Synthesis and Evaluation of Some Xanthone Derivatives for Anti‐Arrhythmic, Hypotensive Properties and Their Affinity for Adrenergic Receptors

A series of 2‐, 4‐ or 2‐methyl‐6‐substituted xanthone derivatives 8 – 17 containing selected piperazine moieties were synthesized and tested for their electrocardiographic, anti‐arrhythmic, and antihypertensive activity, as well as for the α 1 ‐ and β 1 ‐adrenoceptor binding affinities. Of the newly synthesized derivatives, 2‐(2‐hydroxy‐3‐(4‐(2‐phenoxyethyl)piperazin‐1‐yl)propoxy)‐9 H ‐xanthen‐9‐one dihydrochloride 9 , 4‐(2‐hydroxy‐3‐(4‐(2‐phenoxyethyl)piperazin‐1‐yl)propoxy)‐9 H ‐xanthen‐9‐one dihydrochloride 12 , and 4‐(2‐(4‐(pyridin‐2‐yl)piperazin‐1‐yl)ethoxy)‐9 H ‐xanthen‐9‐one dihydrochloride 15 possessed significant anti‐arrhythmic activity in the adrenaline‐induced model of arrhythmia, with the ED 50 values ranging 1.7–7.2 mg/kg. Compound 15 had the lowest ED 50 value equaling 1.7 mg/kg, which was comparable with ED 50 value of propranolol, which was used in this test as a reference compound. Compound 9 showed also the strongest hypotensive activity, which persisted for 60 minutes at the dose of 2.5 mg/kg. 2‐(2‐(4‐(2‐Phenoxyethyl)piperazin‐1‐yl)ethoxy)‐9 H ‐xanthen‐9‐one dihydrochloride 8 also significantly lowered blood pressure at a dose of 2.5 mg/kg but much weaker than compound 9 . Binding studies are in agreement with our pharmacological results and could explain anti‐arrhythmic effect of compound 15 and anti‐arrhythmic and hypotensive effects of compounds 9 and 12 .