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

• Main Authors: Nahed Nasser Eid El-Sayed (Author), Taghreed M. Al-Otaibi (Author), Assem Barakat (Author), Zainab M. Almarhoon (Author), Mohd. Zaheen Hassan (Author), Maha I. Al-Zaben (Author), Najeh Krayem (Author), Vijay H. Masand (Author), Abir Ben Bacha (Author)
• Format: Book
• Published: MDPI AG, 2023-10-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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 <b>3a</b>-<b>3h</b> and <b>5a</b>-<b>5h</b> 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 <b>3a</b>, <b>3g</b> and <b>5a</b> 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 <b>3h</b>, <b>5a</b> and <b>5h</b> were recognized as more potent dual inhibitors than quercetin against α-amylase and α-glucosidase, in addition to <b>3a</b>, <b>3c</b>, <b>3f</b> and <b>5b</b>-<b>5f</b> against α-amylase. Although none of the compounds demonstrated a higher efficiency than the reference inhibitors against COX-2 and LDHA, <b>3a</b> and <b>3g</b> 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 <b>3a</b> and <b>3f</b> showed cytotoxic activities, with IC₅₀ values (µM) 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 <b>3a</b> and <b>3f</b> 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.

Item Description

10.3390/ph16101392
1424-8247