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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Research Article

Inhibitory Efficacy of Thiosemicarbazones for Carbonic Anhydrase II (Bovine and Human) as a Target of Calcification and Tumorigenicity

Author(s): Majid Khan, Sobia Ahsan Halim, Zahid Shafiq, Muhammad Islam, Muhammad Tariq Shehzad, Aliya Ibrar, Farhan A. Khan, Najat Marraiki, Jalal Uddin, Ajmal Khan* and Ahmed Al-Harrasi*

Volume 28, Issue 36, 2022

Published on: 25 August, 2022

Page: [3010 - 3022] Pages: 13

DOI: 10.2174/1381612828666220729105849

Price: $65

Abstract

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.

Keywords: Thiosemicarbazone, carbonic anhydrase II, bovine, human, kinetics studies, molecular docking.

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