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

Abstract

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 alpha1- and beta1-adrenoceptor binding affinities. Of the newly synthesized derivatives, 2-(2-hydroxy-3-(4-(2-phenoxyethyl)piperazin-1-yl)propoxy)-9H-xanthen-9-one dihydrochloride 9, 4-(2-hydroxy-3-(4-(2-phenoxyethyl)piperazin-1-yl)propoxy)-9H-xanthen-9-one dihydrochloride 12, and 4-(2-(4-(pyridin-2-yl)piperazin-1-yl)ethoxy)-9H-xanthen-9-one dihydrochloride 15 possessed significant anti-arrhythmic activity in the adrenaline-induced model of arrhythmia, with the ED50 values ranging 1.7-7.2 mg/kg. Compound 15 had the lowest ED50 value equaling 1.7 mg/kg, which was comparable with ED50 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)-9H-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.

Chemical modifications of a natural xanthone and antimicrobial activity against multidrug resistant Staphylococcus aureus and cytotoxicity against human tumor cell lines

“…For almost all lines, at least 50% of compounds were active, showing IC 50 values below 20 µM (about 10µg/mL for these sub-µM (about 10µg/mL for these sub-M (about 10µg/mL for these subµg/mL for these subg/mL for these substances). Compound (15), containing, tert-butylamino moieties was the most active, with IC 50 = 4.3, 7.6 and 8.5 µM for MCF-7 (breast), 786-0 (kidney) and HT-29 (colon) lines respectively. Compounds (10) and (11), with four or five member chains between N and O atoms and diethylamino moieties were more active than DOX over the resistant line NCI-ADR.…”

“…7 In recent years, xanthones and xanthone derivatives have been reported to have significant pharmacological activities based on their diverse structures. [8][9][10][11][12][13][14][15][16][17][18][19][20] Their interesting structural scaffold and the significant biological activities have led many scientists to isolate, modify or synthesize different xanthones for the development of prospective new drug candidates. 7 Many xanthones bearing nitrogenated side chains connected to the phenolic core in different positions by C, O or N atoms have been synthesized during the last 10 years, and this group of molecules have showed interesting biological effects 14,18,[21][22][23][24][25] including antibacterial 26 and cytotoxic activities.…”

“…Nova Figure 40S. 1 H NMR spectrum of (15), 300 MHz, acetone-d 6 Figure 41S. 13 C NMR spectrum of (15) 1 H NMR spectrum of (17), 300 MHz, DMSO-d 6 Chemical modifications of a natural xanthone and antimicrobial activity S19 Vol.…”

Design, synthesis, and anticonvulsant activity of some derivatives of xanthone with aminoalkanol moieties

“…The following starting materials have been achieved according to formerly published procedures (Scheme ), and their properties were published as well: 2‐(2‐hydroxyethoxy)‐9 H‐ xanthen‐9‐one and 4‐(2‐hydroxyethoxy)‐9 H‐ xanthen‐9‐one, 2‐(2‐chloroethoxy)‐9 H‐ xanthen‐9‐one, 2‐(3‐hydroxypropoxy)‐9 H‐ xanthen‐9‐one, 4‐(3‐hydroxypropoxy)‐9 H‐ xanthen‐9‐one …”

“…2‐(2‐Chloroethoxy)‐9 H‐ xanthen‐9‐one ( 1 ) was obtained from 2‐(2‐hydroxyethoxy)‐9 H‐ xanthen‐9‐one (mp 151–153 °C). The first step was the reaction between 2‐hydroxyxanthone with redistilled 2‐chloroethanol in acetone in the presence of anhydrous K 2 CO 3 and catalytic amount of TEBA and KI.…”