New derivatives of indole-3-propionic acid as potential multi-target ligands for the treatment of neurodegenerative diseases: Synthesis, toxic potential, neuroprotection and quantum chemical calculations

Title

Oral presentation

Description

Kuentin Radev1, Neda Anastassova1, Denitsa Stefanova2, Denitsa Yancheva1, Nadya Hristova-Avakumova3
1Institute of Organic Chemistry with Centre of Phytochemistry, BAS, Sofia, Bulgaria;
2Department of Pharmacology and Toxicology, Faculty of Pharmacy, Medical University-Sofia, Bulgaria
3Department of Medical Physics and Biophysics, Medical University-Sofia, Bulgaria

Subject

Neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease, are an unresolved global health issue. Bearing in mind their complex pathogenesis and the possibility that oxidative stress is one of the possible causes of the manifestation of these diseases, we synthesized methoxy- and hydroxy-substituted arylhydrazone derivatives of indole-3-propionic acid (IPA). IPA is a powerful antioxidant without pro-oxidant activity and has the ability to inhibit aggregation of denatured proteins and also suppresses cell death that is induced by hydrogen peroxide. IPA derivatives were successfully synthesized and qualitatively determined by IR and NMR. Their pharmacological neuroprotective activity was determined experimentally in a model of H2O2-induced oxidative stress on the SH-SY5Y neuroblastoma cell line, and all derivatives showed promising results similar to the control, in combination with low toxicological potential. To evaluate their antioxidant properties, spectrophotometric in vitro systems were used to assess a modulating effect on iron-induced peroxidation. Quantum chemical calculations were performed to reveal the theoretical model of the radical-trapping mechanism - hydrogen atom transfer (HAT), single electron transfer (SET) and sequential proton loss electron transfer (SPLET).
This work was financially supported by The National Science Fund of Bulgaria, Young scientist project КП-06-ПМ59/2.
Keywords: indole derivatives, oxidative stress, neurodegenerative diseases