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  3. Design, synthesis, and biological evaluation of novel 3-naphthylthiophene derivatives as potent SIRT2 inhibitors for the treatment of myocardial fibrosis

Design, synthesis, and biological evaluation of novel 3-naphthylthiophene derivatives as potent SIRT2 inhibitors for the treatment of myocardial fibrosis

  • Bioorg Chem. 2025 Jan:154:108033. doi: 10.1016/j.bioorg.2024.108033.
Zhuo Zhang 1,  Chao Ma 1,  Xiong Gao 2,  Chuncheng Wang 2,  Yanchun Li 2,  Chen Yang 1,  Enlong Ma 3,  Maosheng Cheng 4
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, People's Republic of China.
  • 2 Department of Pharmacology, School of Life Sciences and Biopharmaceutical Science, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, People's Republic of China.
  • 3 Department of Pharmacology, School of Life Sciences and Biopharmaceutical Science, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, People's Republic of China. Electronic address: maenlong@hotmail.com.
  • 4 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, People's Republic of China. Electronic address: mscheng@syphu.edu.cn.
PMID: 39672075 DOI: 10.1016/j.bioorg.2024.108033
Abstract

SIRT2 (sirtuin2) is a NAD+-dependent deacetylase implicated in fibrosis and inflammation of the liver, kidney, and heart. In this study, we designed and synthesized a series of 3-naphthylthiophene derivatives and evaluated their inhibitory activity against the SIRT2 Enzyme. Among them, Z18 demonstrated outstanding SIRT2 inhibitory activity and selectivity. It significantly inhibited both the proliferation of cardiac fibroblasts (CFs) and the activity and expression of SIRT2 in CFs. Moreover, compound Z18 effectively suppressed TGF-β1-induced increases in α-SMA and CoL-1A1 protein expression, as well as hydroxyproline levels. Pharmacological mechanism tests demonstrated that Z18 inhibited SIRT2, thereby suppressing the TGF-β1-induced autocrine production of TGF-β1 and the phosphorylation of SMAD2/3 in CFs. In MTT assays, Z18 exhibited a significant inhibitory effect on the proliferation of CFs induced by TGF-β1. In vivo, Z18 effectively ameliorated TAC- and ISO-induced declines in cardiac function, histopathological morphological changes, and collagen deposition. It also inhibited SIRT2 activity and reduced the expression of α-SMA and p-Smad2/3. In hepatorenal toxicity assays, Z18 exhibited an excellent safety profile. These results support the further development of the selective SIRT2 Inhibitor Z18 as a potential lead compound for the treatment of myocardial fibrosis.

Keywords

3-Naphthylthiophene derivatives; Inhibitor; Myocardial fibrosis; SIRT2; TGF-β1.

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