设计,合成和生物评估morpholinopyrimidine衍生物作为抗炎剂
Sadaf Fatima1,2, Almaz Zaki2,3, Hari Madhav1
1Drug Design and Synthesis Laboratory, Department of Chemistry Jamia Millia Islamia New Delhi 110025 India nhoda@jmi.ac.in.
RSC advances
|June 29, 2023
概括
新型形态胺衍生物通过抑制巨细胞中的氧化,iNOS和COX-2来表现出强大的抗炎作用. 这些化合物代表了炎症相关疾病的有前途的治疗策略.
科学领域:
- 药用化学 医学化学
- 药理学 药理学是指药理学的学科.
- 免疫学 免疫学 免疫学
背景情况:
- 炎症是一种复杂的生物反应,与许多疾病有关.
- 开发新的抗炎药物仍然是制药研究的关键领域.
- 巨细胞在炎症过程中发挥着中心作用,特别是当它们被脂多糖 (LPS) 刺激时.
研究的目的:
- 为了合成新型的2-methoxy-6-((4-(6-morpholinopyrimidin-4-yl) piperazin-1-yl) ((phenyl) methyl) 衍生物.
- 评估这些化合物在LPS刺激的巨细胞中的抗炎活性.
- 研究作用机制,包括对氧化 (NO),可诱导氧化合成酶 (iNOS) 和循环氧化酶-2 (COX-2) 的影响.
主要方法:
- 摩尔福林皮里米丁衍生物的化学合成.
- 使用LPS刺激的RAW 264.7巨细胞对抗炎症活性进行体外评估.
- 测量氧化生产的情况.
- 定量实时PCR (qRT-PCR) 检测iNOS和COX-2mRNA的表达.
- 对于 iNOS 和 COX-2 蛋白质水平的西方斑点分析.
- 分子对接研究,以预测结合相互作用.
主要成果:
- 两种衍生品V4和V8在非细胞毒性度下显著抑制了NO生产.
- 化合物V4和V8显著降低了LPS刺激的巨细胞中的iNOS和COX-2mRNA表达.
- 西方斑点分析证实,V4和V8降低了iNOS和COX-2蛋白质的表达.
- 分子对接揭示了这些化合物与iNOS和COX-2活性位点的强烈亲和力和疏水性相互作用.
结论:
- 合成的胺衍生物,特别是V4和V8,具有显著的抗炎性质.
- 这些化合物有效地抑制了巨细胞中的关键炎症媒介 (NO, iNOS, COX-2).
- 这些发现表明这些化合物是潜在的新型治疗剂,用于管理与炎症相关的疾病.
相关概念视频
Structure-Activity Relationships and Drug Design
794
Drug design is a dynamic field that involves discovering and developing new medications based on specific biological targets. This process heavily relies on structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) to guide the design and optimization of efficient drugs.
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
794
Opioid Analgesics: Morphine and Other Natural Cogeners
301
Opioids are a class of drugs that mimic endogenous opioid peptides and act on opioid receptors, and help in pain relief. These compounds are classified as natural, synthetic, or semi-synthetic. Natural opioids, like morphine, codeine, and thebaine, are derived from the opium poppy plant (Papaver somniferum or Papaver album) and are termed opiates. Synthetic opioids are artificial, while semi-synthetic opioids combine natural and synthetic compounds. Morphine, a prototypical opioid, possesses a...
301
Opioid Analgesics: Synthetic and Semisynthetic Opioids
347
Synthetic and semisynthetic opioids are pivotal in pain management and tackling opioid addiction. Semisynthetic opioids, including morphinans (morphine derivatives), oxycodone, oxymorphone, hydrocodone, and hydromorphone, have improved pharmacokinetic profiles compared to morphine. Additionally, heroin and 6-MAM (6-Monoacetylmorphine) show better CNS penetration than morphine due to heightened lipid solubility. Hydromorphone, a potent opioid, undergoes hepatic metabolism to form the active...
347
Drugs for Treatment of Crohn's Disease in IBD Using Immunomodulatory Agents
201
Crohn's disease is an inflammatory bowel disorder marked by chronic inflammation of the GI tract. Various treatment strategies for Crohn's disease are employed, such as immunomodulatory agents, glucocorticoids, and biologics or anti-TNF therapy. Azathioprine (Imuran), a commonly used immunomodulatory drug for Crohn's disease, is converted in the body to mercaptopurine, which inhibits purine biosynthesis and cell proliferation. Both are utilized in severe cases of Inflammatory Bowel...
201
Adrenergic Agonists: Chemistry and Structure-Activity Relationship
3.1K
Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of...
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of...
3.1K
Drugs for Treatment of Crohn's Disease in IBD Using Biologic Agents: Anti-TNF
177
Tumor Necrosis Factor (TNF), a proinflammatory cytokine, contributes significantly to the inflammation seen in Crohn's disease. It exists as soluble TNF and membrane-bound TNF, with actions mediated through TNF receptors (TNFR). TNFR activation leads to the release of proinflammatory cytokines, T-cell activation, collagen production, and leukocyte migration, all contributing to inflammation in Crohn's disease. Anti-TNF monoclonal antibodies, namely infliximab (Remicade), adalimumab...
177


