Design, synthesis and biological evaluation of isochroman-4-one hybrids bearing piperazine moiety as antihypertensive agent candidates

Xie, Shaowen; Li, Xinnan; Yu, Hao; Zhang, Pengfei; Wang, Jia; Wang, Chaolei; Xu, Shengtao; Wu, Zheng; Liu, Jie; Zhu, Zheying; Xu, Jinyi

Abstract

7,8 Dihydroxy 3 methyl isochromanone 4 XJP is a polyphenolic natural product with moderate antihypertensive activity. T o obtain new agents with stronger potency and safer profile , we employed XJP and naftopidil as the lead compound s t o design and synth esize a novel class of hybrids as antihypertensive candidates, In the present study, a series of hybrids ( 6a r ) of XJP bearing arylpiperazine moiety, which is identified as the pharmacophore of naftopidil, were designed and synthesized as novel α 1 adrenergic receptor antagonists. The biological evaluation showed that target compounds 6c , 6e , 6f , 6g , 6h , 6m and 6q possessed potent in vitro vasodilation potency and α 1 adrenergic receptor antagonistic activity . Furthermore, the most potent compound 6e significantly reduced the systolic and diastolic blood pressure in spontaneously hypertensive rats (SHRs),which was comparable to that of naftopidil, and it had no observable effects on the basal heart rate, suggesting that 6e deserves to be further investigated as a potential clinical candidate for the treatment of hypertension.

Citation

Xie, S., Li, X., Yu, H., Zhang, P., Wang, J., Wang, C., …Xu, J. (2019). Design, synthesis and biological evaluation of isochroman-4-one hybrids bearing piperazine moiety as antihypertensive agent candidates. Bioorganic and Medicinal Chemistry, 27(13), 2764-2770. https://doi.org/10.1016/j.bmc.2019.05.004

• Journal Article Type: Article
• Acceptance Date: May 4, 2019
• Online Publication Date: May 6, 2019
• Publication Date: Jul 1, 2019
• Deposit Date: Jul 6, 2019
• Publicly Available Date: May 7, 2020
• Journal: Bioorganic & Medicinal Chemistry
• Print ISSN: 0968-0896
• Electronic ISSN: 1464-3391
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 27
• Issue: 13
• Pages: 2764-2770
• DOI: https://doi.org/10.1016/j.bmc.2019.05.004
• Keywords: Organic Chemistry; Clinical Biochemistry; Molecular Medicine; Biochemistry; Molecular Biology; Drug Discovery; Pharmaceutical Science
• Public URL: https://nottingham-repository.worktribe.com/output/2257493
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0968089618318637?via%3Dihub