Synthesis of Ofornine mimics from natural product l-vasicine as anti-hypertensive agents.

Abstract 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 up to 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.