Design, synthesis and biological evaluation of isochroman-4-one hybrids bearing piperazine moiety as antihypertensive agent candidates. Issue 13 (1st July 2019)

• Record Type: Journal Article
• Authors: Xie, Shaowen; Li, Xinnan; Yu, Hao; Zhang, Pengfei; Wang, Jia; Wang, Chaolei; Xu, Shengtao; Wu, Zheng; Liu, Jie; Zhu, Zheying; Xu, Jinyi
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 13(2019)
• Page Start: 2764
• Page End: 2770
• Publication Date: 2019-07-01
• Subjects: Antihypertensive activity -- α1-Adrenergic receptor antagonist -- Isochroman-4-one -- Hybrids -- Arylpiperazine; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.05.004
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 7, 8-Dihydroxy-3-methyl-isochromanone-4 (XJP), is a polyphenolic natural product with moderate antihypertensive activity. To obtain new agents with stronger potency and safer profile, we employed XJP and naftopidil as the lead compounds to design and synthesize a novel class of hybrids as antihypertensive agent 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 compounds6c, 6e, 6f, 6g, 6h, 6m and6q possessed potent in vitro vasodilation potency and α1 -adrenergic receptor antagonistic activity. Furthermore, the most potent compound6e 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 that6e deserves to be further investigated as a potential clinical candidate for the treatment of hypertension.