Synthesis of 9-substituted 2,3,4,9-tetrahydro-1H-carbazole derivatives and evaluation of their anti-prion activity in TSE-infected cells |
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| Authors: | Kimura Tsutomu Hosokawa-Muto Junji Asami Kenji Murai Toshiaki Kuwata Kazuo |
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| Institution: | aCenter for Emerging Infectious Diseases, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan;bDepartment of Chemistry, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan;cUnited Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan |
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| Abstract: | 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 silico 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. |
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| Keywords: | Prion diseases Transmissible spongiform encephalopathies Anti-prion compound 2 3 4 9-Tetrahydro-1H-carbazole Ring-opening reaction Structure&ndash activity relationships |
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