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Design and synthesis of novel benzyloxy-tethered-chromone-carboxamide derivatives as potent and selective human monoamine oxidase-b inhibitors

Y. Jayaprakash Rao, K. Abhijit, G. Mallikarjun, and Y. Hemasri

Department of Chemistry, Osmania University, Hyderabad, India

 

E-mail: yjpr_19@yahoo.com

Received: 19 May 2020  Accepted: 19 August 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

Keywords: 7-benzyloxy-chromone-8-carboxamides; hMAO-A; hMAO-B inhibition; Molecular docking

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-020-01332-w

 

Chemical Papers 75 (2) 703–716 (2021)

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