Exploration of Pharmacophore in Chrysosplenol C as Activator in Ventricular Myocyte Contraction

Abstract

Chrysosplenol C (4′,5,6-trihydroxy-3,3′,7-trimethoxyflavone) isolated from Miliusa balansae has unique structural features as a reversible inotropic agent independent of β-adrenergic signaling and with selective activation of cardiac myosin ATPase. Hence, a series of chrysosplenol analogues were synthesized and explored for identification of pharmacophore that is essential for the increasing contractility in rat ventricular myocytes. Analogue 7-chloro-2-(3-hydroxyphenyl)-3-methoxy-4H-chromen-4-one showed highly potent contractility (54.8% at 10 μM) through activating cardiac myosin ATPase (38.7% at 10 μM). Our systematic structure− activity relationship study revealed that flavonoid nucleus of chrososplenol C appears to be an essential basic skeleton and hydrophobic substituent at position 7 of chromenone such as methoxy or chloro enhances the activity. Additionally, our ATPase study suggested that these chrysosplenol analogues have selectivity toward cardiac myosin activation. Thus, the novel flavonone with 3-/7-hydrophobic substituent and 3′-hydrogen bonding donor function is a novel scaffold for discovery of a new positive inotropic agent.

Genus Miliusa: A Review of Phytochemistry and Pharmacology

“…Chrysosplenol C ( 77 ), a flavonol, isolated from M. balansae , proved to be an essential backbone to induce a positive inotropic effect on rat ventricular myocytes [12]. This compound caused the contractive percentage of ventricular cell and the active percentage of cardiac myosin ATPase up to 53.0 ± 4.07% at 50 μ M and 28.1 ± 1.20% at 10 μ M, respectively, compared with those of positive control omecamtiv mecarbil [59.3 ± 2.60% at 400 nM and 80.4 ± 2.89% at 10 μ M, respectively] [12].…”

Trifluoromethylated Flavonoid-Based Isoxazoles as Antidiabetic and Anti-Obesity Agents: Synthesis, In Vitro α-Amylase Inhibitory Activity, Molecular Docking and Structure–Activity Relationship Analysis

“…Many biological proprieties have been reported for this type of polyphenolic compound, such as α-amylase inhibition [7,[13][14][15], antidiabetic [16,17], anticancer [18,19], and antioxidant effects [20], and other biological activities [21][22][23][24][25]. However, this rich biological profile has motivated several chemical research teams to synthesize flavonoids with special moieties and substituents to target particular biological activities [26][27][28][29][30].…”