Evaluation of Pyrrole Heterocyclic Derivatives as Selective MAO-B Inhibitors and Neuroprotectors.

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Novel pyrrole-based derivatives were synthesized in high purity and yields (52-89%), with 17i and 17j displaying selective MAO-B inhibition (50-60%), comparable to Selegiline, and negligible MAO-A activity. In rat brain subcellular fractions, both compounds showed low intrinsic neurotoxicity at 100 μM while exerting significant neuroprotective and antioxidant effects under 6-OHDA, t-BuOOH, and Fe2+/ascorbate-induced stress. Mechanistic studies indicate dual protection via reactive oxygen species scavenging and preservation of reduced glutathione, with mitochondria and microsomes being the most responsive compartments. The performed in silico analysis revealed no general toxicity alerts, though hydrazine groups classify the compounds as contact allergens, and the furan ring in 17i poses hepatotoxic and carcinogenic risks. Metabolic predictions suggest ester hydrolysis at the pyrrole ring as the main biotransformation pathway. Overall, 17i and 17j are promising lead compounds for developing therapeutics targeting oxidative stress-related neurodegenerative diseases, such as Parkinson's and Alzheimer's, supporting further in vivo studies.

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