Ultrasound-Assisted Synthesis of Pyrazoline Derivatives as Potential Antagonists of RAGE-Mediated Pathologies: Insights from SAR Studies and Biological Evaluations

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem Pub Date : 2024-09-17 DOI:10.1002/cmdc.202400527

Anca-Elena Dascălu, Christophe Furman, Steve Lancel, Emmanuelle Lipka, Maxime Liberelle, Eric Boulanger, Alina Ghinet

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Abstract

In the context of age-related disorders, the receptor of advanced glycation end products (RAGE), plays a pivotal role in the pathogenesis of these conditions by triggering downstream signaling pathways associated with chronic inflammation and oxidative stress. Targeting this inflammaging phenomenon with RAGE antagonists holds promise for interventions with broad implications in healthy aging and the management of age-related conditions. This study explores the structure-activity relationship (SAR) of pyrazoline-based RAGE antagonists synthesized using an ultrasound-assisted green one-pot two-steps methodology. Our investigation identifies phenylurenyl-pyrazoline 2g as a promising candidate, demonstrating superior efficiency compared to the reference antagonist Azeliragon (IC50 = 13 µM). Compound 2g exhibits potent inhibition of the AGE2-BSA/sRAGE interaction (IC50 = 22 µM) and favorable affinity in Microscale Thermophoresis (MST) assays (Kd = 17.1 µM), along with a favorable safety profile, with no apparent cytotoxicity observed in vitro in the MTS assay. These findings underscore the potential of pyrazoline-derived RAGE antagonists as therapeutic agents for addressing age-related disorders.

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超声辅助合成吡唑啉衍生物作为 RAGE 介导的病理学的潜在拮抗剂：SAR 研究和生物评估的启示

在与年龄有关的疾病中，高级糖化终产物受体（RAGE）通过触发与慢性炎症和氧化应激有关的下游信号通路，在这些疾病的发病机制中发挥着关键作用。利用 RAGE 拮抗剂靶向这一炎症现象，有望对健康老龄化和老年相关疾病的治疗产生广泛影响。本研究采用超声辅助绿色一锅两步法合成了吡唑啉基 RAGE 拮抗剂，并对其结构-活性关系（SAR）进行了探索。我们的研究发现，苯基脲基吡唑啉 2g 是一种很有前途的候选化合物，与参考拮抗剂 Azeliragon（IC50 = 13 µM）相比，具有更高的效率。化合物 2g 对 AGE2-BSA/sRAGE 相互作用具有强效抑制作用（IC50 = 22 µM），在微尺度热泳 (MST) 试验中具有良好的亲和力（Kd = 17.1 µM），同时具有良好的安全性，在体外 MTS 试验中未观察到明显的细胞毒性。这些研究结果凸显了吡唑啉衍生的 RAGE 拮抗剂作为治疗药物治疗老年相关疾病的潜力。

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来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

期刊介绍： Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.