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.
Highlights
Apoptosis is an essential programmed biological process in cells during animal development, [1] homeostasis [2], and immune responses [3]
The results demonstrated by Park et al suggested that Rufinamide V can display a neuroprotective effect against cerebral ischemia involving the attenuation of ischemia-induced glial activation [34] (Figure 1)
To obtain 4-azidoquinolin-2(1H)-ones 4a–d, 4-hydroxy-2-quinolinones 1a–d were synthesized according to literature procedures [35,36], treated with excess POCl3 in the presence of PCl5 at reflux for 1 h to give 2,4-dichloroquinolines 2a–c and 4-chloro-2-quinolinone 2d [37]
Summary
Apoptosis is an essential programmed biological process in cells during animal development, [1] homeostasis [2], and immune responses [3]. Apoptosis occurs normally in tissues, imbalance probably occurs in some cases between apoptotic and antiapoptotic mediators leading to some diseases [4]. On the other hand, when apoptosis exaggerated, it kills too many cells and inflicts grave tissue damage; as in strokes [7], neurodegenerative disorders such as Alzheimer’s [8], retinal cell death [9], myocardial and testicular ischemia [10,11] inflammatory diseases such as rheumatoid arthritis [12], sepsis [13], osteoarthritis (OA) [14], and asthma [15]. Caspase-3 was found to be generally more promiscuous than caspase-7, 8, and 9 and revealed the major executioner caspase during the demolition phase of apoptosis [16,17]. Caspase-3 plays a key executioner role and its inhibition can drastically prevent apoptosis in vitro and in vivo [1]
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