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Benzopyran-2-ones as attractive scaffold for MAO inhibitors: synthesis, biological evaluation and docking studies
Published: 25 October 2011 by MDPI in The 15th International Electronic Conference on Synthetic Organic Chemistry session Bioorganic, Medicinal and Natural Products
Abstract: Neurodegenerative diseases are becoming prevalent pathologies in developed societies due to increasing average of life expectancy of the population. This fact has encouraged an active research in the development of new drugs, since they may represent an important advance in the treatment of complex diseases such as Alzheimer and Parkinson\'s diseases. Coumarins are a large family of compounds, of both natural and synthetic origin, important because of the pharmacological activities that this compounds display. Therefore, they occupy an important place in the organic and medicinal chemistry realm. In recent years, coumarins have been attracting interest because of their ability of inhibiting some enzymes. The versatility of the Perkin and Knoevenagel reactions has led to a large family of differently substituted compounds. In order to find the structural features for the human MAO inhibitory activity and selectivity, in the present communication we report the synthesis, pharmacological evaluation and a comparative study of a new series of 3-phenylcoumarins versus 3-benzoylcoumarins. A bromo atom and a methoxy/hydroxy substituent were introduced in these scaffolds at different positions of the coumarin moiety. The synthesized compounds were evaluated as MAO-A and B inhibitors using R-(-)-deprenyl and iproniazide as reference compounds. The presence or absence of a carbonyl group between the coumarin and the phenyl substituent in 3 position remarks, respectively, the MAO-A or MAO-B inhibitory activity. Some of the new compounds showed MAO-B inhibitory activities in the low nanomolar range. Compound 2 (IC50 = 1.35 nM) showed higher inhibitory activity than the R-(-)-deprenyl (IC50 = 19.60 nM) and higher MAO-B selectivity, with more than 74,074-fold inhibition level, respecting to the MAO-A isoform. In addition, docking experiments were carried out on hMAO-A and h-MAO-B structures. This study has provided new information about the enzyme-inhibitor interaction and the potential therapeutic application of this coumarin scaffolds.
Keywords: Coumarin, MAO, Parkinson, Alzheimer, Knoevenagel, Perkin