Khan Majid, Halim Sobia Ahsan, Shafiq Zahid, Islam Muhammad, Shehzad Muhammad Tariq, Ibrar Aliya, Khan Farhan A, Marraiki Najat, Uddin Jalal, Khan Ajmal, Al-Harrasi Ahmed
Natural and Medical Sciences Research Center, University of Nizwa, PO Box 33, 616 Birkat Al Mauz, Nizwa, Oman.
International Center for Chemical and Biological Sciences, H.E.J. Research Institute of Chemistry, University of Karachi, Karachi-75270, Pakistan.
Curr Pharm Des. 2022;28(36):3010-3022. doi: 10.2174/1381612828666220729105849.
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.
In search for potent CA-II inhibitors, a series of thiosemicarbazone derivatives (3a-u) was synthesized.
This series was evaluated against bovine and human carbonic anhydrase II (bCA-II and hCA-II) and their docking studies were carried out.
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).
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.
碳酸酐酶II（CA-II）与钙化、肿瘤发生、癫痫、骨质疏松症以及其他一些生理或病理过程相关。CA-II抑制剂可用于降低通常与青光眼相关的眼压。
为寻找有效的CA-II抑制剂，合成了一系列缩氨基硫脲衍生物（3a-u）。
对该系列化合物进行了针对牛和人碳酸酐酶II（bCA-II和hCA-II）的评估，并开展了对接研究。
在初步筛选中，大多数化合物对bCA-II和hCA-II表现出显著抑制作用。预测的构效关系表明，缩氨基硫脲部分在抑制酶活性中起关键作用，R位取代对整体活性有显著贡献。分别针对bCA-II和hCA-II对bCA-II（3d、3e、3l、3f和3p）和hCA-II（3g）的最活性抑制剂进行动力学研究，以研究它们的抑制模式和解离常数（Ki）。
随后，鉴定出（3e、3f、3l和3p）为bCA-II的竞争性抑制剂，Ki值为5.02-14.70μM，而（3d）为bCA-II的非竞争性抑制剂（Ki = 2.5±0.015μM），然而，（3g）对hCA-II表现出竞争性抑制，Ki值为5.95±0.002μM。选择性指数表明化合物（3g）对hCA-II更具选择性。通过基于结构的分子对接研究了这些化合物与bCA-II和hCA-II的结合模式，对接结果与实验结果完全一致。
