2. Academic Validation
  3. Design, synthesis, and evaluation of quinolin-2(1H)-ones as PDE1 inhibitors for the treatment of inflammatory bowel disease

Design, synthesis, and evaluation of quinolin-2(1H)-ones as PDE1 inhibitors for the treatment of inflammatory bowel disease

  • Bioorg Chem. 2024 Nov 19:154:107979. doi: 10.1016/j.bioorg.2024.107979.
Qian Zhou 1,  Wei-Hao Luo 2,  Bei Zhang 3,  Zhao-Hang Xue 2,  Qing-Hua Huang 4,  Ling-Ling Feng 4,  Yinuo Wu 5,  Chen Zhang 6
Affiliations

Affiliations

  • 1 Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, PR China.
  • 2 School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, PR China.
  • 3 State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China; Jiangmen Central Hospital, Jiangmen 529030, PR China.
  • 4 State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
  • 5 State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China. Electronic address: wyinuo3@mail.sysu.edu.cn.
  • 6 School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, PR China. Electronic address: zhangch12020@gdpu.edu.cn.
PMID: 39603073 DOI: 10.1016/j.bioorg.2024.107979
Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory disease that affects the entire gastrointestinal tract. The complex etiology of IBD made it difficult to cure. Phosphodiesterases (PDEs) have garnered significant attention due to their involvement in immune and inflammatory responses in IBD. Most recently, we have reported a novel PDE1 Inhibitor 1 with quinolin-2(1H)-one scaffold, demonstrating anti-IBD effects. However, its short half-life (t1/2) in the rat liver microsomes (RLMs) is relatively short. In this study, structural optimization of compound 1 was performed to improve metabolic stability. Combined with molecular docking and dynamics simulations, a series of quinolin-2(1H)-one derivatives were synthesized. Among them, compound 7a showed an excellent IC50 value of 11 nM, high selectivity to PDE1 compared to Other PDEs, and good metabolic stability with RLM t1/2 of 67.3 min. The binding pattern between 7a and PDE1 revealed an additional hydrogen bond with Cys410, which could enhance the inhibitory activity. Furthermore, compound 7a demonstrated anti-inflammatory properties by reducing cytokine production and antioxidant activity in LPS-induced Raw264.7 cells, which contributed to its effectiveness against IBD. We believe that compound 7a could serve as an ideal tool for further pharmacological research on IBD.

Keywords

Inflammatory bowel disease; Metabolic stability; Molecular docking; Phosphodiesterase 1; Quinolin-2(1H)-one.

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