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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Novel 5-fluoro-6-(4-(2-fluorophenyl)piperazin-1-yl)-2-(4-(4-methylpiperazin- 1-yl)phenyl)-1H-benzo[d]imidazole Derivatives as Promising Urease Inhibitors

Author(s): Ebrahim Saeedian Moghadam, Abdullah Mohammed Al-Sadi, Meysam Talebi, Massoud Amanlou, Raphael Stoll, Mohsen Amini* and Raid Abdel-Jalil*

Volume 21, Issue 2, 2024

Published on: 21 September, 2022

Page: [297 - 304] Pages: 8

DOI: 10.2174/1570180819666220811145303

Price: $65

Abstract

Background: Highly pathogenic bacteria colonize and maintain themselves with the aid of an enzyme called urease. Consequently, inhibiting urease enzymes can be a promising method for preventing ureolytic bacterial infections.

Objective: This study aimed at synthesizing and screening a novel series of benzimidazole derivatives..

Methods: Nine novel benzimidazole derivatives 10α-Ɣ were synthesized and isolated. Their structures were elucidated by 1H-NMR and IR spectroscopic techniques besides HRMS. The urease inhibition activity of these compounds was evaluated using the standard urease enzyme inhibition kit. An MTT assay was performed on the NIH-3T3 cell line to investigate the cytotoxicity profile.

Results: All benzimidazoles 10α-Ɣ exhibited higher urease inhibition activity (3.06–4.40 μM) than the reference standards thiourea and hydroxyurea (IC50: 22 and 100 μM, respectively). 10Ɣ-1 and 10α-1 exhibited the best activity with the IC50 values of 3.06 and 3.13 μM, respectively. Investigation of the cytotoxicity profile of the target compound showed that all 10α-Ɣ have IC50 values higher than 50 μM on the tested cell line.

Conclusion: The results showed that synthesized benzimidazole derivatives could be highly effective as urease inhibitors.

Keywords: Benzimidazole, drug design, helicobacter pylori, heterocyclic chemistry, synthesis, urease inhibitor.

