Biological Evaluation, Molecular Docking Analyses, and ADME Profiling of Certain New Quinazolinones as Anti-colorectal Agents

• Published in: ACS omega 2022-06, Vol.7 (22), p.18443-18458
• Main Authors: El-Sayed, Nahed N. E., Almaneai, Norah M., Ben Bacha, Abir, El-Ashrey, Mohamed K., Al-Zaben, Maha I., Almarhoon, Zainab M.
• Format: Article
• Language: English
• ISSN: 2470-1343; 2470-1343
• DOI: 10.1021/acsomega.2c00812

Colorectal carcinogenesis is a complex process, which is linked to dysregulation of human secretory phospholipases A2 (hsPLA2-G-IIA, hsPLA2-G-V, and hsPLA2-G-X), proteases (cathepsin-B, collagenase, thrombin, elastase, and trypsin), carbohydrate hydrolyzing enzymes (α-amylase and α-glucosidase), and free radical generating enzyme (xanthine oxidoreductase (XOR)). Therefore, some new quinazolinones were synthesized and evaluated as inhibitors against this array of enzymes as well as cytotoxic agents on LoVo and HCT-116 cells of colorectal cancer. Compounds 3g, 10, 8, 3c, and 1c exhibited promising cytotoxic effects with IC50 values ranging from 206.07 to 459.79 μM. Nine compounds showed promising enzymatic inhibitory effects, 3b, 3d, 3f, 5, 1a, and 12 (α-amylase), 8 (thrombin, elastase and trypsin), 10 (hsPLA2-G-IIA and hsPLA2-G-V), and 3f (α-glucosidase and XOR). Therefore, the most active inhibitors, were subjected to validated molecular docking studies to identify their affinities and binding modes. The expected physicochemical and pharmacokinetic features of the active candidates, 1a, 1c, 3b, 3c, 3d, 3f, 3g, 5, 8, 10, and 12 were predicted using bioavailability radar charts and boiled-egg graphical representations along with the Lipinski rule of five filter. Collectively, these studies showed the significance of derivatives 1c, 3b, 3c, 3d, 8, 10, and 12 as lead scaffolds for further optimization to develop enzymes inhibitors and anti-colorectal agents.