Synthesis of piperazine-based benzimidazole derivatives as potent urease inhibitors and molecular docking studies
Abstract The development of new bioactive compounds is important for progress in therapeutic research. In the present study, we describe the multistep synthetic approach to develop a library of novel benzimidazole analogs incorporating piperazine rings in order to increase their biological activity....
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Nature Portfolio
2025-08-01
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| Online Access: | https://doi.org/10.1038/s41598-025-14723-4 |
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| author | Delaram Shahriarynejad Navid Dastyafteh Fouzia Naz Meysam Talebi Sajedeh Safapoor Seyedeh Niloufar Ghafouri Homa Azizian Maryam Mohammadi-Khanaposhtani Bagher Larijani Mehdi Asadi Massoud Amanlou Mohammad Mahdavi Khalid Mohammed Khan |
| author_facet | Delaram Shahriarynejad Navid Dastyafteh Fouzia Naz Meysam Talebi Sajedeh Safapoor Seyedeh Niloufar Ghafouri Homa Azizian Maryam Mohammadi-Khanaposhtani Bagher Larijani Mehdi Asadi Massoud Amanlou Mohammad Mahdavi Khalid Mohammed Khan |
| author_sort | Delaram Shahriarynejad |
| collection | DOAJ |
| description | Abstract The development of new bioactive compounds is important for progress in therapeutic research. In the present study, we describe the multistep synthetic approach to develop a library of novel benzimidazole analogs incorporating piperazine rings in order to increase their biological activity. In order to synthesize the desired benzimidazole analogs, the synthesis started with the easily accessible precursors between aniline and chloroacetyl chloride. It proceeded via a series of reactions, such as condensation, cyclization, and N-alkylation. TLC optimized each step, and spectroscopic methods such as CHN, IR, EIMS, 1H-NMR, and 13C-NMR were used to characterize the final products. The urease inhibitory activity of the synthesized compounds was evaluated. It was discovered that almost all compounds were quite effective, even more potent (IC50 = 0.15–12.17 µM) than the standard thiourea (IC50 = 23.11 ± 0.21 µM). The structure-activity relationship (SAR) is also established, which displayed that compound 9 L (IC50 = 0.15 ± 0.09 µM) with -NO2 substitutions at meta position play a major role in urease inhibition and figure out as the most potent analog of the library. These results were further verified by molecular docking analysis, which indicated favorable binding energies and interactions of the compounds with the urease active site. This study not only depicts the importance of multistep synthesis but also the structure-based modification approach to produce new pharmacophores for therapeutic applications. |
| format | Article |
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| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-08-01 |
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| series | Scientific Reports |
| spelling | doaj-art-eb3a71758fb749d4bf599061e10bb79e2025-08-20T03:45:52ZengNature PortfolioScientific Reports2045-23222025-08-0115111610.1038/s41598-025-14723-4Synthesis of piperazine-based benzimidazole derivatives as potent urease inhibitors and molecular docking studiesDelaram Shahriarynejad0Navid Dastyafteh1Fouzia Naz2Meysam Talebi3Sajedeh Safapoor4Seyedeh Niloufar Ghafouri5Homa Azizian6Maryam Mohammadi-Khanaposhtani7Bagher Larijani8Mehdi Asadi9Massoud Amanlou10Mohammad Mahdavi11Khalid Mohammed Khan12Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical SciencesEndocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical SciencesInternational Center for Chemical and Biological Sciences, H. E. J. Research Institute of Chemistry, University of KarachiDepartment of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical SciencesEndocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical SciencesSchool of Chemistry, College of Science, University of TehranDepartment of Medicinal Chemistry, School of Pharmacy, Iran University of Medical SciencesCellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical SciencesEndocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical SciencesDepartment of Medicinal Chemistry, School of Pharmacy, Iran University of Medical SciencesDepartment of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical SciencesEndocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical SciencesInternational Center for Chemical and Biological Sciences, H. E. J. Research Institute of Chemistry, University of KarachiAbstract The development of new bioactive compounds is important for progress in therapeutic research. In the present study, we describe the multistep synthetic approach to develop a library of novel benzimidazole analogs incorporating piperazine rings in order to increase their biological activity. In order to synthesize the desired benzimidazole analogs, the synthesis started with the easily accessible precursors between aniline and chloroacetyl chloride. It proceeded via a series of reactions, such as condensation, cyclization, and N-alkylation. TLC optimized each step, and spectroscopic methods such as CHN, IR, EIMS, 1H-NMR, and 13C-NMR were used to characterize the final products. The urease inhibitory activity of the synthesized compounds was evaluated. It was discovered that almost all compounds were quite effective, even more potent (IC50 = 0.15–12.17 µM) than the standard thiourea (IC50 = 23.11 ± 0.21 µM). The structure-activity relationship (SAR) is also established, which displayed that compound 9 L (IC50 = 0.15 ± 0.09 µM) with -NO2 substitutions at meta position play a major role in urease inhibition and figure out as the most potent analog of the library. These results were further verified by molecular docking analysis, which indicated favorable binding energies and interactions of the compounds with the urease active site. This study not only depicts the importance of multistep synthesis but also the structure-based modification approach to produce new pharmacophores for therapeutic applications.https://doi.org/10.1038/s41598-025-14723-4BenzimidazolePiperazineUrease inhibitionDocking study |
| spellingShingle | Delaram Shahriarynejad Navid Dastyafteh Fouzia Naz Meysam Talebi Sajedeh Safapoor Seyedeh Niloufar Ghafouri Homa Azizian Maryam Mohammadi-Khanaposhtani Bagher Larijani Mehdi Asadi Massoud Amanlou Mohammad Mahdavi Khalid Mohammed Khan Synthesis of piperazine-based benzimidazole derivatives as potent urease inhibitors and molecular docking studies Scientific Reports Benzimidazole Piperazine Urease inhibition Docking study |
| title | Synthesis of piperazine-based benzimidazole derivatives as potent urease inhibitors and molecular docking studies |
| title_full | Synthesis of piperazine-based benzimidazole derivatives as potent urease inhibitors and molecular docking studies |
| title_fullStr | Synthesis of piperazine-based benzimidazole derivatives as potent urease inhibitors and molecular docking studies |
| title_full_unstemmed | Synthesis of piperazine-based benzimidazole derivatives as potent urease inhibitors and molecular docking studies |
| title_short | Synthesis of piperazine-based benzimidazole derivatives as potent urease inhibitors and molecular docking studies |
| title_sort | synthesis of piperazine based benzimidazole derivatives as potent urease inhibitors and molecular docking studies |
| topic | Benzimidazole Piperazine Urease inhibition Docking study |
| url | https://doi.org/10.1038/s41598-025-14723-4 |
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