We report the chemical synthesis of Ofornine mimics from l-vasicine, structure-activity relationship studies and their in vivo screening for anti-hypertensive action in Wistar rats. It was observed that most of the analogs possessed anti-hypertensive effect; however, the duration of the effect was variable and mostly transient. The results demonstrated that the analogs 12, 13, 14, 15, and 16 showed a sharp and significant decrease in systolic and diastolic blood pressure for 30-60 min after intravenous administration. Analog (S)-(3-hydroxypyrrolidin-1-yl)(2-(pyridin-4-ylamino)phenyl)methanone (8) showed a significant decrease in blood pressure in a dose dependent manner whose maximal response lowered to 79.29±4.26 mmHg of SBP and 62.55±2.9 of DBP at 10 mg/kg intravenous dose. Further, the significant anti-hypertensive effect of 8 lasted for about 2.5 h at 10 mg/kg dose. We also evaluated the acute toxicity of the analog 8 as per the OECD guidelines and the compound was found to be safe upto the dose of 2000 mg/kg body weight. These preclinical findings suggest that the analog 8 could be considered as a promising lead and a durable anti-hypertensive drug candidate and deserves further investigation. The SAR studies clearly showed that the amide, hydroxyl and pyridine ring plays important role in showing the activity.

中文翻译：

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从天然产物l-Vasicine合成Ofornine模拟物作为抗高血压药

我们报告了L-vasicine的Ofornine模拟物的化学合成，结构-活性关系研究以及它们在Wistar大鼠中的抗高血压作用的体内筛选。据观察，大多数类似物都具有抗高血压作用。但是，效果的持续时间是可变的，并且大多是短暂的。结果表明，类似物12、13、14、15和16在静脉内给药后30-60分钟内显示收缩压和舒张压急剧而显着降低。类似物（S）-（3-羟基吡咯烷-1-基）（2-（吡啶-4-基氨基）苯基）甲酮（8）以剂量依赖性方式显示血压显着降低，最大反应降至79.29±4.26静脉内剂量为10 mg / kg时，mmBg SBP和DBP为62.55±2.9。进一步，10 mg / kg剂量下8的显着抗高血压作用持续约2.5小时。我们还根据OECD指南评估了类似物8的急性毒性，发现该化合物在剂量为2000 mg / kg体重时是安全的。这些临床前发现表明，类似物8可以被认为是有前途的先导和持久的抗高血压药物候选者，值得进一步研究。SAR研究清楚地表明，酰胺，羟基和吡啶环在显示活性方面起着重要作用。这些临床前发现表明，类似物8可以被认为是有前途的先导和持久的抗高血压药物候选者，值得进一步研究。SAR研究清楚地表明，酰胺，羟基和吡啶环在显示活性方面起着重要作用。这些临床前发现表明，类似物8可以被认为是有前途的先导和持久的抗高血压药物候选者，值得进一步研究。SAR研究清楚地表明，酰胺，羟基和吡啶环在显示活性方面起着重要作用。