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ORIGINAL PAPER

Design and synthesis of novel benzyloxy‑tethered‑chromone‑carboxamide derivatives as potent and selective human monoamine oxidase‑b inhibitors Y. Jayaprakash Rao1 · K. Abhijit2 · G. Mallikarjun3 · Y. Hemasri4 Received: 19 May 2020 / Accepted: 19 August 2020 © Institute of Chemistry, Slovak Academy of Sciences 2020

Abstract A series of new bifunctional 7-benzyloxy-2, 3-dimethyl-4-oxo-4H-chromene-8-carboxamides 5a-5 l were synthesized from 7-hydroxy 2,3 dimethyl chromone via key intermediate 7-benzyloxy 2,3 dimethyl-8-carboxylic acid using Jones oxidation and HBTU/HOBt (Hexafluorophosphate Benzotriazole Tetramethyl Uronium/Hydroxybenzotriazole) as selective amide coupling agent. All the amide derivatives 5a-5 l were screened for their in vitro human monoamine oxidase, hMAO-A and hMAO-B inhibitory activity. Two compounds 5c and 5e, identified as more potent MAO-B inhibitors ­(IC50 values within nanomolar range) compared to the standard MAO-B inhibitor, Selegiline. Five compounds 5b, 5c, 5e, 5 g and 5 k exhibited high MAO-B inhibition selectivity with selectivity index (SI) value > 50. The most potent compound 5e has also showed reversibility of MAO-B inhibition in dialysis method with relative recovery percentage up to 69.9%. Furthermore, the MAO-B selective binding affinities of these newly synthesized chromone amides and structure activity relationships were scrutinized with the help of quantified scoring function values from Genetic Optimization of Ligand Docking (GOLD). The docking results have conclusively lain out that these chromone carboxamides show positive interactions with hMAO-B and repulsive interactions with hMAO-A which affirm its selectivity towards MAO-B. Graphic abstract Design, Synthesis and Evaluaon of MAO-B inhibitory acvity of novel potent and selecve 7-benzyloxy-8-carboxamide chromones

MAO-B inhibitory Effect IC50 = 88.381±0.0027 nM Selecvity Index: 323.97

O

O O

5c

Me

NH O

Me Me

O

Monoamineoxidase-B

Keywords 7-benzyloxy-chromone-8-carboxamides · hMAO-A · hMAO-B inhibition · Molecular docking Electronic supplementary material  The online version of this article (https​://doi.org/10.1007/s1169​6-020-01332​-w) contains supplementary material, which is available to authorized users. * Y. Jayaprakash Rao [email protected] Extended author information available on the last page of the article

Introduction Neurodegenerative diseases like Parkinson’s and Alzheimer’s diseases are incurable and characterized by progressive degeneration of nerve cells which lead to gradual decline in quality of mental and physical health of the

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patients. The oxidative deamination of many biologically significant monoamines, catalyzed by monoamine oxidases (MAOs) is one of the substantial causes of neurodegenerative process. In mammals, MAO is present in two isoforms MAO-A and MAO-B. These two are differentiated by their substrate selectivity. MAO-A metabolize tyramine, norepinephrine and serotonin, whereas, MAO-B principally metabolize dopamine and beta phenyl ethyl

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