Inhibitory Efficacy of Thiosemicarbazones for Carbonic Anhydrase II (Bovine and Human) as a Target of Calcification and Tumorigenicity
Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net..
BACKGROUND: Carbonic anhydrase II (CA-II) is associated with calcification, tumorigenicity, epilepsy, osteoporosis, and several other physiological or pathological processes. CA-II inhibitors can be used to reduce the intraocular pressure usually associated with glaucoma.
OBJECTIVE: In search for potent CA-II inhibitors, a series of thiosemicarbazone derivatives (3a-u) was synthesized.
METHODS: This series was evaluated against bovine and human carbonic anhydrase II (bCA-II and hCA-II) and their docking studies were carried out.
RESULTS: In the preliminary screening, most of the compounds exhibited significant inhibition of bCA-II and hCA-II. The predictive structure-activity relationship suggested that the thiosemicarbazide moiety plays a key role in the inhibition of enzyme activity and substitution at R position and has a remarkable contribution to the overall activity. The kinetic studies of the most active inhibitors of bCA-II (3d, 3e, 3l, 3f, and 3p) and hCA-II (3g) were performed against bCA-II and hCA-II, respectively to investigate their mode of inhibition and dissociation constants (Ki).
CONCLUSION: Subsequently, (3e, 3f, 3l and 3p) were identified as competitive inhibitors of bCA-II with Ki values of 5.02-14.70 μM, while (3d) as a noncompetitive inhibitor of bCA-II (Ki = 2.5 ± 0.015 μM), however, (3g) demonstrated competitive inhibition of hCA-II with a Ki value of 5.95 ± 0.002 μM. The selectivity index reflects that compound (3g) is more selective for hCA-II. The binding modes of these compounds with bCA-II and hCA-II were investigated by structure-based molecular docking, and the docking results are in complete agreement with the experimental findings.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:28 |
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| Enthalten in: |
Current pharmaceutical design - 28(2022), 36 vom: 21., Seite 3010-3022 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Khan, Majid [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.11.2022 Date Revised 15.12.2022 published: Print Citation Status MEDLINE |
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| doi: |
10.2174/1381612828666220729105849 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM344289761 |
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| 245 | 1 | 0 | |a Inhibitory Efficacy of Thiosemicarbazones for Carbonic Anhydrase II (Bovine and Human) as a Target of Calcification and Tumorigenicity |
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| 500 | |a Date Revised 15.12.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net. | ||
| 520 | |a BACKGROUND: Carbonic anhydrase II (CA-II) is associated with calcification, tumorigenicity, epilepsy, osteoporosis, and several other physiological or pathological processes. CA-II inhibitors can be used to reduce the intraocular pressure usually associated with glaucoma | ||
| 520 | |a OBJECTIVE: In search for potent CA-II inhibitors, a series of thiosemicarbazone derivatives (3a-u) was synthesized | ||
| 520 | |a METHODS: This series was evaluated against bovine and human carbonic anhydrase II (bCA-II and hCA-II) and their docking studies were carried out | ||
| 520 | |a RESULTS: In the preliminary screening, most of the compounds exhibited significant inhibition of bCA-II and hCA-II. The predictive structure-activity relationship suggested that the thiosemicarbazide moiety plays a key role in the inhibition of enzyme activity and substitution at R position and has a remarkable contribution to the overall activity. The kinetic studies of the most active inhibitors of bCA-II (3d, 3e, 3l, 3f, and 3p) and hCA-II (3g) were performed against bCA-II and hCA-II, respectively to investigate their mode of inhibition and dissociation constants (Ki) | ||
| 520 | |a CONCLUSION: Subsequently, (3e, 3f, 3l and 3p) were identified as competitive inhibitors of bCA-II with Ki values of 5.02-14.70 μM, while (3d) as a noncompetitive inhibitor of bCA-II (Ki = 2.5 ± 0.015 μM), however, (3g) demonstrated competitive inhibition of hCA-II with a Ki value of 5.95 ± 0.002 μM. The selectivity index reflects that compound (3g) is more selective for hCA-II. The binding modes of these compounds with bCA-II and hCA-II were investigated by structure-based molecular docking, and the docking results are in complete agreement with the experimental findings | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Thiosemicarbazone | |
| 650 | 4 | |a bovine | |
| 650 | 4 | |a carbonic anhydrase II | |
| 650 | 4 | |a human | |
| 650 | 4 | |a kinetics studies | |
| 650 | 4 | |a molecular docking | |
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| 650 | 7 | |a EC 4.2.1.- |2 NLM | |
| 650 | 7 | |a Thiosemicarbazones |2 NLM | |
| 650 | 7 | |a Carbonic Anhydrase Inhibitors |2 NLM | |
| 700 | 1 | |a Halim, Sobia Ahsan |e verfasserin |4 aut | |
| 700 | 1 | |a Shafiq, Zahid |e verfasserin |4 aut | |
| 700 | 1 | |a Islam, Muhammad |e verfasserin |4 aut | |
| 700 | 1 | |a Shehzad, Muhammad Tariq |e verfasserin |4 aut | |
| 700 | 1 | |a Ibrar, Aliya |e verfasserin |4 aut | |
| 700 | 1 | |a Khan, Farhan A |e verfasserin |4 aut | |
| 700 | 1 | |a Marraiki, Najat |e verfasserin |4 aut | |
| 700 | 1 | |a Uddin, Jalal |e verfasserin |4 aut | |
| 700 | 1 | |a Khan, Ajmal |e verfasserin |4 aut | |
| 700 | 1 | |a Al-Harrasi, Ahmed |e verfasserin |4 aut | |
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