Antimicrobial Activity and Molecular Docking of Benzoyl-N,N’-dialkylurea against Target Proteins in Microbial Cells
Artikel Sidebar
-
Benzoyl-N,N’-dialkylurea, Antimicrobial activity, Five microbes, Molecular docking
Abstrak
This research aims to evaluate the antimicrobial activity of benzoyl dialkylurea derivatives to meet the global need for new antibiotic lead compounds. Four compounds were tested in vitro against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans by broth dilution method using ciprofloxacin and nystatin as standards. Docking simulations were performed to target essential proteins including DNA gyrase, FabH, RNA polymerase in bacterial cells and DHFR in C. albicans. BDMU, BEU1, BEU2, BEU3 exhibited antibacterial activity while BEU1 and BEU2 showed weak antifungal activity against C. albicans. The BDMU, BEU2, BEU3 considered promising growth inhibition against P. aeruginosa. In silico molecular docking on DNA gyrase from P. aeruginosa (PDB. 6M1S) was proposed as a model for mechanism of action in bacterial cells. The monobenzoyl of dialkylurea containing urea functionality with chloro-substituent at position-2 and 4 on aromatic rings were potential as lead compound to generate new antibacterial agent.
Artikel teks lengkap
Referensi
Z.L. Li, Q. S. Li, H. J. Zhang, Y. Hu, D. Di Zhu, and H. L. Zhu, “Design, synthesis and biological evaluation of urea derivatives from o-hydroxybenzylamines and phenylisocyanate as potential FabH inhibitors,” Bioorganic Med. Chem., vol. 19, no. 15, pp. 4413–4420, 2011, doi: 10.1016/j.bmc.2011.06.049.
Q. Z. Zheng, K. Cheng, X. M. Zhang, K. Liu, Q. C. Jiao, and H. L. Zhu, “Synthesis of some N-alkyl substituted urea derivatives as antibacterial and antifungal agents,” Eur. J. Med. Chem., vol. 45, no. 7, pp. 3207–3212, 2010, doi: 10.1016/j.ejmech.2010.03.027.
P.Umadevi, K.Deepti, I. Srinath, G.Vijayalakshmi, and M.Tarakaramji, “Synthesis and In-Vitro Antibacterial Activity of Some New Urea, Thiourea and Thiosemicarbazide Derivatives,” Int. J. Pharm. Pharm. Sci., vol. 4, no. Suppl. 3, pp. 379–383, 2012.
T. Librowski, M. Kubacka, M. Meusel, S. Scolari, C. E. Müller, and M. Gütschow, “Evaluation of anticonvulsant and analgesic effects of benzyl- and benzhydryl ureides,” Eur. J. Pharmacol., vol. 559, no. 2–3, pp. 138–149, 2007, doi: 10.1016/j.ejphar.2006.12.002.
F. Azam, M. Vijaya Vara Prasad, N. Thangavel, A. Kumar Shrivastava, and G. Mohan, “Structure-Based Design, Synthesis and Molecular Modeling Studies of Thiazolyl Urea Derivatives as Novel Anti-Parkinsonian Agents,” Med. Chem. (Los. Angeles)., vol. 8, no. 6, pp. 1057–1068, 2012, doi: 10.2174/1573406411208061057.
E. El-Sawy, A. Mandour, K. Mahmoud, I. Islam, and H. Abo-Salem, “Synthesis, antimicrobial and anti-cancer activities of some new N-ethyl, N-benzyl and N-benzoyl-3-indolyl heterocycles,” Acta Pharm., vol. 62, no. 2, pp. 157–179, 2012, doi: 10.2478/v10007-012-0020-3.
D. Lokwani, S. Bhandari, R. Pujari, P. Shastri, G. Shelke, and V. Pawar, “Use of Quantitative Structure - Activity Relationship (QSAR) and ADMET prediction studies as screening methods for design of benzyl urea derivatives for anti-cancer activity,” J. Enzyme Inhib. Med. Chem., vol. 26, no. 3, pp. 319–331, 2011, doi: 10.3109/14756366.2010.506437.
É. Petitclerc et al., “Antiangiogenic and antitumoral activity of phenyl-3-(2-chloroethyl)ureas: A class of soft alkylating agents disrupting microtubules that are unaffected by cell adhesion-mediated drug resistance,” Cancer Res., vol. 64, no. 13, pp. 4654–4663, 2004, doi: 10.1158/0008-5472.CAN-03-3715.