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[1]
Kahveci, B. Menteşe, E.; Özil, M.; Ülker, S.; Ertürk, M. An efficient synthesis of benzimidazoles via a microwave technique and evaluation of their biological activities. Monatsh. Chem., 2013, 144(7), 993-1001.
[http://dx.doi.org/10.1007/s00706-012-0916-0]
[2]
Menteşe, E.; Ülker, S.; Kahveci, B. Synthesis and study of α-glucosidase inhibitory, antimicrobial and antioxidant activities of some benzimidazole derivatives containing triazole, thiadiazole, oxadiazole, and morpholine rings. Chem. Heterocycl. Compd., 2015, 50(12), 1671-1682.
[http://dx.doi.org/10.1007/s10593-015-1637-1]
[3]
Yılmaz, F.; Mentese, E.; Baltas, N. Synthesis and antioxidant evaluation of some novel benzimidazole derivatives containing a triazole nucleus. Lett. Drug Des. Discov., 2017, 14(2), 201-208.
[http://dx.doi.org/10.2174/1570180813666160609082633]
[4]
Eldebss, T.M.; Farag, A.M.; Abdulla, M.M.; Arafa, R.K. Novel Benzo [d] imidazole-based heterocycles as broad spectrum anti-viral agents: Design, synthesis and exploration of molecular basis of action. Mini Rev. Med. Chem., 2016, 16(1), 67-83.
[http://dx.doi.org/10.2174/138955751601151029115533] [PMID: 26527409]
[5]
Stuchlíková, L.; Jirásko, R.; Skálová, L.; Pavlík, F.; Szotáková, B. Holčapek, M.; Vaněk, T.; Podlipná, R. Metabolic pathways of benzimidazole anthelmintics in harebell (Campanula rotundifolia). Chemosphere, 2016, 157, 10-17.
[http://dx.doi.org/10.1016/j.chemosphere.2016.05.015] [PMID: 27208642]
[6]
Menteşe, E.; Yılmaz, F.; Emirik, M.; Ülker, S.; Kahveci, B. Synthesis, molecular docking and biological evaluation of some benzimidazole derivatives as potent pancreatic lipase inhibitors. Bioorg. Chem., 2018, 76, 478-486.
[http://dx.doi.org/10.1016/j.bioorg.2017.12.023] [PMID: 29306066]
[7]
Velík, J.; Baliharová, V.; Fink-Gremmels, J.; Bull, S.; Lamka, J.; Skálová, L. Benzimidazole drugs and modulation of biotransformation enzymes. Res. Vet. Sci., 2004, 76(2), 95-108.
[http://dx.doi.org/10.1016/j.rvsc.2003.08.005] [PMID: 14672851]
[8]
Gaba, M.; Mohan, C. Development of drugs based on imidazole and benzimidazole bioactive heterocycles: Recent advances and future directions. Med. Chem. Res., 2016, 25(2), 173-210.
[http://dx.doi.org/10.1007/s00044-015-1495-5]
[9]
Barker, H.A.; Smyth, R.D.; Weissbach, H.; Toohey, J.I.; Ladd, J.N.; Volcani, B.E. Isolation and properties of crystalline cobamide coenzymes containing benzimidazole or 5, 6-dimethylbenzimidazole. J. Biol. Chem., 1960, 235(2), 480-488.
[http://dx.doi.org/10.1016/S0021-9258(18)69550-X] [PMID: 13796809]
[10]
Kumar, B.V.S.; Vaidya, S.D.; Kumar, R.V.; Bhirud, S.B.; Mane, R.B. Synthesis and anti-bacterial activity of some novel 2-(6-fluorochroman-2-yl)-1-alkyl/acyl/aroyl-1H-benzimidazoles. Eur. J. Med. Chem., 2006, 41(5), 599-604.
[http://dx.doi.org/10.1016/j.ejmech.2006.01.006] [PMID: 16527375]
[11]
Menteşe, E.; Bektaş H.; Sokmen, B.B.; Emirik, M.; Çakır, D.; Kahveci, B. Synthesis and molecular docking study of some 5,6-dichloro-2-cyclopropyl-1H-benzimidazole derivatives bearing triazole, oxadiazole, and imine functionalities as potent inhibitors of urease. Bioorg. Med. Chem. Lett., 2017, 27(13), 3014-3018.
[http://dx.doi.org/10.1016/j.bmcl.2017.05.019] [PMID: 28526368]
[12]
Arshad, T.; Khan, K.M.; Rasool, N.; Salar, U.; Hussain, S.; Asghar, H.; Ashraf, M.; Wadood, A.; Riaz, M.; Perveen, S.; Taha, M.; Ismail, N.H. 5-Bromo-2-aryl benzimidazole derivatives as non-cytotoxic potential dual inhibitors of α-glucosidase and urease enzymes. Bioorg. Chem., 2017, 72, 21-31.
[http://dx.doi.org/10.1016/j.bioorg.2017.03.007] [PMID: 28346872]
[13]
