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Biological Evaluation, Molecular Docking Analyses, and ADME Profiling of Certain New Quinazolinones as
Nahed N E El-Sayed1, Norah M Almaneai2, Abir Ben Bacha3,4
1National Organization for Drug Control and Research, Egyptian Drug Authority, 51 Wezaret El-Zerra Street, Giza 35521, Egypt.
Abstract:
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.
Insights
New quinazolinone derivatives were synthesized and tested as potential treatments for colorectal cancer. Several compounds showed promising cytotoxic effects and enzyme inhibition, indicating their potential as lead scaffolds for developing new anti-colorectal agents.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Enzymology
Background:
- Colorectal cancer development involves dysregulation of key enzymes including human secretory phospholipases A2 (hsPLA2), proteases, carbohydrate hydrolyzing enzymes, and xanthine oxidoreductase (XOR).
- Targeting these enzymes and cancer cell proliferation are crucial strategies for developing novel colorectal cancer therapeutics.
Purpose of the Study:
- To synthesize novel quinazolinone derivatives.
- To evaluate their inhibitory activity against a panel of enzymes implicated in colorectal carcinogenesis.
- To assess their cytotoxic effects on colorectal cancer cell lines (LoVo and HCT-116).
Main Methods:
- Synthesis of new quinazolinone compounds.
- In vitro enzymatic inhibition assays.
- Cytotoxicity assays on LoVo and HCT-116 cell lines.
- Molecular docking studies to predict binding modes and affinities.
- In silico prediction of physicochemical and pharmacokinetic properties (Lipinski's rule of five, bioavailability radar, boiled-egg plots).
Main Results:
- Compounds 3g, 10, 8, 3c, and 1c demonstrated significant cytotoxic effects against colorectal cancer cells (IC50 values: 206.07–459.79 μM).
- Nine compounds exhibited notable enzyme inhibitory activities, with specific derivatives showing potent inhibition against hsPLA2-G-IIA, hsPLA2-G-V, thrombin, elastase, trypsin, α-amylase, α-glucosidase, and XOR.
- Molecular docking and pharmacokinetic predictions supported the potential of active compounds as drug candidates.
Conclusions:
- Derivatives 1c, 3b, 3c, 3d, 8, 10, and 12 emerged as promising lead scaffolds.
- These compounds warrant further investigation and optimization for the development of novel enzyme inhibitors and anti-colorectal agents.
