| Autor: |
El-Sayed NNE; Egyptian Drug Authority (EDA), 51 Wezaret El-Zeraa St., Giza 35521, Egypt., Al-Otaibi TM; Department of Chemistry, College of Sciences, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia., Barakat A; Department of Chemistry, College of Sciences, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia., Almarhoon ZM; Department of Chemistry, College of Sciences, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia., Hassan MZ; Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia., Al-Zaben MI; Department of Chemistry, College of Sciences, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia., Krayem N; Laboratoire de Biochimie et de Génie Enzymatique des Lipases, ENIS, Université de Sfax, Route de Soukra 3038, Sfax BP 1173, Tunisia., Masand VH; Department of Chemistry, Vidya Bharati College, Camp, Amravati, Maharashtra 444602, India., Ben Bacha A; Biochemistry Department, College of Sciences, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia. |
| Abstrakt: |
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 IC 50 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 α-amylase and α-glucosidase, in addition to 3a , 3c , 3f and 5b - 5f against α-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 IC 50 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 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. |
