Synthesis and virtual screening of bis-(4-(tert-butyl)-N-(methylcarbamothioyl) benzamide)-Iron (III) complex as an anticancer candidate

Authors

  • Ruswanto Ruswanto Prodi Farmasi, STIKes Bakti Tunas Husada Tasikmalaya
  • Winda Trisna Wulandari Prodi Farmasi, STIKes Bakti Tunas Husada Tasikmalaya
  • Richa Mardianingrum Prodi Farmasi, Universitas Perjuangan Tasikmalaya
  • Indah Cantika Prodi Farmasi, STIKes Bakti Tunas Husada Tasikmalaya

DOI:

https://doi.org/10.12928/pharmaciana.v11i1.17837

Keywords:

Complex, Docking, Fe (III Metal), Synthesis, 4-(Tert-Butyl)-N-(Methylcarbamothioyl) Benzamide

Abstract

Thiourea derivatives were much used in drug discovery and drug-making, such as for an anticancer. The formation of drug complexes can increase lipophilicity through chelation formation, and the drug action is significantly upward due to the effective permeability to the center. In another study, the alteration of the compound becomes the complex with metal will grow in its activity so recently we have synthesized the Bis-(4-(Tert-Butyl)-N-(Methylcarbamothioyl) Benzamide)-Iron (III) complex.  The synthesis of Fe (III) metal with the 4-(Tert-Butyl)-N-(Methylcarbamothioyl) Benzamide in ethanol by reflux at 75oC for 7 hours. Hot Stage Microscopy, UV-Visible Spectrophotometry Infrared Spectrophotometry, and Massa Spectrophotometry were used to characterize the complex. This study concerns representing, inferring, and predicting pharmacokinetics and toxicity and molecular docking complexes. The complex weight was 0.29469 g. Its purity has been tested using the melting point determination and has obtained its range was 113o-115oC. The Characteristics of Bis-(4-(Tert-Butyl)-N-(Methylcarbamothioyl) Benzamide)-Iron(III) complex have a maximum wavelength of 260,0 nm and provide absorption of Fe-O vibrations at wavenumbers 478,2 cm-1and 588 cm-1, and the m/z complex of spectrophotometry mass was 559,31. The molecular docking process was performed using AutodockTools-1.5.6 software. It showed that Bis-(4-(Tert-Butyl)-N-(Methylcarbamo-thioyl)Benzamide)-Iron(III) complex could interact with ribonucleotide reductase enzyme, and it has better interaction than the 4-(Tert-Butyl)-N-(Methylcarbamothioyl)Benzamide with the binding affinity energy (ΔG)of  -8,52 kcal/mole and the constant inhibition (Ki ) of 568,55 nM.

References

Bielenica, A., Drzewiecka-Antonik, A., Rejmak, P., Stefańska, J., Koliński, M., Kmiecik, S., Lesyng, B., Włodarczyk, M., Pietrzyk, P., & Struga, M. (2018). Synthesis, structural and antimicrobial studies of type II topoisomerase-targeted copper(II) complexes of 1,3-disubstituted thiourea ligands. Journal of Inorganic Biochemistry, 182, 61–70. https://doi.org/10.1016/j.jinorgbio.2018.01.005

Binzet, G., Gumus, I., Dogen, A., Flörke, U., Kulcu, N., & Arslan, H. (2018). Nickel(II) and copper(II) complexes of N,N-dialkyl-N′-3-chlorobenzoylthiourea: Synthesis, characterization, crystal structures, Hirshfeld surfaces and antimicrobial activity. Journal of Molecular Structure, 1161, 519–529. https://doi.org/10.1016/j.molstruc.2018.02.073

Brown, J. R., North, E. J., Hurdle, J. G., Morisseau, C., Scarborough, J. S., Sun, D., Korduláková, J., Scherman, M. S., Jones, V., Grzegorzewicz, A., Crew, R. M., Jackson, M., McNeil, M. R., & Lee, R. E. (2011). The structure–activity relationship of urea derivatives as anti-tuberculosis agents. Bioorganic & Medicinal Chemistry, 19(18), 5585–5595. https://doi.org/10.1016/j.bmc.2011.07.034

