Design, synthesis, and anti-respiratory syncytial virus potential of novel 3-(1,2,3-triazol-1-yl)furoxazine-fused benzimidazole derivatives

Eur J Med Chem. 2023 Dec 5:261:115799. doi: 10.1016/j.ejmech.2023.115799.

Lu Mao ¹, Song Wang ², Ying Qu ¹, Haixia Wang ², Yifan Zhao ², Chuantao Zhu ², Zhongmou Zhang ¹, Chengyun Jin ³, Piet Herdewijn ⁴, Feng-Wu Liu ⁵, Zhenya Wang ⁶

Affiliations

1 XNA Platform, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of "Runliang" Anti-viral Medicines Research and Development, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
2 XNA Platform, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China.
3 XNA Platform, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
4 XNA Platform, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China; Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: [email protected].
5 XNA Platform, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China. Electronic address: [email protected].
6 XNA Platform, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of "Runliang" Anti-viral Medicines Research and Development, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China; International Joint Research Centre of National Animal Immunology, College of Veterinary Medicine, Henan Agricultural University, Zhengdong New District Longzi Lake 15#, Zhengzhou 450046, China. Electronic address: [email protected].

PMID: 37722289 DOI: 10.1016/j.ejmech.2023.115799

Abstract

Respiratory syncytial virus (RSV) is a major cause of serious lower respiratory tract infections in infants, children, and older persons. Currently, the only approved anti-viral chemotherapeutic drug for RSV treatment is ribavirin aerosol; however, its significant toxicity has led to restricted clinical use. In a previous study, we developed various benzimidazole derivatives against RSV. In this study, we synthesised 3-azide substituted furoxazine-fused benzimidazole derivatives by sulfonylation and azide substitution of the 3-hydroxyl group of the furoxazine-fused benzimidazole derivatives. Subsequently, a series of 3-(1,2,3-triazol-1-yl)-substituted furoxazine-fused benzimidazole derivatives were synthesised using the classical click reaction. Biological evaluations of the target compounds indicated that compound 4a-2 had higher activity against RSV (EC₅₀ = 12.17 μM) and lower cytotoxicity (CC₅₀ = 390.64 μM). Compound 4a-2 exerted anti-viral effects against the RSV Long strain by inhibiting Apoptosis and the elevation of Reactive Oxygen Species (ROS) and inflammatory factors caused by viral Infection in vitro. Additionally, the clinical symptoms of the virus-infected mice were markedly relieved, and the viral load in the lung tissues was dramatically decreased. The biosafety profile of compound 4a-2 was also favourable, showing no detectable adverse effects on any of the major organs in vivo. These findings underscore the potential of compound 4a-2 as a valuable therapeutic option for combating RSV infections while also laying the foundation for further research and development in the field.

Keywords

1,2,3-Triazole; Anti-RSV activity; Apoptosis inflammatory factor; Benzimidazole; Click reaction.

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