Design, synthesis and biological evaluation of hydrogen sulfide-releasing isochroman-4-one derivatives as new antihypertensive agent candidates

Cardiovascular diseases are increasingly threating the global human health, hypertension is the most important risk factor for cardiovascular and cerebrovascular diseases. To improve the antihypertensive activity and cardiovascular protective effect of natural product (±)-7,8-dihydroxy-3-methyl-isochroman-4-one [(±)-XJP], a series of novel H₂S-releasing isochroman-4-one derivatives were designed and synthesized by coupling hydrogen sulfide (H₂S)-releasing donors with the analogs of (±)-XJP. Further, the H₂S-releasing assay indicated that some target compounds showed excellent H₂S generating ability. Moreover, these novel hybrids exhibited moderate to good in vitro vasodilation efficacy. Among them, the most potent compound exhibited potent in vivo antihypertensive activity with the maximum antihypertensive amplitude about 27%, which was more potent than that of the lead compound (±)-XJP. These results suggested that the hybridization of H₂S-donors and (±)-XJP analogs may provide a promising approach for the discovery of novel antihypertensive agents.