Synthesis and neuroprotective activity of novel 5,6-diaryl-1,2,4-triazine derivatives with ethyl acetate moiety against H2O2 and Aβ-induced neurotoxicity

6^th World Congress on Medicinal Chemistry and Drug Design

June 07-08, 2017 Milan, Italy

Hamid Irannejad and Tuba Tuylu Kucukkilinc

Mazandaran University of Medical Sciences, Iran
Hacettepe University, Turkey

Posters & Accepted Abstracts: Med Chem (Los Angeles)

Abstract :

Alzheimerâ��s disease (AD) is a neuropathological disorder characterized by intracellular neurofibrillary tangles and amyloid aggregates in the CNS. In recent years, numerous approaches have been used to combat AD like small molecule inhibitors of A�² aggregation, anti-inflammatory agents, cholinesterase, and �²- and �³-secretase. Herein, we report synthesis of some 5,6-diaryl- 1,2,4-triazines 3a-f and 8a-e as potential agents for treatment of AD. We evaluated them against both H2O2 and �²-amyloid induced toxicity in PC-12 and SH-SY5Y cells and the extent of cell viability and apoptosis were assessed. The synthesis of compounds (3a-f) was started by 1,2-diketones, in which triazine ring closure was performed by thiosemicarbazide and alkylation by ethyl chloroacetate to afford compounds 3a-f. Synthetic route for compounds 8a-e was started by an acylation reaction of anisole with phenyl acetic acid derivatives. The oximation in the alpha position of carbonyl group was performed by use of sodium methoxide and butylnitrite. The next two steps were performed similarly to afford final compounds 8a-e. All compounds showed significant neuroprotective activity with EC50 values ranging from 14-30 �¼M. Most compounds could increase cell viability compared to amyloid treated group. Surprisingly, 3-thioxo-1,2,4-triazin-2(3H)-yl)acetate derivative 8e was the most potent compound in both tests with EC50 of 14 �¼M and could increase 40% of cell viability revealed by cytometric analysis with Annexin V/PI staining. It was also shown that 8e has more neuroprotective activity than quercetin. Morphologic evaluation of cells by DAPI staining and TUNEL assay showed the effectiveness of this compound to improve neurite outgrowth in neuronal cells.

Biography :

Email: irannejadhamid@gmail.com