Misfolded or unfolded proteins are accumulated in lumen of endoplasmic reticulum (ER) in ER stress condition. It has been implicated in many pathological conditions such as Alzheimer’s disease, diabetic retinopathy, atherosclerosis, b-cell apoptosis and lung inflammation. A high throughput screen to identify compounds which reduce ER stress identified a series of <i>N</i>-substituted-2-arylcarbonylhydrazinecarbothioamides to potently decrease ER stress signal, showing up to almost two orders of magnitude better activity than salicylate and hydroxynaphthoic acids as chemical chaperone. Structure-activity relationship (SAR) study showed that 2-arylcarbonyl moiety is critical for the activity of the hydrazinecarbothioamide analogues and side chains on thioamide moiety were relatively insensitive to the activity. Some analogues were found to consistently exert the potency under more physiologically relevant condition where ER stress was induced by palmittic acid. ER stress markers such as CHOP and phosphorylation of eIF2a and PERK were decreased in western blotting upon treatment of compound 4h.

Synthesis and anti-endoplasmic reticulum stress activity of 2-arylcarbonylhydrazinecarbothioamides

2019 Fall National Meeting

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