Design, Synthesis, Molecular Docking, Antiapoptotic and Caspase-3 Inhibition of New 1,2,3-Triazole/Bis-2(1H)-Quinolinone Hybrids

Abstract

A series of novel 1,2,3-triazoles hybridized with two quinolin-2-ones, was designed and synthesized through click reactions. The structures of the synthesized compounds were elucidated by NMR, IR, and mass spectra in addition to elemental analysis. The synthesized compounds were assessed for their antiapoptotic activity in testis, as testicular torsion is the main cause of male infertility. This effect was studied in light of decreasing tissue damage induced by I/R in the testis of rats using N-acetylcysteine (NAC) as an antiapoptotic reference. Compounds 6a–c were the most active antiapoptotic hybrids with significant measurements for malondialdehyde (MDA) and total antioxidant capacity (TAC) and the apoptotic biomarkers (testicular testosterone, TNFα, and caspase-3) in comparison to the reference. A preliminary mechanistic study was performed to improve the antiapoptotic activity through caspase-3 inhibition. A compound assigned as 6-methoxy-4-(4-(((2-oxo-1,2-dihydroquinolin-4-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)quinolin-2(1H)-one (6c) was selected as a representative of the most active hybrids in comparison to NAC. Assay of cytochrome C for 6c revealed an attenuation of cytochrome C level about 3.54 fold, comparable to NAC (4.13 fold). In caspases-3,8,9 assays, 6c was found to exhibit more potency and selectivity toward caspase-3 than other caspases. The testicular histopathological investigation was carried out on all targeted compounds 6a–g, indicating a significant improvement in the spermatogenesis process for compounds 6a–c if compared to the reference relative to the control. Finally, molecular docking studies were done at the caspase-3 active site to suggest possible binding modes. Hence, it could conceivably be hypothesized that compounds 6a–c could be considered good lead candidate compounds as antiapoptotic agents.

Azides in the Synthesis of Various Heterocycles

“…Addi tionally, the target compounds 221a-d were synthesized, in very good yields, via the re action of 4-{[1-(2-oxo-1,2-dihydroquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methoxy}benzalde hydes 222a-d [73] with acetophenone (Scheme 85). Aly et al [74] also reported that the synthesis of hybrids 228a-g through click chemistry which is a powerful tool for a quick, highly selective, and reliable access to a reaction product with high yields. The Aly et al [74] also reported that the synthesis of hybrids 228a-g through click chemistry which is a powerful tool for a quick, highly selective, and reliable access to a reaction product with high yields.…”

“…Aly et al [74] also reported that the synthesis of hybrids 228a-g through click chemistry which is a powerful tool for a quick, highly selective, and reliable access to a reaction product with high yields. The Aly et al [74] also reported that the synthesis of hybrids 228a-g through click chemistry which is a powerful tool for a quick, highly selective, and reliable access to a reaction product with high yields. The Aly et al [74] also reported that the synthesis of hybrids 228a-g through click chemistry which is a powerful tool for a quick, highly selective, and reliable access to a reaction product with high yields.…”

“…The Aly et al [74] also reported that the synthesis of hybrids 228a-g through click chemistry which is a powerful tool for a quick, highly selective, and reliable access to a reaction product with high yields. The Aly et al [74] also reported that the synthesis of hybrids 228a-g through click chemistry which is a powerful tool for a quick, highly selective, and reliable access to a reaction product with high yields. The [3+2] cycloadditions of 4-azidoquinolin-2(1H)-ones 219a-d with 4-(prop-2-yn-1-yloxy)quinolin-2(1H)-ones 227a-c, gave the corresponding 4-((1-(2oxo-1,2-dihydroquinolin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)quinolin-2(1H)-ones 228a-g (Scheme 87).…”

“…In caspases-3,8,9 assays, 228c was found to exhibit more potency and selectivity toward caspase-3 than other caspases. Testicular histopathological investigation was carried out on all targeted compounds 228a-g, indicating a significant improvement in spermatogenesis process for compounds 228a-c if compare with the reference relative to the control [74].…”

Phytoconstituents from Markhamia tomentosa Bind To HPV Oncoprotein with Apoptogenic Potential: A Molecular Modeling Approach

“…Caspase family of cysteine protease enzymes has been an intensely studied target in drug design for many years (Ghavami et al, 2009;Shalini et al, 2015). Among the identified 14 mammalian caspases caspase -2, -3, -6, -7, -8, -9, and -10 were described as apoptotic caspases (Aly et al, 2020;El-Sheref et al, 2020). Apoptotic caspases are classified based on the site and mechanism of action as initiator caspases (caspase-2, -8, -9, -10) and executioner caspases (caspase-3, -6, -7).…”