A large series of substituted chalcones have been synthesized and tested in vitro for their ability to inhibit human monoamine oxidases A and B (hMAO-A and hMAO-B). While all the compounds showed hMAO-B selective activity in the micro- and nanomolar ranges, the best results were obtained in the presence of chlorine and hydroxyl or methoxyl substituents. To better understand the enzyme-inhibitor interaction and to explain the selectivity of the most active compounds toward hMAO-B, molecular modeling studies were carried out on new, high resolution, hMAO-B crystallographic structures. For the only compound that also showed activity against hMAO-A as well as low selectivity, the molecular modeling study was also performed on the hMAO-A crystallographic structure. The docking technique provided new insight on the inhibition mechanism and the rational drug design of more potent/selective hMAO inhibitors based on the chalcone scaffold.
Chalcones: A Valid Scaffold for Monoamine Oxidases Inhibitors / Franco, Chimenti; Fioravanti, Rossella; Rossella, ; Bolasco, Adriana; Adriana, ; Chimenti, Paola; Paola, ; Secci, Daniela; Daniela, ; Rossi, Francesca. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 52:9(2009), pp. 2818-2824. [10.1021/jm801590u]