C. A. Higley et al., “Acyl CoA:Cholesterol Acyltransferase (ACAT) Inhibitors: Synthesis and Structure-Activity Relationship Studies of a New Series of Trisubstituted Imidazoles,” J. Med. Chem., vol. 37, no. 21, pp. 3511–3522, 1994, doi: 10.1021/jm00047a009.
D. J. Morre et al., “Antitumor sulfonylurea-inhibited NADH oxidase of cultured HeLa cells shed into media,” Biochim. Biophys. Acta, vol. 1280, pp. 197–206, 1996, doi: 10.1016/0005-2736(95)00290-1.
O. Deeb and M. Jawabreh, “Exploring QSARs for Inhibitory Activity of Cyclic Urea and Nonpeptide-Cyclic Cyanoguanidine Derivatives HIV-1 Protease Inhibitors by Artificial Neural Network,” Adv. Chem. Eng. Sci., vol. 02, no. 01, pp. 82–100, 2012, doi: 10.4236/aces.2012.21010.
D. M. Sammond et al., “Discovery of a novel and potent series of dianilinopyrimidineurea and urea isostere inhibitors of VEGFR2 tyrosine kinase,” Bioorganic Med. Chem. Lett., vol. 15, no. 15, pp. 3519–3523, 2005, doi: 10.1016/j.bmcl.2005.05.096.
S. A. Mitchell, M. D. Danca, P. A. Blomgren, J. W. Darrow, and S. Kevin, “Imidazo[1,2-a]pyrazine diaryl ureas: Inhibitors of the receptor tyrosine kinase EphB4,” Bioorganic Med. Chem. Lett., vol. 19, no. 24, p. 6995, 2009, doi: 10.1016/j.bmcl.2009.10.037.
W. Zhan et al., “Design, synthesis and antitumor activities of novel bis-aryl ureas derivatives as Raf kinase inhibitors,” Bioorganic Med. Chem., vol. 20, no. 14, pp. 4323–4329, 2012, doi: 10.1016/j.bmc.2012.05.051.
D. Kopečný et al., “Phenyl- and benzylurea cytokinins as competitive inhibitors of cytokinin oxidase/dehydrogenase: A structural study https://doi.org/10.1016/j.biochi.2010.05.006,” Biochimie, vol. 92, no. 8, pp. 1052–1062, 2010, doi: 10.1016/j.biochi.2010.05.006.
N. W. Diyah, S. Siswandono, and B. T. Purwanto, “Synthesis, Molecular Docking, And Cytotoxic Activity Of N-Ethyl-N- (Ethylcarbamoyl)Benzamide Derivatives Against MCF-7 Cell Line,” Res. J. Pharm. , Biol. Chem. Sci., vol. 8, no. 1S, pp. 164–173, 2017.
N. W. Diyah, J. Ekowati, and Siswandono, “Synthesis and antitumor activity evaluation of N,N’-dibenzoyl-N,N’- Diethylurea against human breast cancer cell line (MCF-7),” Int. J. Pharm. Pharm. Sci., vol. 6, no. 2, pp. 315–318, 2014.
N. W. Diyah, “Synthesis, molecular docking, and antitumor activity of N,N’-Dibenzoyl-N,N’-Dimethylurea against human breast cancer cell line (MCF-7),” in The 1st International Conference on Pharmaceutics & Pharmaceutical Sciences Proceedings, 2014, pp. 203–205, [Online]. Available: http://repository.unair.ac.id/48082/1/Proceeding ICCPS 2014.pdf.
J. J. Champoux, “DNA Topoisomerases: Structure, Function, and Mechanism,” Annu. Rev. Biochem., vol. 70, no. 1, pp. 369–413, 2001, doi: 10.1146/annurev.biochem.70.1.369.
Y. Pommier, E. Leo, H. Zhang, and C. Marchand, “DNA topoisomerases and their poisoning by anticancer and antibacterial drugs,” Chem. Biol., vol. 17, no. 5, pp. 421–433, 2010, doi: 10.1016/j.chembiol.2010.04.012.
K. H. Choi, R. J. Heath, and C. O. Rock, “β-ketoacyl-acyl carrier protein synthase III (FabH) is a determining factor in branched-chain fatty acid biosynthesis,” J. Bacteriol., vol. 182, no. 2, pp. 365–370, 2000, doi: 10.1128/JB.182.2.365-370.2000.
