Synthesis and Biological Evaluation of Some New 3-Aryl-2-thioxo-2,3-dihydroquinazolin-4(1H)-ones and 3-Aryl-2-(benzylthio)quinazolin-4(3H)-ones as Antioxidants; COX-2, LDHA, α-Glucosidase and α-Amylase Inhibitors; and Anti-Colon Carcinoma and Apoptosis-Inducing Agents

Oxidative stress, COX-2, LDHA and hyperglycemia are interlinked contributing pathways in the etiology, progression and metastasis of colon cancer. Additionally, dysregulated apoptosis in cells with genetic alternations leads to their progression in malignant transformation. Therefore, quinazolinones 3a-3h and 5a-5h were synthesized and evaluated as antioxidants, enzymes inhibitors and cytotoxic agents against LoVo and HCT-116 cells. Moreover, the most active cytotoxic derivatives were evaluated as apoptosis inducers. The results indicated that 3a, 3g and 5a were efficiently scavenged DPPH radicals with lowered IC50 values (mM) ranging from 0.165 +/- 0.0057 to 0.191 +/- 0.0099, as compared to 0.245 +/- 0.0257 by BHT. Derivatives 3h, 5a and 5h were recognized as more potent dual inhibitors than quercetin against alpha-amylase and alpha-glucosidase, in addition to 3a, 3c, 3f and 5b-5f against alpha-amylase. Although none of the compounds demonstrated a higher efficiency than the reference inhibitors against COX-2 and LDHA, 3a and 3g were identified as the most active derivatives. Molecular docking studies were used to elucidate the binding affinities and binding interactions between the inhibitors and their target proteins. Compounds 3a and 3f showed cytotoxic activities, with IC50 values (mu M) of 294.32 +/- 8.41 and 383.5 +/- 8.99 (LoVo), as well as 298.05 +/- 13.26 and 323.59 +/- 3.00 (HCT-116). The cytotoxicity mechanism of 3a and 3f could be attributed to the modulation of apoptosis regulators (Bax and Bcl-2), the activation of intrinsic and extrinsic apoptosis pathways via the upregulation of initiator caspases-8 and-9 as well as executioner caspase-3, and the arrest of LoVo and HCT-116 cell cycles in the G2/M and G1 phases, respectively. Lastly, the physicochemical, medicinal chemistry and ADMET properties of all compounds were predicted.