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  • Title: Synthesis, structure-activity relationships and molecular modeling studies of new indole inhibitors of monoamine oxidases A and B.
    Author: La Regina G, Silvestri R, Gatti V, Lavecchia A, Novellino E, Befani O, Turini P, Agostinelli E.
    Journal: Bioorg Med Chem; 2008 Nov 15; 16(22):9729-40. PubMed ID: 18951803.
    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.
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