Burmistrov, V., Morisseau, C., Pitushkin, D., Karlov, D., Fayzullin, R. R., Butov, G. M., & Hammock, B. D. (2018). Adamantyl thioureas as soluble epoxide hydrolase inhibitors. Bioorganic & Medicinal Chemistry Letters, 28(13), 2302–2313. https://doi.org/10.1016/j.bmcl.2018.05.024

Do Couto Almeida, J., Marzano, I. M., Pivatto, M., Lopes, N. P., Da Costa Ferreira, A. M., Pavan, F. R., Silva, I. C., Pereira-Maia, E. C., Von Poelhsitz, G., & Guerra, W. (2016). Synthesis, cytotoxic and antitubercular activities of copper(II) complexes with heterocyclic bases and 3-hydroxypicolinic acid. Inorganica Chimica Acta, 446, 87–92. https://doi.org/10.1016/j.ica.2016.03.005

Domínguez, J. N., León, C., Rodrigues, J., Gamboa de Domínguez, N., Gut, J., & Rosenthal, P. J. (2005). Synthesis and Evaluation of New Antimalarial Phenylurenyl Chalcone Derivatives. Journal of Medicinal Chemistry, 48(10), 3654–3658. https://doi.org/10.1021/jm058208o

Karakuş, S., Güniz Küçükgüzel, Ş., Küçükgüzel, İ., De Clercq, E., Pannecouque, C., Andrei, G., Snoeck, R., Şahin, F., & Faruk Bayrak, Ö. (2009). Synthesis, antiviral and anticancer activity of some novel thioureas derivedfrom N-(4-nitro-2-phenoxyphenyl)-methanesulfonamide. European Journal of Medicinal Chemistry, 44(9), 3591–3595. https://doi.org/10.1016/j.ejmech.2009.02.030

Khan, S. A., Singh, N., & Saleem, K. (2008). Synthesis, characterization and in vitro antibacterial activity of thiourea and urea derivatives of steroids. European Journal of Medicinal Chemistry, 43(10), 2272–2277. https://doi.org/10.1016/j.ejmech.2007.12.012

Lan, J., Huang, L., Lou, H., Chen, C., Liu, T., Hu, S., Yao, Y., Song, J., Luo, J., Liu, Y., Xia, B., Xia, L., Zeng, X., Ben-David, Y., & Pan, W. (2018). Design and synthesis of novel C14-urea-tetrandrine derivatives with potent anti-cancer activity. European Journal of Medicinal Chemistry, 143, 1968–1980. https://doi.org/10.1016/j.ejmech.2017.11.007

Lin, P. Z., Chun, L. C., Zhou, J., Ming, X. L., & Yan, J. W. (2008). Synthesis, crystal structure and antitumor study of an iron(III) complex of 2-acetylpyrazine N(4)-methylthiosemicarbazone. Zeitschrift Fur Naturforschung - Section B Journal of Chemical Sciences, 63(11), 1257–1261. https://doi.org/10.1515/znb-2008-1103

Manjula, S. N., Malleshappa Noolvi, N., Vipan Parihar, K., Manohara Reddy, S. A., Ramani, V., Gadad, A. K., Singh, G., Gopalan Kutty, N., & Mallikarjuna Rao, C. (2009). Synthesis and antitumor activity of optically active thiourea and their 2-aminobenzothiazole derivatives: A novel class of anticancer agents. European Journal of Medicinal Chemistry, 44(7), 2923–2929. https://doi.org/10.1016/j.ejmech.2008.12.002

Mardianingrum, R., Susanti, & Ruswanto, R. (2019). Bis(N′-(3-chlorobenzoyl)isonicotinohydrazide)iron(III) Complex. Molbank, 2020(1), M1101. https://doi.org/10.3390/M1101

North, E. J., Scherman, M. S., Bruhn, D. F., Scarborough, J. S., Maddox, M. M., Jones, V., Grzegorzewicz, A., Yang, L., Hess, T., Morisseau, C., Jackson, M., McNeil, M. R., & Lee, R. E. (2013). Design, synthesis and anti-tuberculosis activity of 1-adamantyl-3-heteroaryl ureas with improved in vitro pharmacokinetic properties. Bioorganic & Medicinal Chemistry, 21(9), 2587–2599. https://doi.org/10.1016/j.bmc.2013.02.028

Nursamsiar, Toding, A. T., & Awaluddin, A. (2016). Studi in silico senyawa turunan analog kalkon dan pirimidin sebagai antiinflamasi: prediksi absorpsi, distribusi dan toksisitas. Pharmacy, 13(1), 92–100.

