A series of new pyrrole derivatives have been synthesized and evaluated for their monoamine oxidase (MAO) A and B inhibitory activity and selectivity. N-Methyl,N-(benzyl),N-(pyrrol-2-ylmethyl)amine (7) and N-(2-benzyl),N-(1-methylpyrrol-2-ylmethyl)amine (18) were the most selective MAO-B (7, SI = 0.0057) and MAO-A (18, SI = 12500) inhibitors, respectively. Docking and molecular dynamics simulations gave structural insights into the MAO-A and MAO-B selectivity. Compound 18 forms an H-bond with Gln215 through its protonated amino group into the MAO-A binding site. This H-bond is absent in the 7/MAO-A complex. In contrast, compound 7 places its phenyl ring into an aromatic cage of the MAO-B binding pocket, where it forms charge-transfer interactions. The slightly different binding pose of 18 into the MAO-B active site seems to be forced by a bulkier Tyr residue, which replaces a smaller Ile residue present in MAO-A.

New Pyrrole Inhibitors of Monoamine Oxidase: Synthesis, Biological Evaluation and Structural Determinants of MAO-A and MAO-B Selectivity / G., LA REGINA; R., Silvestri; M., Artico; Lavecchia, Antonio; Novellino, Ettore; O., Befani; P., Turini; E., Agostinelli. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - ELETTRONICO. - 50:(2007), pp. 922-931. [10.1021/jm060882y]

New Pyrrole Inhibitors of Monoamine Oxidase: Synthesis, Biological Evaluation and Structural Determinants of MAO-A and MAO-B Selectivity

LAVECCHIA, ANTONIO;NOVELLINO, ETTORE;
2007

Abstract

A series of new pyrrole derivatives have been synthesized and evaluated for their monoamine oxidase (MAO) A and B inhibitory activity and selectivity. N-Methyl,N-(benzyl),N-(pyrrol-2-ylmethyl)amine (7) and N-(2-benzyl),N-(1-methylpyrrol-2-ylmethyl)amine (18) were the most selective MAO-B (7, SI = 0.0057) and MAO-A (18, SI = 12500) inhibitors, respectively. Docking and molecular dynamics simulations gave structural insights into the MAO-A and MAO-B selectivity. Compound 18 forms an H-bond with Gln215 through its protonated amino group into the MAO-A binding site. This H-bond is absent in the 7/MAO-A complex. In contrast, compound 7 places its phenyl ring into an aromatic cage of the MAO-B binding pocket, where it forms charge-transfer interactions. The slightly different binding pose of 18 into the MAO-B active site seems to be forced by a bulkier Tyr residue, which replaces a smaller Ile residue present in MAO-A.
2007
New Pyrrole Inhibitors of Monoamine Oxidase: Synthesis, Biological Evaluation and Structural Determinants of MAO-A and MAO-B Selectivity / G., LA REGINA; R., Silvestri; M., Artico; Lavecchia, Antonio; Novellino, Ettore; O., Befani; P., Turini; E., Agostinelli. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - ELETTRONICO. - 50:(2007), pp. 922-931. [10.1021/jm060882y]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/201572
Citazioni
  • ???jsp.display-item.citation.pmc??? 9
  • Scopus 118
  • ???jsp.display-item.citation.isi??? 118
social impact