Novel Coumarin Derivatives as Potential Urease Inhibitors for Kidney Stone Prevention and Antiulcer Therapy: From Synthesis to In Vivo Evaluation
The presence of ammonium ions in urine, along with basic pH in the presence of urease-producing bacteria, promotes the production of struvite stones. This causes renal malfunction, which is manifested by symptoms such as fever, nausea, vomiting, and blood in the urine. The involvement of urease in s...
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MDPI AG
2023-11-01
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| Series: | Pharmaceuticals |
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| author | Kiran Shahzadi Syed Majid Bukhari Asma Zaidi Tanveer A. Wani Muhammad Saeed Jan Seema Zargar Umer Rashid Umar Farooq Aneela Khushal Sara Khan |
| author_facet | Kiran Shahzadi Syed Majid Bukhari Asma Zaidi Tanveer A. Wani Muhammad Saeed Jan Seema Zargar Umer Rashid Umar Farooq Aneela Khushal Sara Khan |
| author_sort | Kiran Shahzadi |
| collection | DOAJ |
| description | The presence of ammonium ions in urine, along with basic pH in the presence of urease-producing bacteria, promotes the production of struvite stones. This causes renal malfunction, which is manifested by symptoms such as fever, nausea, vomiting, and blood in the urine. The involvement of urease in stone formation makes it a good target for finding urease enzyme inhibitors, which have the potential to be developed as lead drugs against kidney stones in the future. The documented ethnopharmacology of coumarin 2-one against bacterial, fungal and viral strains encouraged us to synthesize new derivatives of coumarins by reacting aromatic aldehydes with 4-aminocoumarin. The synthesized compounds (<b>2a</b> to <b>11a</b>) were evaluated for their antimicrobial, in vitro, and in silico properties against the urease enzyme. The study also covers in vivo determination of the synthesized compounds with respect to different types of induced ulcers. The molecular docking study along with extended MD simulations (100 ns each) and MMPBSA study confirmed the potential inhibitory candidates as evident from computed ∆G<sub>bind</sub> (<b>3a</b> = −11.62 and <b>5a</b> = −12.08 Kcal/mol) against the urease enzyme. The in silico analyses were augmented by an enzymatic assay, which revealed that compounds <b>3a</b> and <b>5a</b> had strong inhibitory action, with IC<sub>50</sub> of 0.412 µM (64.0% inhibition) and 0.322 µM (77.7% inhibition), respectively, compared to standard (Thiourea) with 82% inhibition at 0.14 µM. Moreover, the most active compound, <b>5a</b>, was further tested in vivo for antiulcer activity by different types of induced ulcers, including pyloric ligation-, ethanol-, aspirin-, and histamine-induced ulcers. Compound <b>5a</b> effectively reduced gastric acidity, lipid peroxidation, and ulceration in a rat model while also inhibiting gastric ATPase activity, which makes it a promising candidate for ulcer treatment. As a result of the current research, <b>3a</b> and <b>5a</b> may be used as new molecules for developing potent urease inhibitors. Additionally, the compound <b>3a</b> showed antibacterial activity against <i>Staphylococcus aureus</i> and <i>Salmonella typhimurium</i>, with zones of inhibition of 41 ± 0.9 mm and 35 ± 0.9 mm, respectively. Compound <b>7a</b> showed antibacterial activity against <i>Staphylococcus aureus</i> and <i>Salmonella typhimurium</i>, with zones of inhibition of 30 ± 0.8 mm and 42 ± 0.8 mm, respectively. These results prove that the synthesized compounds also possess good antibacterial potential against Gram-positive and Gram-negative bacterial strains. |
| first_indexed | 2024-03-09T16:32:45Z |
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| language | English |
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| spelling | doaj.art-d90adda5ea78470190791b79f70f15a82023-11-24T15:00:13ZengMDPI AGPharmaceuticals1424-82472023-11-011611155210.3390/ph16111552Novel Coumarin Derivatives as Potential Urease Inhibitors for Kidney Stone Prevention and Antiulcer Therapy: From Synthesis to In Vivo EvaluationKiran Shahzadi0Syed Majid Bukhari1Asma Zaidi2Tanveer A. Wani3Muhammad Saeed Jan4Seema Zargar5Umer Rashid6Umar Farooq7Aneela Khushal8Sara Khan9Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, KPK, PakistanDepartment of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, KPK, PakistanDepartment of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, KPK, PakistanDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi ArabiaDepartment of Pharmacy, The Professional Institute of Health Sciences, Mardan 23200, KPK, PakistanDepartment of Biochemistry, College of Science, King Saud University, P.O. Box 