Stefanova_2025_Int.J.Mol.Sci_26_

Neurodegenerative diseases involve oxidative stress and enzyme dysregulation, necessitating novel neuroprotective agents. This study evaluates the neuroprotective and antioxidant potential of seven pyrrole-based compounds with predicted radical scavenging activity and inhibitory effects on monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE). The compounds were tested in vitro using SH-SY5Y neuroblastoma cells and subcellular rat brain fractions, including synaptosomes, mitochondria, and microsomes. Neuroprotective and antioxidant effects were assessed in oxidative stress models, including H(2)O(2)-induced stress in SH-SY5Y cells, 6-hydroxydopamine toxicity in synaptosomes, tert-butyl hydroperoxide-induced stress in mitochondria, and non-enzyme lipid peroxidation in microsomes. In silico screening for lipophilicity, hydrogen bonding, total polar surface area (TPSA), and ionization properties, was performed to evaluate bioavailability. All compounds exhibited a weak neurotoxic effect on the subcellular fractions at a concentration of 100 microM. However, in oxidative stress models, they demonstrated significant neuroprotective and antioxidant effects at 100 microM. In SH-SY5Y cells, compounds 7, 9, 12, 14, and 15 exhibited low toxicity and strong protective effects at concentrations as low as 1 microM. In silico analysis prioritized compounds 1, 7, 9, 12, and 14 for further development based on their favorable bioavailability. The tested pyrrole-based compounds exhibit promising neuroprotective and antioxidant properties, with several candidates showing potential for further development based on both in vitro efficacy and predicted oral bioavailability.