A. Esteves-Souza, K. Pissinate, M. Da Graça Nascimento, N. F. Grynberg, and A. Echevarria, “Synthesis, cytotoxicity, and DNA-topoisomerase inhibitory activity of new asymmetric ureas and thioureas,” Bioorganic Med. Chem., vol. 14, no. 2, pp. 492–499, 2006, doi: 10.1016/j.bmc.2005.08.031.
J. Liu, D. B. Bolstad, A. E. Smith, N. D. Priestley, L. Dennis, and A. C. Anderson, “The crystal structure of Candida glabrata dihydrofolate reductase drives new inhibitor design toward efficacious antifungal agents,” Chem. Biol., vol. 15, no. 9, pp. 990–996, 2008, doi: 10.1016/j.chembiol.2008.07.013.The.
European Committee for Antimicrobial Susceptibility Testing (EUCAST) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), “EUCAST Discussion Document E . Dis 5 . 1 MARCH 2003 Determination of minimum inhibitory concentrations ( MICs ) of antibacterial agents by broth dilution,” Clin. Microbiol. Infect., vol. 9, no. 8, pp. ix–xv, 2003, [Online]. Available: http://dx.doi.org/10.1046/j.1469-0691.2003.00790.x.
S. Khadka et al., “Isolation, speciation and antifungal susceptibility testing of Candida isolates from various clinical specimens at a tertiary care hospital, Nepal,” BMC Res. Notes, vol. 10, no. 1, pp. 1–5, 2017, doi: 10.1186/s13104-017-2547-3.
Departemen Kesehatan Republik Indonesia, Farmakope Indonesia edisi IV, IV. Jakarta, 1995.
J. J. Rojas, V. J. Ochoa, S. A. Ocampo, and J. F. Muñoz, “Screening for antimicrobial activity of ten medicinal plants used in Colombian folkloric medicine: A possible alternative in the treatment of non-nosocomial infections,” BMC Complement. Altern. Med., vol. 6, pp. 1–6, 2006, doi: 10.1186/1472-6882-6-2.
J. M. Andrews, “Determination of minimum inhibitory concentrations,” J. Antimicrob. Chemother., vol. 48, no. Suppl. S1, pp. 5–16, 2001, doi: 10.1093/jac/48.suppl_1.5.
S. Fortin et al., “N-Phenyl-N′-(2-chloroethyl)ureas (CEU) as potential antineoplastic agents. Part 2: Role of ω-hydroxyl group in the covalent binding to β-tubulin,” Bioorganic Med. Chem., vol. 15, no. 3, pp. 1430–1438, 2007, doi: 10.1016/j.bmc.2006.11.005.
N. Saban and M. Bujak, “Hydroxyurea and hydroxamic acid derivatives as antitumor drugs,” Cancer Chemother. Pharmacol., vol. 64, no. 2, pp. 213–221, 2009, doi: 10.1007/s00280-009-0991-z.
A. M. Dar and S. Mir, “Molecular Docking: Approaches, Types, Applications and Basic Challenges,” J. Anal. Bioanal. Tech., vol. 08, no. 02, pp. 8–10, 2017, doi: 10.4172/2155-9872.1000356.
S. K. Burley et al., “RCSB Protein Data Bank: Biological macromolecular structures enabling research and education in fundamental biology, biomedicine, biotechnology and energy,” Nucleic Acids Res., vol. 47, no. D1, pp. D464–D474, 2019, doi: 10.1093/nar/gky1004.
S. Bellon et al., “Crystal Structures of Escherichia coli Topoisomerase IV ParE Subunit (24 and 43 Kilodaltons): A Single Residue Dictates Differences in Novobiocin Potency against Topoisomerase IV and DNA Gyrase,” Antimicrob. Agents Chemother., vol. 48, no. 5, pp. 1856–1864, 2004, doi: 10.1128/AAC.48.5.1856-1864.2004.
B. D. Bax et al., “Type IIA topoisomerase inhibition by a new class of antibacterial agents,” Nature, vol. 466, no. 7309, pp. 935–940, 2010, doi: 10.1038/nature09197.
D. C. McKinney et al., “Antibacterial FabH Inhibitors with Mode of Action Validated in Haemophilus influenzae by in Vitro Resistance Mutation Mapping,” ACS Infect. Dis., vol. 2, no. 7, pp. 456–464, 2016, doi: 10.1021/acsinfecdis.6b00053.
