemrev.0c00215; PMCID: PMC8253488; PMID; 32609495
7. Ölmez NA, Waseer F. New Potential Biologically Active Compounds: Synthesis and Characterization of Urea and Thiourea Derivativpes Bearing 1,2,4-oxadiazole Ring. Curr Org Synth. 2020;17(7):525-34. DOI: 10.2174/1570179417666200417112106; PMID: 32303172
8. Çelen A, Kaymakçıoğlu B, Gümrü S, Toklu H, Arıcıoğlu F. Synthesis and anticonvulsant activity of substituted thiourea derivatives. Marmara Pharm J. 2011;15(2):43-7. DOI: 10.12991/mpj.60092
9. Hardjono S, Siswandono S, Andayani R. Evaluation of N-benzoylthiourea derivatives as possible analgesic agents by predicting their physicochemical and pharmacokinetic properties, toxicity, and analgesic activity. Indones J Biotechnol. 2017;22(2):76-85. DOI: 10.22146/ijbiotech.27171
10. Razak R, Siswandono S, Ekowati J. Synthesis and Activity Test of 1-Allyl-3-(4-tertiary-Butylbenzoyl) Thioureaas a Candidate of an Analgesic Drug. J Farmasi Ilmu Kefarmasian Indones. 2022;9(1):17-23. DOI: 10.20473/jfiki.v9i12022.17-23
11. Fawwaz M, Purwono B, Sidiq Y, Arwansyah, Arsul MI, Fitriana, et al. Anti-inflammatory, Antioxidant, and Antibacterial Activities with Molecular Docking Studies of Vitex Trifolia L. Targeting Human COX-2 and Peroxiredoxin-5. ChemistrySelect. 2024;9(39):e202403834. DOI: 10.1002/slct.202403834
12. Budiati T, Suzana, Surdijati S. Sintesis, uji aktivitas analgesik dan anti-inflamasi senyawa benzoiltiourea Tersubstitusi. Majalah Farmasi Indones. 2010;21(1):68-76.
13. Meng XY, Zhang HX, Mezei M, Cui M. Molecular docking: a powerful approach for structure-based drug discovery. Curr Comput Aided Drug Des. 2011;7(2):146-57. DOI: 10.2174/157340911795677602; PMCID: PMC3151162; PMID: 21534921
14. Salmaso V, Moro S. Bridging Molecular Docking to Molecular Dynamics in Exploring Ligand-Protein Recognition Process: An Overview. Front Pharmacol. 2018;9:923. DOI: 10.3389/fphar.2018.00923; PMCID: PMC6113859; PMID: 30186166
15. Kocyigit-Kaymakcioglu B, Celen AO, Tabanca N, Ali A, Khan SI, Khan IA, et al. Synthesis and biological activity of substituted urea and thiourea derivatives containing 1,2,4-triazole moieties. Molecules. 2013;18(3):3562-76. DOI: 10.3390/molecules18033562; PMCID: PMC6270039; PMID: 23519199
16. Ronchetti R, Moroni G, Carotti A, Gioiello A, Camaioni E. Recent advances in urea- and thiourea-containing compounds: focus on innovative approaches in medicinal chemistry and organic synthesis. RSC Med Chem. 2021;12(7):1046-64. DOI: 10.1039/d1md00058f; PMCID: PMC8293013; PMID: 34355177
17. Fawwaz M, Mishiro K, Nishii R, Sawazaki I, Shiba K, Kinuya S, et al. Synthesis and Fundamental Evaluation of Radioiodinated Rociletinib (CO-1686) as a Probe to Lung Cancer with L858R/T790M Mutations of Epidermal Growth Factor Receptor (EGFR). Molecules. 2020;25(12):2914. DOI: 10.3390/molecules25122914; PMCID: PMC7356761; PMID: 32599930
18. Fawwaz M, Mishiro K, Nishii R, Makino A, Kiyono Y, Shiba K, et al. A Radiobrominated Tyrosine Kinase Inhibitor for EGFR with L858R/T790M Mutations in Lung Carcinoma. Pharmaceuticals. 2021;14(3):256. DOI: 10.3390/ph14030256; PMCID: PMC7998589; PMID: 33809064
19. Rowlinson SW, Kiefer JR, Prusakiewicz JJ, Pawlitz JL, Kozak KR, Kalgutkar AS, et al. A novel mechanism of cyclooxygenase-2 inhibition involving interactions with Ser-530 and Tyr-385. J Biol Chem. 2003;278(46):45763-9. DOI: 10.1074/jbc.m305481200; PMID: 12925531
