Synthesis of benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives and its potential applications in atherosclerosis

  • Bioorg Med Chem Lett. 2026 May:134:130554. doi: 10.1016/j.bmcl.2026.130554.
Xia Chen  1 ,  Ruilin Zhang  2 ,  Zhaolong He  1 ,  Xin Qian  2 ,  Chuxin Yao  1 ,  Xiaoyu Xiong  1 ,  Fangke Weng  1 ,  Shiqiang Xu  3 ,  Ya Wu  4 ,  Zihui Li  5
Affiliations
  • 1. Institute of Pharmaceutical Process, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China.
  • 2. Department of Vascular Surgery, The Affiliated Hospital of Southwest Medical University, 646000 Luzhou, China; Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, 646000 Luzhou, China.
  • 3. Institute of Pharmaceutical Process, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China. Electronic address: [email protected].
  • 4. Department of Vascular Surgery, The Affiliated Hospital of Southwest Medical University, 646000 Luzhou, China; Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, 646000 Luzhou, China. Electronic address: [email protected].
  • 5. Department of Cardiovascular Medicine, The Affiliated Hospital, Southwest Medical University, 646000 Luzhou, China. Electronic address: [email protected].
PMID: 41554381 DOI: 10.1016/j.bmcl.2026.130554
Abstract

In the search for novel anti-atherosclerotic agents, we herein report the design, synthesis, and evaluation of a series of benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives (5a-5n). Cytotoxicity assessment in RAW 264.7 cells indicated minimal toxicity for most compounds under experimental conditions. Notably, compound 5j exhibited superior anti-inflammatory activity, significantly attenuating intracellular Reactive Oxygen Species (ROS) while maintaining exceptional cytocompatibility (>100% cell viability at 1.25-20 μM) and demonstrating the most potent suppression of lipid accumulation. Mechanistic studies revealed that compound 5j synergistically modulates two key pathways: downregulation of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and restoration of Cholesterol homeostasis via upregulation of ABCG1, leading to enhanced Cholesterol efflux and 69.9% inhibition of foam cell formation at 3.25 μM (p < 0.001). SwissADME predictions indicated that compound 5j possesses favorable membrane permeability, high gastrointestinal absorption, and potential oral bioavailability. These findings establish compound 5j as a potential lead for developing atherosclerosis therapies through coordinated modulation of inflammation and lipid metabolism.

Keywords
Anti-inflammatory; Atherosclerosis; Benzo[e][1,2,4]thiadiazine; Cholesterol efflux.
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