Pal, S., Kumar, V., Kundu, B., Bhattacharya, D., Preethy, N., Reddy, M. P., & Talukdar, A. (2019). Ligand-based Pharmacophore Modeling, Virtual Screening and Molecular Docking Studies for Discovery of Potential Topoisomerase I Inhibitors. Computational and Structural Biotechnology Journal, 17, 291–310. https://doi.org/10.1016/j.csbj.2019.02.006

Pingaew, R., Prachayasittikul, V., Anuwongcharoen, N., Prachayasittikul, S., Ruchirawat, S., & Prachayasittikul, V. (2018). Synthesis and molecular docking of N,N′-disubstituted thiourea derivatives as novel aromatase inhibitors. Bioorganic Chemistry, 79, 171–178. https://doi.org/10.1016/j.bioorg.2018.05.002

Rao, C. N. R., & Venkataraghavan, R. (1962). The C=S stretching frequency and the “-N-C=S bands†in the infrared. Spectrochimica Acta, 18(4), 541–547. https://doi.org/10.1016/S0371-1951(62)80164-7

Ren, F., Zhong, Y., Mai, X., Liao, Y. J., Liu, C., Feng, L. H., Sun, W., Zen, W. Bin, Liu, W. M., Liu, J., & Jin, N. (2014). Synthesis and Anticancer Evaluation of Benzyloxyurea Derivatives. Chemical and Pharmaceutical Bulletin, 62(9), 898–905. https://doi.org/10.1248/cpb.c14-00305

RI, K. (2019). Hari Kanker Sedunia 2019. Kementerian Kesehatan Republik Indonesia.

Rozano, L., Abdullah Zawawi, M. R., Ahmad, M. A., & Jaganath, I. B. (2017). Computational Analysis of Gynura bicolor Bioactive Compounds as Dipeptidyl Peptidase-IV Inhibitor. Advances in Bioinformatics, 2017, 1–16. https://doi.org/10.1155/2017/5124165

Ruswanto, R., Mardianingrum, R., Lestari, T., Nofianti, T., & Siswandono, S. (2018). 1-(4-Hexylbenzoyl)-3-methylthiourea. Molbank, 2018(3), M1005. https://doi.org/10.3390/M1005

Ruswanto, R., Sarwatiningsih, Y., Pratita, A., Indra, & Dewi, R. (2019). Synthesis and Characterization of Fe(III) Complex with N’- (3-Nitrobenzoyl)Isonicotinohydrazide as an Anti-tuberculosis Candidate. Journal of Physics: Conference Series, 1179, 012136. https://doi.org/10.1088/1742-6596/1179/1/012136

Santos, A. F. M., Macedo, L. J. A., Chaves, M. H., Espinoza-Castañeda, M., Merkoçi, A., Lima, F. das C. A., & Cantanhêde, W. (2015). Hybrid Self-Assembled Materials Constituted by Ferromagnetic Nanoparticles and Tannic Acid: a Theoretical and Experimental Investigation. Journal of the Brazilian Chemical Society. https://doi.org/10.5935/0103-5053.20150322

Saratovskikh, E. A., Psikha, B. L., & Sanina, N. A. (2013). The reaction of the iron thiosulfate-nitrosyl complex with adenosine triphosphoric acid. Natural Science, 05(07), 800–810. https://doi.org/10.4236/ns.2013.57097

Sartori, E., Camy, F., Teulon, J., Camborde, F., Meignen, J., Hertz, F., & Cloarec, A. (1994). Synthesis and analgesic activities of urea derivatives of α-amino-N-pyridyl benzene propanamide. European Journal of Medicinal Chemistry, 29(6), 431–439. https://doi.org/10.1016/0223-5234(94)90070-1

Schwartz, B. D., Skinner-Adams, T. S., Andrews, K. T., Coster, M. J., Edstein, M. D., MacKenzie, D., Charman, S. A., Koltun, M., Blundell, S., Campbell, A., Pouwer, R. H., Quinn, R. J., Beattie, K. D., Healy, P. C., & Davis, R. A. (2015). Synthesis and antimalarial evaluation of amide and urea derivatives based on the thiaplakortone A natural product scaffold. Organic and Biomolecular Chemistry, 13(5), 1558–1570. https://doi.org/10.1039/c4ob01849d

