New monoamine oxidase inhibitors were synthesized as indole analogues of a previously reported pyrrole series. Several compounds were potent MAO-A (12, 17, 19-22, 31, 36, and 37) or MAO-B (14, 20, 24, 38, 44, and 46) inhibitors, and had K(i) values in the nanomolar concentration range. In particular, 22 (K(i)=0.00092 microM, and SI=68,478) was exceptionally potent and selective as MAO-A inhibitor. In molecular modeling studies, compounds 22, 24, 44, and 46 positioned the indole ring into an aromatic cavity of MAO-A, and established pi-pi stacking interactions with Tyr407, Tyr444, and FAD cofactor. However, only compound 22 was able to form hydrogen bonds with FAD, a finding which was in accordance with its potent anti-MAO-A activity. Conversely, 22/MAOB complex was highly unstable during the MD simulation.
Synthesis, structure-activity relationships and molecular modeling studies of new indole inhibitors of monoamine oxidases A and B / LA REGINA, Giuseppe; Silvestri, Romano; Gatti, Valerio; Lavecchia, A.; Novellino, E.; Befani, O.; Turini, P.; Agostinelli, Enzo. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 22:(2008), pp. 9729-9740. [10.1016/j.bmc.2008.09.072]
Synthesis, structure-activity relationships and molecular modeling studies of new indole inhibitors of monoamine oxidases A and B.
LA REGINA, GIUSEPPE;SILVESTRI, Romano;GATTI, VALERIO;AGOSTINELLI, Enzo
2008
Abstract
New monoamine oxidase inhibitors were synthesized as indole analogues of a previously reported pyrrole series. Several compounds were potent MAO-A (12, 17, 19-22, 31, 36, and 37) or MAO-B (14, 20, 24, 38, 44, and 46) inhibitors, and had K(i) values in the nanomolar concentration range. In particular, 22 (K(i)=0.00092 microM, and SI=68,478) was exceptionally potent and selective as MAO-A inhibitor. In molecular modeling studies, compounds 22, 24, 44, and 46 positioned the indole ring into an aromatic cavity of MAO-A, and established pi-pi stacking interactions with Tyr407, Tyr444, and FAD cofactor. However, only compound 22 was able to form hydrogen bonds with FAD, a finding which was in accordance with its potent anti-MAO-A activity. Conversely, 22/MAOB complex was highly unstable during the MD simulation.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
