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

• Published in: Medicinal chemistry research Vol. 28; no. 12; pp. 2142 - 2152
• Main Authors: Choi, Hoon, Yun, Wheesahng, Lee, Jung-hun, Jang, Seoul, Park, Sang Won, Kim, Dong Hwan, Seon, Kyoung Pyo, Hyun, Jung-mi, Jeong, Kwiwan, Ku, Jin-mo, Nam, Tae-gyu
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.12.2019; Springer Nature B.V
• Subjects: Alzheimer's disease; Apoptosis; Arteriosclerosis; Atherosclerosis; Beta cells; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Diabetes mellitus; Diabetic retinopathy; Endoplasmic reticulum; Hydroxynaphthoic acid; Neurodegenerative diseases; Organic chemistry; Original Research; Palmitic acid; Pharmacology/Toxicology; Protein folding; Proteins; Retinopathy; Substitutes; Tethering; Western blotting; 2-Arylcarbonylhydrazinecarbothioamides; Chemical chaperone; Misfolded protein; Endoplasmic reticulum stress
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-019-02442-1

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, β-cell apoptosis and lung inflammation. We found a series of N -substituted-2-arylcarbonylhydrazinecarbothioamides to potently decrease ER stress signal, showing up to almost 300-fold better activity than 1-hydroxynaphthoic acid and tauro-ursodesoxycholic acid, positive controls, respectively. Structure−activity relationship (SAR) study showed that 2-arylcarbonyl moiety is critical for the activity of the hydrazinecarbothioamide analogues and side chains tethering 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 palmitic acid. ER stress markers such as CHOP and phosphorylated eIF2α and PERK were accordingly decreased in western blotting upon treatment of compound 4h . Potential ER stress inhibitory activity and novel structures could provide a novel platform for new chemical chaperone and therapy for protein misfolding diseases.