Cardiotoxicity and ROS Protection Assessment of three Structure-Related N-Acylhydrazones with Potential for the Treatment of Neurodegenerative Diseases.
Eduarda Santa HelenaAnna De FalcoDaphne S CukiermanAdriana GiodaCarolina Rosa GiodaNicolás A ReyPublished in: Chemistry & biodiversity (2024)
The senescence process is associated with accumulated oxidative damage and increased metal concentration in the heart and brain. Besides, abnormal metal-protein interactions have also been linked with the development of several conditions, including Alzheimer's and Parkinson's diseases. Over the years we have described a series of structure-related compounds with different activities towards models of such diseases. In this work, we evaluated the potential of three N-acylhydrazones (INHHQ: 8-hydroxyquinoline-2-carboxaldehyde isonicotinoyl hydrazone, HPCIH: pyridine-2-carboxaldehyde isonicotinoyl hydrazone and X1INH: 1-methyl-1H-imidazole-2-carboxaldehyde isonicotinoyl hydrazone) to prevent oxidative stress in cellular models, with the dual intent of being active on this pathway and also to confirm their lack of cardiotoxicity as an important step in the drug development process, especially considering that the target population often presents cardiovascular comorbidity. The 8-hydroxyquinoline-contaning compound, INHHQ, exhibits a significant cardioprotective effect against hydrogen peroxide and a robust antioxidant activity. However, this compound is the most toxic to the studied cell models and seems to induce oxidative damage on its own. Interestingly, although not possessing a phenol group in its structure, the new-generation 1-methylimidazole derivative X1INH showed a cardioprotective tendency towards H9c2 cells, demonstrating the importance of attaining a compromise between activity and intrinsic cytotoxicity when developing a drug candidate.
Keyphrases
- hydrogen peroxide
- induced apoptosis
- oxidative stress
- dna damage
- nitric oxide
- single cell
- endoplasmic reticulum stress
- cognitive decline
- emergency department
- cell cycle arrest
- endothelial cells
- drug induced
- ischemia reperfusion injury
- stress induced
- protein protein
- binding protein
- cell proliferation
- adverse drug
- amino acid
- electronic health record
- subarachnoid hemorrhage
- smoking cessation
- solid state
- heat stress