20. Hussain S, Guruvayoorappan C, Komal KP, Ennaganti S. Molecular docking analysis of doronine derivatives with human COX-2. Bioinformation. 2020;16(6):483-92. DOI: 10.6026/97320630016483; PMCID: PMC7452741; PMID: 32884214
21. Kufareva I, Abagyan R. Methods of protein structure comparison. Methods Mol Biol. 2012;857:231-57. DOI: 10.1007/978-1-61779-588-6_10; PMCID: PMC4321859; PMID: 22323224
22. Ramírez D, Caballero J. Is It Reliable to Take the Molecular Docking Top Scoring Position as the Best Solution without Considering Available Structural Data? Molecules. 2018;23(5):1038. DOI: 10.3390/molecules23051038; PMCID: PMC6102569; PMID: 29710787
23. Agu PC, Afiukwa CA, Orji OU, Ezeh EM, Ofoke IH, Ogbu CO, et al. Molecular docking as a tool for the discovery of molecular targets of nutraceuticals in diseases management. Sci Rep. 2023;13(1):13398. DOI: 10.1038/s41598-023-40160-2; PMCID: PMC10435576; PMID: 37592012
24. Bitencourt-Ferreira G, de Azevedo WF, Jr. Molegro Virtual Docker for Docking. Methods Mol Biol. 2019;2053:149-67. DOI: 10.1007/978-1-4939-9752-7_10; PMID: 31452104
25. Pires DEV, Blundell TL, Ascher DB. pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. J Med Chem. 2015;58(9):4066-72. DOI: 10.1021/acs.jmedchem.5b00104; PMCID: PMC4434528; PMID: 25860834
26. Erhirhie EO, Ihekwereme CP, Ilodigwe EE. Advances in acute toxicity testing: strengths, weaknesses and regulatory acceptance. Interdiscip Toxicol. 2018;11(1):5-12. DOI: 10.2478/intox-2018-0001; PMCID: PMC6117820; PMID: 30181707
27. Chang Y, Hawkins BA, Du JJ, Groundwater PW, Hibbs DE, Lai F. A Guide to In Silico Drug Design. Pharmaceutics. 2022;15(1):49. DOI: 10.3390/pharmaceutics15010049; PMCID: PMC9867171; PMID: 36678678
28. Hursthouse MB, Hughes DS, Geblich T, Threlfall TL. Describing hydrogen-bonded structures; topology graphs, nodal symbols and connectivity tables, exemplified by five polymorphs of each of sulfathiazole and sulfapyridine. Chem Cent J. 2015;9(1):1. DOI: 10.1186/s13065-014-0076-x; PMCID: PMC4309923; PMID: 25649693
29. Nivatya HK, Singh A, Kumar N, Sonam, Sharma L, Singh V, et al. Assessing molecular docking tools: understanding drug discovery and design. Futur J Pharm Sci. 2015;11:111. DOI: 10.1186/s43094-025-00862-y
Authors
Copyright (c) 2025 Rahmawati Rahmawati, Rais Razak, Muammar Fawwaz
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Authors continue to retain the copyright to the article if the article is published in the Borneo Journal of Pharmacy. They will also retain the publishing rights to the article without any restrictions.
Authors who publish in this journal agree to the following terms:
- Any article on the copyright is retained by the author(s).
- The author grants the journal the right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share work with an acknowledgment of the work authors and initial publications in this journal.
- Authors can enter into separate, additional contractual arrangements for the non-exclusive distribution of published articles (e.g., post-institutional repository) or publish them in a book, with acknowledgment of their initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their websites) prior to and during the submission process. This can lead to productive exchanges and earlier and greater citations of published work.
- The article and any associated published material are distributed under the Creative Commons Attribution-ShareAlike 4.0 International License.
Article Details
