4H-1,4-oxazines were designed as transthyretin (TTR) amyloid fibril inhibitors based on an analysis of the interactions between known small molecule inhibitors and TTR by molecular docking. A series of 2,4,6-triaryl-4H-1,4-oxazines was synthesized by the cyclization of N,N-bis(phenacyl)anilines with POCl3 in pyridine. Inhibition of TTR amyloid fibril was evaluated by a fibril formation assay. The results indicate that 4H-1,4-oxazines significantly inhibit TTR amyloid fibril at a concentration of 7.2 μM.
The inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has demonstrated potential for the treatment of various components of metabolic syndrome. In this study, a series of 1,4-diaryl-1,4-dihydropyrazines were designed as inhibitors of 11β-HSD1 based on the structure-activity relationship of known 11β-HSD1 inhibitors through docking simulations. The docking simulation results supported the initial pharmacophore hypothesis: the docking results of the known inhibitors with 11β-HSD1 suggested a similar interaction of 1,4-diaryl-1,4-dihydropyrazines with the catalytic site of 11β-HSD1. Twelve of these compounds were synthesized through the cyclization of N,N-dialkylanilines with anilines, and their structures were determined by (1)H-NMR, (13)C-NMR, high resolution (HR)-MS, and single-crystal X-ray diffraction. The inhibitory activities of these compounds against human 11β-HSD1 were investigated in vitro through a scintillation proximity assay using microsomes containing 11β-HSD1.
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