title: Synthesis of GN8 derivatives and evaluation of their antiprion activity in TSE-infected cells.
abstract: A series of GN8 derivatives were synthesized from various diamines, carboxylic acid derivatives, and nitrogen nucleophiles, and their antiprion activity was tested in TSE-infected mouse neuronal cells. We found that two ethylenediamine units, hydrophobic substituents on the nitrogen atoms, and the diphenylmethane scaffold were essential structural features responsible for the activity. Seven derivatives bearing substituents at the benzylic position exhibited an improved antiprion activity with the IC(50) values of 0.51-0.83 μM. Conformational analysis of model compounds suggested that the introduction of the substituent at the benzylic position restricted the conformational variability of the diphenylmethane unit.
authors.affiliation: Center for Emerging Infectious Diseases, Gifu University, Gifu, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kimura
authors.forename: Junji
authors.initials: J
authors.lastname: Hosokawa-Muto
authors.forename: Yuji O
authors.initials: YO
authors.lastname: Kamatari
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kuwata
mesh_terms: D000083:Acetanilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000977:Antiparasitic Agents / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects; D017096:Prion Diseases / Q000473:pathology; D011328:Prions / Q000037:antagonists & inhibitors*; D017510:Protein Folding; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000083:Acetanilides; D000977:Antiparasitic Agents; D001559:Benzhydryl Compounds; D011328:Prions; D011994:Recombinant Proteins