Quinazolinones as Competitive Inhibitors of Carbonic Anhydrase-II (Human and Bovine): Synthesis, in-vitro, in-silico, Selectivity, and Kinetics Studies
Carbonic anhydrase-II (CA-II) is associated with glaucoma, malignant brain tumors, and renal, gastric, and pancreatic carcinomas and is mainly involved in the regulation of the bicarbonate concentration in the eyes. CA-II inhibitors can be used to reduce the intraocular pressure usually associated w...
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Frontiers Media S.A.
2020-12-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2020.598095/full |
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| author | Ajmal Khan Majid Khan Majid Khan Sobia Ahsan Halim Zulfiqar Ali Khan Zahid Shafiq Ahmed Al-Harrasi |
| author_facet | Ajmal Khan Majid Khan Majid Khan Sobia Ahsan Halim Zulfiqar Ali Khan Zahid Shafiq Ahmed Al-Harrasi |
| author_sort | Ajmal Khan |
| collection | DOAJ |
| description | Carbonic anhydrase-II (CA-II) is associated with glaucoma, malignant brain tumors, and renal, gastric, and pancreatic carcinomas and is mainly involved in the regulation of the bicarbonate concentration in the eyes. CA-II inhibitors can be used to reduce the intraocular pressure usually associated with glaucoma. In search of potent CA-II inhibitors, a series of quinazolinones derivatives (4a-p) were synthesized and characterized by IR and NMR spectroscopy. The inhibitory potential of all the compounds was evaluated against bovine carbonic anhydrase-II (bCA-II) and human carbonic anhydrase-II (hCA-II), and compounds displayed moderate to significant inhibition with IC50 values of 8.9–67.3 and 14.0–59.6 μM, respectively. A preliminary structure-activity relationship suggested that the presence of a nitro group on the phenyl ring at R position contributes significantly to the overall activity. Kinetics studies of the most active inhibitor, 4d, against both bCA-II and hCA-II were performed to investigate the mode of inhibition and to determine the inhibition constants (Ki). According to the kinetics results, 4d is a competitive inhibitor of bCA-II and hCA-II with Ki values of 13.0 ± 0.013 and 14.25 ± 0.017 μM, respectively. However, the selectivity index reflects that the compounds 4g and 4o are more selective for hCA-II. The binding mode of these compounds within the active sites of bCA-II and hCA-II was investigated by structure-based molecular docking. The docking results are in complete agreement with the experimental findings. |
| first_indexed | 2024-12-16T13:11:32Z |
| format | Article |
| id | doaj.art-705c67b7184c48d582829de581f957e9 |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-12-16T13:11:32Z |
| publishDate | 2020-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-705c67b7184c48d582829de581f957e92022-12-21T22:30:36ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462020-12-01810.3389/fchem.2020.598095598095Quinazolinones as Competitive Inhibitors of Carbonic Anhydrase-II (Human and Bovine): Synthesis, in-vitro, in-silico, Selectivity, and Kinetics StudiesAjmal Khan0Majid Khan1Majid Khan2Sobia Ahsan Halim3Zulfiqar Ali Khan4Zahid Shafiq5Ahmed Al-Harrasi6Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, OmanNatural and Medical Sciences Research Center, University of Nizwa, Nizwa, OmanInternational Center for Chemical and Biological Sciences, H. E. J. Research Institute of Chemistry, University of Karachi, Karachi, PakistanNatural and Medical Sciences Research Center, University of Nizwa, Nizwa, OmanDepartment of Chemistry, Government College University, Faisalabad, PakistanInstitute of Chemical Sciences, Bahauddin Zakariya University, Multan, PakistanNatural and Medical Sciences Research Center, University of Nizwa, Nizwa, OmanCarbonic anhydrase-II (CA-II) is associated with glaucoma, malignant brain tumors, and renal, gastric, and pancreatic carcinomas and is mainly involved in the regulation of the bicarbonate concentration in the eyes. CA-II inhibitors can be used to reduce the intraocular pressure usually associated with glaucoma. In search of potent CA-II inhibitors, a series of quinazolinones derivatives (4a-p) were synthesized and characterized by IR and NMR spectroscopy. The inhibitory potential of all the compounds was evaluated against bovine carbonic anhydrase-II (bCA-II) and human carbonic anhydrase-II (hCA-II), and compounds displayed moderate to significant inhibition with IC50 values of 8.9–67.3 and 14.0–59.6 μM, respectively. A preliminary structure-activity relationship suggested that the presence of a nitro group on the phenyl ring at R position contributes significantly to the overall activity. Kinetics studies of the most active inhibitor, 4d, against both bCA-II and hCA-II were performed to investigate the mode of inhibition and to determine the inhibition constants (Ki). According to the kinetics results, 4d is a competitive inhibitor of bCA-II and hCA-II with Ki values of 13.0 ± 0.013 and 14.25 ± 0.017 μM, respectively. However, the selectivity index reflects that the compounds 4g and 4o are more selective for hCA-II. The binding mode of these compounds within the active sites of bCA-II and hCA-II was investigated by structure-based molecular docking. The docking results are in complete agreement with the experimental findings.https://www.frontiersin.org/articles/10.3389/fchem.2020.598095/fullquinazolinonesbovine carbonic anhydrase-IIhuman carbonic anhydrase-IIstructure-activity relationshipkineticsmolecular docking |
| spellingShingle | Ajmal Khan Majid Khan Majid Khan Sobia Ahsan Halim Zulfiqar Ali Khan Zahid Shafiq Ahmed Al-Harrasi Quinazolinones as Competitive Inhibitors of Carbonic Anhydrase-II (Human and Bovine): Synthesis, in-vitro, in-silico, Selectivity, and Kinetics Studies Frontiers in Chemistry quinazolinones bovine carbonic anhydrase-II human carbonic anhydrase-II structure-activity relationship kinetics molecular docking |
| title | Quinazolinones as Competitive Inhibitors of Carbonic Anhydrase-II (Human and Bovine): Synthesis, in-vitro, in-silico, Selectivity, and Kinetics Studies |
| title_full | Quinazolinones as Competitive Inhibitors of Carbonic Anhydrase-II (Human and Bovine): Synthesis, in-vitro, in-silico, Selectivity, and Kinetics Studies |
| title_fullStr | Quinazolinones as Competitive Inhibitors of Carbonic Anhydrase-II (Human and Bovine): Synthesis, in-vitro, in-silico, Selectivity, and Kinetics Studies |
| title_full_unstemmed | Quinazolinones as Competitive Inhibitors of Carbonic Anhydrase-II (Human and Bovine): Synthesis, in-vitro, in-silico, Selectivity, and Kinetics Studies |
| title_short | Quinazolinones as Competitive Inhibitors of Carbonic Anhydrase-II (Human and Bovine): Synthesis, in-vitro, in-silico, Selectivity, and Kinetics Studies |
| title_sort | quinazolinones as competitive inhibitors of carbonic anhydrase ii human and bovine synthesis in vitro in silico selectivity and kinetics studies |
| topic | quinazolinones bovine carbonic anhydrase-II human carbonic anhydrase-II structure-activity relationship kinetics molecular docking |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2020.598095/full |
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