Synthesis of Novel 2-(Pyridin-2-yl) Pyrimidine Derivatives and Study of Their Anti-Fibrosis Activity

• Main Authors: Yi-Fei Gu, Yue Zhang, Feng-li Yue, Shao-tong Li, Zhuo-qi Zhang, Jing Li, Xu Bai
• Format: Article
• Language: English
• Published: MDPI AG 2020-11-01
• Series: Molecules
• Subjects: anti-fibrosis; collagen prolyl 4-hydroxylases; pyrimidine; COL1A1; synthesis
• Online Access: https://www.mdpi.com/1420-3049/25/22/5226

A pyrimidine moiety exhibiting a wide range of pharmacological activities has been employed in the design of privileged structures in medicinal chemistry. To prepare libraries of novel heterocyclic compounds with potential biological activities, a series of novel 2-(pyridin-2-yl) pyrimidine derivatives were designed, synthesized and their biological activities were evaluated against immortalized rat hepatic stellate cells (HSC-T6). Fourteen compounds were found to present better anti-fibrotic activities than Pirfenidone and Bipy55′DC. Among them, compounds ethyl 6-(5-(<i>p</i>-tolylcarbamoyl)pyrimidin-2-yl)nicotinate (<b>12m</b>) and ethyl 6-(5-((3,4-difluorophenyl)carbamoyl)pyrimidin-2-yl)nicotinate (<b>12q</b>) show the best activities with IC₅₀ values of 45.69 μM and 45.81 μM, respectively. Furthermore, the study of anti-fibrosis activity was evaluated by Picro-Sirius red staining, hydroxyproline assay and ELISA detection of Collagen type I alpha 1 (COL1A1) protein expression. Our study showed that compounds <b>12m</b> and <b>12q</b> effectively inhibited the expression of collagen, and the content of hydroxyproline in cell culture medium in vitro, indicating that compounds <b>12m</b> and <b>12q</b> might be developed the novel anti-fibrotic drugs.