Design, Synthesis, and In Vitro Evaluation of Novel 8-Amino-Quinoline Combined with Natural Antioxidant Acids

Overproduction of reactive oxygen species (ROS) and alterations in metallostasis are common and related hallmarks in several neurodegenerative diseases (NDDs). Nature-based derivatives always represent an attractive tool in MTDL drug design, especially against ROS in NDDs. On this notion, we designed a new series of 8-quinoline-N-substituted derivatives with a natural antioxidant portion (i.e., lipoic, caffeic, and ferulic acids). These compounds were shown to chelate copper, a metal involved in ROS-induced degeneration, and scavenger oxygen radicals in DPPH assay. Then, selected compounds 4 and 5 were evaluated in an in vitro model of oxidative stress and shown to possess cytoprotective effects in 661W photoreceptor-like cells. The obtained results may represent a starting point for the application of the proposed class of compounds in retinal neurodegenerative diseases such as retinitis pigmentosa (RP), comprising a group of hereditary rod-cone dystrophies that represent a major cause of blindness in patients of working age, where the progression of the disease is a multifactorial event, with oxidative stress contributing predominantly.

Automated summary

Overproduction of reactive oxygen species (ROS) and metal imbalance are common features in neurodegenerative diseases (NDDs). In this study, a series of 8-quinoline-N-substituted derivatives with natural antioxidant properties were designed to target ROS in NDDs. The compounds showed the ability to chelate copper, a metal involved in ROS-induced degeneration, and scavenge oxygen radicals. In addition, selected compounds 4 and 5 demonstrated cytoprotective effects in an in vitro model of oxidative stress. These findings provide a starting point for the potential application of these compounds in retinal neurodegenerative diseases.