Aman, H.; Rashid, N.; Ashraf, Z.; Bibi, A.; Chen, H.T.; Sathishkumar, N. Synthesis, density functional theory (DFT) studies and urease inhibition activity of chiral benzimidazoles. Heliyon, 2020, 6(10), e05187.
[http://dx.doi.org/10.1016/j.heliyon.2020.e05187] [PMID: 33088954]
[14]
Zaman, K.; Rahim, F.; Taha, M.; Ullah, H.; Wadood, A.; Nawaz, M.; Khan, F.; Wahab, Z.; Shah, S.A.A.; Rehman, A.U.; Kawde, A.N.; Gollapalli, M. Synthesis, in vitro urease inhibitory potential and molecular docking study of Benzimidazole analogues. Bioorg. Chem., 2019, 89, 103024.
[http://dx.doi.org/10.1016/j.bioorg.2019.103024] [PMID: 31176853]
[15]
Menteşe, E.; Emirik, M.; Sökmen, B.B. Design, molecular docking and synthesis of novel 5,6-dichloro-2-methyl-1H-benzimidazole derivatives as potential urease enzyme inhibitors. Bioorg. Chem., 2019, 86, 151-158.
[http://dx.doi.org/10.1016/j.bioorg.2019.01.061] [PMID: 30710848]
[16]
Arshia; Begum, F.; Almandil, N.B.; Lodhi, M.A.; Khan, K.M.; Hameed, A.; Perveen, S. Synthesis and urease inhibitory potential of benzophenone sulfonamide hybrid in vitro and in silico. Bioorg. Med. Chem., 2019, 27(6), 1009-1022.
[http://dx.doi.org/10.1016/j.bmc.2019.01.043] [PMID: 30738655]
[17]
Kazmi, M.; Khan, I.; Khan, A.; Halim, S.A.; Saeed, A.; Mehsud, S.; Al-Harrasi, A.; Ibrar, A. Developing new hybrid scaffold for urease inhibition based on carbazole-chalcone conjugates: Synthesis, assessment of therapeutic potential and computational docking analysis. Bioorg. Med. Chem., 2019, 27(22), 115123.
[http://dx.doi.org/10.1016/j.bmc.2019.115123] [PMID: 31623971]
[18]
Abdulwahab, H.G.; Harras, M.F.; El Menofy, N.G.; Hegab, A.M.; Essa, B.M.; Selim, A.A.; Sakr, T.M.; El-Zahabi, H.S.A. Novel thiobarbiturates as potent urease inhibitors with potential antibacterial activity: Design, synthesis, radiolabeling and biodistribution study. Bioorg. Med. Chem., 2020, 28(23), 115759.
[http://dx.doi.org/10.1016/j.bmc.2020.115759] [PMID: 32992246]
[19]
Mustafa, M.; Nazef, M.Z.; El-Abadla, N.S. Dioxides. Part I. 2-(N-2-Hydroxyalkylcarba-Moyl) derivatives. Heterocycles, 1995, 41(10), 2203.
[http://dx.doi.org/10.3987/COM-95-7128]
[20]
Abdel‐Jalil, R.J.; Voelter, W. Synthesis of new 2‐ferrocenyl‐5‐ fluoro‐6‐(4‐substituted‐1‐piperazinyl)‐1H‐benzimidazoles of potential biological interest J. Heterocycl. Chem., 2005, 42(1), 67-71.
[http://dx.doi.org/10.1002/jhet.5570420109]
[21]
Saeedian Moghadam, E.; Mohammed Al-Sadi, A.; Talebi, M.; Amanlou, M.; Amini, M.; Abdel-Jalil, R. Design, synthesis, and bioactivity investigation of novel benzimidazole derivatives as potent urease inhibitors. Synth. Commun., 2022, 52, 106-116.
[http://dx.doi.org/10.1080/00397911.2021.2001661]
[22]
Talebi, M.; Hamidian, E.; Niasari-Naslaji, F.; Rahmani, S.; Hosseini, F.S.; Boumi, S.; Montazer, M.N.; Asadi, M.; Amanlou, M. Synthesis, molecular docking, and biological evaluation of nitroimidazole derivatives as potent urease inhibitors. Med. Chem. Res., 2021, 30(6), 1220-1229.
[http://dx.doi.org/10.1007/s00044-021-02727-4]
[23]
Saravani, F.; Moghadam, E.S.; Salehabadi, H.; Ostad, S.; Hamedani, M.P.; Amanlou, M.; Faramarzi, M.A.; Amini, M. Synthesis, anti-proliferative evaluation, and molecular docking studies of 3-(alkylthio)-5, 6-diaryl-1, 2, 4-triazines as tubulin polymerization inhibitors. Lett. Drug Des. Discov., 2019, 16(11), 1194-1201.
[http://dx.doi.org/10.2174/1570180815666180727114216]
[24]
Saeedian Moghadam, E.; Saravani, F.; Ostad, S.; Tavajohi, S.; Hamedani, M.P.; Amini, M. Design, synthesis and cytotoxicity evaluation of indibulin analogs. Heterocycl. Commun., 2018, 24(4), 211-217.
[http://dx.doi.org/10.1515/hc-2018-0016]

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