Carbazole-containing arylcarboxamides as BACE1 inhibitors |
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Authors: | Bertini Simone Asso Valentina Ghilardi Elisa Granchi Carlotta Manera Clementina Minutolo Filippo Saccomanni Giuseppe Bortolato Andrea Mason Jonathan Moro Stefano Macchia Marco |
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Institution: | Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. |
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Abstract: | β-Secretase (BACE1) is widely recognized as a prime drug target for the treatment of Alzheimer's disease (AD). In this Letter, we report the synthesis and the BACE1 inhibitory activity of novel, variously substituted N-3-(9H-carbazol-9-yl)-2-hydroxypropyl]-arylcarboxamides. The best results have been obtained with the introduction of a 4-OMe substituent (IC(50)=3.8 μM) or a 3,4-dichloro substituent (IC(50)=2.5 μM) in the amidic aromatic ring. The blood-brain barrier penetration predictions resulted to be promising for this type of compounds. To better understand the structure-activity relationships (SAR) of the new derivatives, a docking study procedure has been applied exploiting different conformational and ionic states of BACE1. |
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Keywords: | Alzheimer BACE1 Carbazole Molecular docking Flap |
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