22452, Riyadh 11451, Saudi ArabiaDepartment of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, KPK, PakistanDepartment of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, KPK, PakistanDepartment of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, KPK, PakistanDepartment of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, KPK, PakistanThe presence of ammonium ions in urine, along with basic pH in the presence of urease-producing bacteria, promotes the production of struvite stones. This causes renal malfunction, which is manifested by symptoms such as fever, nausea, vomiting, and blood in the urine. The involvement of urease in stone formation makes it a good target for finding urease enzyme inhibitors, which have the potential to be developed as lead drugs against kidney stones in the future. The documented ethnopharmacology of coumarin 2-one against bacterial, fungal and viral strains encouraged us to synthesize new derivatives of coumarins by reacting aromatic aldehydes with 4-aminocoumarin. The synthesized compounds (<b>2a</b> to <b>11a</b>) were evaluated for their antimicrobial, in vitro, and in silico properties against the urease enzyme. The study also covers in vivo determination of the synthesized compounds with respect to different types of induced ulcers. The molecular docking study along with extended MD simulations (100 ns each) and MMPBSA study confirmed the potential inhibitory candidates as evident from computed ∆G<sub>bind</sub> (<b>3a</b> = −11.62 and <b>5a</b> = −12.08 Kcal/mol) against the urease enzyme. The in silico analyses were augmented by an enzymatic assay, which revealed that compounds <b>3a</b> and <b>5a</b> had strong inhibitory action, with IC<sub>50</sub> of 0.412 µM (64.0% inhibition) and 0.322 µM (77.7% inhibition), respectively, compared to standard (Thiourea) with 82% inhibition at 0.14 µM. Moreover, the most active compound, <b>5a</b>, was further tested in vivo for antiulcer activity by different types of induced ulcers, including pyloric ligation-, ethanol-, aspirin-, and histamine-induced ulcers. Compound <b>5a</b> effectively reduced gastric acidity, lipid peroxidation, and ulceration in a rat model while also inhibiting gastric ATPase activity, which makes it a promising candidate for ulcer treatment. As a result of the current research, <b>3a</b> and <b>5a</b> may be used as new molecules for developing potent urease inhibitors. Additionally, the compound <b>3a</b> showed antibacterial activity against <i>Staphylococcus aureus</i> and <i>Salmonella typhimurium</i>, with zones of inhibition of 41 ± 0.9 mm and 35 ± 0.9 mm, respectively. Compound <b>7a</b> showed antibacterial activity against <i>Staphylococcus aureus</i> and <i>Salmonella typhimurium</i>, with zones of inhibition of 30 ± 0.8 mm and 42 ± 0.8 mm, respectively. These results prove that the synthesized compounds also possess good antibacterial potential against Gram-positive and Gram-negative bacterial strains.https://www.mdpi.com/1424-8247/16/11/15524-aminocoumarinSchiff basesurease inhibitionmolecular dockingantibacterial activityMD simulation |
| spellingShingle | Kiran Shahzadi Syed Majid Bukhari Asma Zaidi Tanveer A. Wani Muhammad Saeed Jan Seema Zargar Umer Rashid Umar Farooq Aneela Khushal Sara Khan Novel Coumarin Derivatives as Potential Urease Inhibitors for Kidney Stone Prevention and Antiulcer Therapy: From Synthesis to In Vivo Evaluation Pharmaceuticals 4-aminocoumarin Schiff bases urease inhibition molecular docking antibacterial activity MD simulation |
| title | Novel Coumarin Derivatives as Potential Urease Inhibitors for Kidney Stone Prevention and Antiulcer Therapy: From Synthesis to In Vivo Evaluation |
| title_full | Novel Coumarin Derivatives as Potential Urease Inhibitors for Kidney Stone Prevention and Antiulcer Therapy: From Synthesis to In Vivo Evaluation |
| title_fullStr | Novel Coumarin Derivatives as Potential Urease Inhibitors for Kidney Stone Prevention and Antiulcer Therapy: From Synthesis to In Vivo Evaluation |
| title_full_unstemmed | Novel Coumarin Derivatives as Potential Urease Inhibitors for Kidney Stone Prevention and Antiulcer Therapy: From Synthesis to In Vivo Evaluation |
| title_short | Novel Coumarin Derivatives as Potential Urease Inhibitors for Kidney Stone Prevention and Antiulcer Therapy: From Synthesis to In Vivo Evaluation |
| title_sort | novel coumarin derivatives as potential urease inhibitors for kidney stone prevention and antiulcer therapy from synthesis to in vivo evaluation |
| topic | 4-aminocoumarin Schiff bases urease inhibition molecular docking antibacterial activity MD simulation |
| url | https://www.mdpi.com/1424-8247/16/11/1552 |
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