AUTHOR=Khan Ajmal , Khan Majid , Halim Sobia Ahsan , Khan Zulfiqar Ali , Shafiq Zahid , Al-Harrasi Ahmed 

TITLE=Quinazolinones as Competitive Inhibitors of Carbonic Anhydrase-II (Human and Bovine): Synthesis, in-vitro, in-silico, Selectivity, and Kinetics Studies

JOURNAL=Frontiers in Chemistry

VOLUME=8

YEAR=2020

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2020.598095

DOI=10.3389/fchem.2020.598095

ISSN=2296-2646

ABSTRACT=<p>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 (<bold>4a-p</bold>) were synthesized and characterized by IR and NMR spectroscopy. The inhibitory potential of all the compounds was evaluated against bovine carbonic anhydrase-II (<italic>b</italic>CA-II) and human carbonic anhydrase-II (<italic>h</italic>CA-II), and compounds displayed moderate to significant inhibition with IC<sub>50</sub> 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, <bold>4d</bold>, against both <italic>b</italic>CA-II and <italic>h</italic>CA-II were performed to investigate the mode of inhibition and to determine the inhibition constants (Ki). According to the kinetics results, <bold>4d</bold> is a competitive inhibitor of <italic>b</italic>CA-II and <italic>h</italic>CA-II with Ki values of 13.0 ± 0.013 and 14.25 ± 0.017 μM, respectively. However, the selectivity index reflects that the compounds <bold>4g</bold> and <bold>4o</bold> are more selective for <italic>h</italic>CA-II. The binding mode of these compounds within the active sites of <italic>b</italic>CA-II and <italic>h</italic>CA-II was investigated by structure-based molecular docking. The docking results are in complete agreement with the experimental findings.</p>