title: 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 30-60min 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±4.26mmHg of SBP and 62.55±2.9 of DBP at 10mg/kg intravenous dose. Further, the significant anti-hypertensive effect of 8 lasted for about 2.5h at 10mg/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 2000mg/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.
authors.affiliation: Bio-organic Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, J&K, India. Electronic address: mushtaqahmadaga@gmail.com.
authors.forename: Mushtaq A
authors.initials: MA
authors.lastname: Aga
authors.affiliation: Department of Pharmacology, University of Illinois, Chicago, IL, USA(1).
authors.forename: Sheikh
authors.initials: S
authors.lastname: Rayees
authors.affiliation: Department of Chemistry, University of Florida, Gainesville, FL, USA(1). Electronic address: roufdr99@gmail.com.
authors.forename: Abdul
authors.initials: A
authors.lastname: Rouf
authors.affiliation: Bio-organic Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, J&K, India.
authors.forename: Brijesh
authors.initials: B
authors.lastname: Kumar
authors.affiliation: PK-PD Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, J&K, India.
authors.forename: Anjna
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Chemistry, MVR College Andhra University, Gajuwaka, Visakhapatnam 530026, India.
authors.forename: P V V S
authors.initials: PVVS
authors.lastname: Nagaraju
authors.affiliation: PK-PD Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, J&K, India.
authors.forename: Gurdarshan
authors.initials: G
authors.lastname: Singh
authors.affiliation: Bio-organic Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, J&K, India. Electronic address: drsctaneja@gmail.com.
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Taneja
mesh_terms: D000470:Alkaloids / Q000737:chemistry*; D000631:Aminopyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006973:Hypertension / Q000188:drug therapy*; D007275:Injections, Intravenous; D051379:Mice; D015394:Molecular Structure; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D000631:Aminopyridines; D000959:Antihypertensive Agents; D001688:Biological Products; D010880:Piperidines; D011799:Quinazolines; C000621708:ofornine; C019592:vasicine
keywords: 3-Hydroxypyrrolidine; Anti-hypertensive activity; Blood pressure; Ofornine; l-Vasicine