Synthesis of 9-substituted 2,3,4,9-tetrahydro-1H-carbazole derivatives and evaluation of their anti-prion activity in TSE-infected cells

2,3,4,9-Tetrahydro-9-[2-hydroxy-3-(1-piperidinyl)propyl]-6-methyl-1H-carbazol-1-one (GJP14) is a novel anti-prion compound that we previously discovered by in silica screening and cellular assay. In this study, a variety of GJP14 derivatives were prepared using pyrrole derivatives, (haloalkyl)oxiranes, and amines, and their anti-prion activity was evaluated in TSE-infected cells. It was found that the tricyclic aromatic ring, a hydroxy group at the 2-position and an amino group at the 3-position of the N-propyl group were the basic requirements for anti-prion activity. The derivatives bearing an N-ortho-halobenzyl group exhibited an improved activity, and the most potent derivative was 8 times as effective as the original lead compound, GJP14. (C) 2011 Elsevier Masson SAS. All rights reserved.