Y. Hu et al., “Discovery of Pyrido[2,3-b]indole Derivatives with Gram-Negative Activity Targeting Both DNA Gyrase and Topoisomerase IV,” J. Med. Chem., vol. 63, no. 17, pp. 9623–9649, 2020, doi: 10.1021/acs.jmedchem.0c00768.
F. J. Enguita, E. Pohl, D. L. Turner, H. Santos, and M. A. Carrondo, “Structural evidence for a proton transfer pathway coupled with haem reduction of cytochrome c″ from Methylophilus methylotrophus,” J. Biol. Inorg. Chem., vol. 11, no. 2, pp. 189–196, 2006, doi: 10.1007/s00775-005-0065-6.
M. Alexeeva, E. Åberg, R. A. Engh, and U. Rothweiler, “The structure of a dual-specificity tyrosine phosphorylation-regulated kinase 1A-PKC412 complex reveals disulfide-bridge formation with the anomalous catalytic loop HRD(HCD) cysteine,” Acta Crystallogr. Sect. D Biol. Crystallogr., vol. 71, no. Pt 5, pp. 1207–1215, 2015, doi: 10.1107/S1399004715005106.
Y. Yuan and J. Wang, “6KVS Staphylococcus aureus FabH with covalent inhibitor Oxa1,” RCSB Protein Data Bank, 2020. https://www.rcsb.org/structure/6KVS.
S. Yavuz and H. Yildirim, “Ferrocene derivatives carrying urea, thiourea, and sulfonamide moieties: Synthesis and evaluation of antibacterial and antifungal activities,” J. Chem., vol. 2013, pp. 1–7, 2013, doi: 10.1155/2013/149693.
Y. G. Shi et al., “Alkyl Ferulate Esters as Multifunctional Food Additives: Antibacterial Activity and Mode of Action against Escherichia coli in Vitro,” J. Agric. Food Chem., vol. 66, no. 45, pp. 12088–12101, 2018, doi: 10.1021/acs.jafc.8b04429.
B. Wu, X. Yang, and M. Yan, “Synthesis and Structure-Activity Relationship Study of Antimicrobial Auranofin against ESKAPE Pathogens,” J. Med. Chem., vol. 62, no. 17, pp. 7751–7768, 2019, doi: 10.1021/acs.jmedc chem.9b00550.
B. D. Palmer et al., “Synthesis and Structure-Activity Relationships for Extended Side Chain Analogues of the Antitubercular Drug (6 S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5 H -imidazo[2,1- b ][1,3]oxazine (PA-824),” J. Med. Chem., vol. 58, no. 7, pp. 3036–3059, 2015, doi: 10.1021/jm501608q.
M. Schübler, B. Sadek, T. Kottke, L. Weizel, and H. Stark, “Synthesis, molecular properties estimations, and dual dopamine D2 and D3 receptor activities of benzothiazole-based ligands,” Front. Chem., vol. 5, no. Sep, pp. 1–19, 2017, doi: 10.3389/fchem.2017.00064.
M. I. Garbi et al., “Cytotoxicity of Vitex trifolia leaf extracts on MCF-7 and Vero cell lines,” J. Sci. Innov. Res., vol. 4, no. 2, pp. 89–93, 2015, [Online]. Available: www.jsirjournal.com.
D. J. Abraham, Burger’s Medicinal Chemistry and Drug Discovery, vol. 1. 2003.
G. Thomas, Medicinal Chemistry - An Introduction: Second Edition. New York: Wiley, 2007.
T. L. Lemke, D. A. Williams, and V. F. Roche, Foye’s principles of medicinal chemistry: Sixth Edition. Philadelphia: Lippincott Williams & Wilkins, 2008.
Qing Zhang, M. Sanner, and A. J. Olson, “Shape Complementarity of Protein-Protein Complexes at Multiple Resolutions,” Proteins, vol. 75, no. 2, pp. 453–467, 2009, doi: 10.1002/prot.22256.
Penulis
Hak Cipta (c) 2024 Nuzul Wahyuning Diyah, Gita Miranda Warsito, Isnaeni, Shabrina Wahyu Hidayati
Artikel ini berlisensiCreative Commons Attribution-ShareAlike 4.0 International License.
Penulis tetap memegang hak atas karyanya dan memberikan hak publikasi pertama kepada jurnal ini yang secara simultan karya tersebut dilisensikan di bawah: Creative Commons Attribution-ShareAlike 4.0 International (CC BY-SA 4.0)