Seth, P. P., Ranken, R., Robinson, D. E., Osgood, S. A., Risen, L. M., Rodgers, E. L., Migawa, M. T., Jefferson, E. A., & Swayze, E. E. (2004). Aryl urea analogs with broad-spectrum antibacterial activity. Bioorganic and Medicinal Chemistry Letters, 14(22), 5569–5572. https://doi.org/10.1016/j.bmcl.2004.08.059

Šimek, M., Grünwaldová, V., & Kratochvíl, B. (2014). Hot-Stage Microscopy for Determination of API Particles in a Formulated Tablet. BioMed Research International, 2014, 1–6. https://doi.org/10.1155/2014/832452

Upadhayaya, R. S., Kulkarni, G. M., Vasireddy, N. R., Vandavasi, J. K., Dixit, S. S., Sharma, V., & Chattopadhyaya, J. (2009). Design, synthesis and biological evaluation of novel triazole, urea and thiourea derivatives of quinoline against Mycobacterium tuberculosis. Bioorganic and Medicinal Chemistry, 17(13), 4681–4692. https://doi.org/10.1016/j.bmc.2009.04.069

Vega-Pérez, J. M., Periñán, I., Argandoña, M., Vega-Holm, M., Palo-Nieto, C., Burgos-Morón, E., López-Lázaro, M., Vargas, C., Nieto, J. J., & Iglesias-Guerra, F. (2012). Isoprenyl-thiourea and urea derivatives as new farnesyl diphosphate analogues: Synthesis and in vitro antimicrobial and cytotoxic activities. European Journal of Medicinal Chemistry, 58, 591–612. https://doi.org/10.1016/j.ejmech.2012.10.042

Wang, X., & Andrews, L. (2006). Infrared Spectra of M(OH) 1,2,3 (M = Mn, Fe, Co, Ni) Molecules in Solid Argon and the Character of First Row Transition Metal Hydroxide Bonding. The Journal of Physical Chemistry A, 110(33), 10035–10045. https://doi.org/10.1021/jp0624698

World Health Organitazion. (2018). Raised cholesterol.

Xu, H., Faber, C., Uchiki, T., Racca, J., & Dealwis, C. (2006). Structures of eukaryotic ribonucleotide reductase I define gemcitabine diphosphate binding and subunit assembly. Proceedings of the National Academy of Sciences, 103(11), 4028–4033. https://doi.org/10.1073/pnas.0600440103

Yamashita, S., Furubayashi, T., Kataoka, M., Sakane, T., Sezaki, H., & Tokuda, H. (2000). Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells. European Journal of Pharmaceutical Sciences, 10(3), 195–204. https://doi.org/10.1016/S0928-0987(00)00076-2

Yang, W., Hu, Y., Yang, Y. S., Zhang, F., Zhang, Y. Bin, Wang, X. L., Tang, J. F., Zhong, W. Q., & Zhu, H. L. (2013). Design, modification and 3D QSAR studies of novel naphthalin-containing pyrazoline derivatives with/without thiourea skeleton as anticancer agents. Bioorganic and Medicinal Chemistry, 21(5), 1050–1063. https://doi.org/10.1016/j.bmc.2013.01.013

Yao, J., Chen, J., He, Z., Sun, W., & Xu, W. (2012). Design, synthesis and biological activities of thiourea containing sorafenib analogs as antitumor agents. Bioorganic and Medicinal Chemistry, 20(9), 2923–2929. https://doi.org/10.1016/j.bmc.2012.03.018

Yee, S. (1997). In vitro permeability across caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man—fact or myth. Pharmaceutical Research, 14(4), 763–766.

Zhao, Y. H., Le, J., Abraham, M. H., Hersey, A., Eddershaw, P. J., Luscombe, C. N., Boutina, D., Beck, G., Sherborne, B., Cooper, I., & Platts, J. A. (2001). Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure–activity relationship (QSAR) with the Abraham descriptors. Journal of Pharmaceutical Sciences, 90(6), 749–784. https://doi.org/10.1002/jps.1031

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Published

2021-03-31

Issue

Vol. 11 No. 1 (2021): Pharmaciana

Section

Analytical Pharmacy and Medicinal Chemistry

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