Marek Cegła

Preliminary evaluation of pharmacological properties of some xanthone derivatives

A series of xanthone derivatives were synthesized and examined for electrocardiographic, antiarrhythmic, hypotensive and anticonvulsant activities as well as for alpha(1)- and beta(1)-adrenergic binding affinities. Among the investigated compounds, some of them exhibited significant antiarrhythmic and/or hypotensive activity. The data obtained via receptor binding assay are in agreement with pharmacological results and could explain antiarrhythmic and/or hypotensive activity of the newly synthesized structures.

Antifungal and Antibacterial Activity of the Newly Synthesized 2-Xanthone Derivatives

A series of 2‐substituted xanthone derivatives 8–20 containing selected allyl, cinnamyl, morpholine, and imidazole moieties were synthesized and tested for their antifungal and antibacterial in‐vitro properties. Of the newly synthesized derivatives, ten revealed antifungal activity especially against Trichophyton mentagrophytes (the biggest inhibition zones ranged 35 mm for 11 and 13). 2‐(3‐(Allylamino)propoxy)‐9H‐xanthen‐9‐one hydrochloride 9 inhibited growth of all of the examined fungal species. Significant efficacy against evaluated yeasts and dermatophytes was also observed for 6‐chloro‐2‐methyl‐9H‐xanthen‐9‐one derivatives 11–13 containing encyclic amine moieties. Additionally, compounds 9, 11, and 12 hindered development of bacteria species but in a lesser degree. They were efficacious against Staphylococcus aureus, Escherichia coli, and Enterococcus faecalis.

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 α1‐ and β1‐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.

Preliminary Evaluation of Anticonvulsant Activity of Some Aminoalkanol and Amino Acid Cinnamic Acid Derivatives

A series of aminoalkanol and amino acid derivatives of trans-cinnamic acid as well as aminoalkanol derivatives of �-phenylcinnamic acid was synthesized and evaluated for anticonvulsant activity. All compounds were verified in mice after intraperitoneal (i.p.) administration in maximal electroshock (MES) and subcutaneous pentetrazole (ScMet) induced seizures as well as neurotoxicity assessment. Six of them showed protection in MES at 100 mg/kg b.w. and one at 300 mg/kg b.w. For selected derivatives evaluation in ScMet test in rats after per os (p.o.) administration, 6-Hz test in mice and pilocarpine-induced status in rats were performed. The results are quite encouraging and further modification of the structures might lead to discovering new potential anticonvulsants.

Anticonvulsant evaluation of aminoalkanol derivatives of 2- and 4-methylxanthone.

A series of 17 new aminoalkanol derivatives of 6-methoxy- or 7-chloro-2-methylxanthone as well as 6-methoxy-4-methylxanthone was synthesized and evaluated for anticonvulsant activity. All compounds were verified in mice after intraperitoneal (ip) administration in maximal electroshock (MES) and subcutaneous pentetrazole (scMet) induced seizures as well as neurotoxicity assessment. Eleven of the tested substances showed protection against electrically evoked seizures in the majority of the tested mice at the dose of 100 mg/kg. Additionally, one was effective at the dose of 30 mg/kg. Five substances were active at the dose of 300 mg/kg or at the dose of 100 mg/kg in the minority of the tested mice. The most promising compound revealed ED(50) value of 47.57 mg/kg in MES (mice, ip, 1h after administration) and at the same time its TD(50) was evaluated as above 400 mg/kg. Those values gave PI (calculated as TD(50)/ED(50)) of more than 8.41. Three other synthesized xanthone derivatives also proved to act as anticonvulsants and showed ED(50) values in MES test (mice, ip) ranged 80-110 mg/kg. Results were quite encouraging and suggested that in the group of xanthone derivatives new potential anticonvulsants might be found.

N-[(2,6-Dimethylphenoxy)alkyl]aminoalkanols-their physicochemical and anticonvulsant properties.

Twenty four new N-[(dimethylphenoxy)alkyl]aminoalkanols have been synthesized and evaluated for anticonvulsant activity in a series of in vivo tests: the maximum electroshock (MES), 6 Hz, and subcutaneous metrazole (ScMet). The compounds were also evaluated for possible neurotoxicity in the rotarod test. The majority of the achieved compounds exhibit quantified anticonvulsant activity. The most active compound 4: R-(-)-2N-[(2,6-dimethylphenoxy)ethyl]aminopropan-1-ol is active in MES with ED50=5.34 (male mice, ip), 22.28 (female mice, ip), 51.19 (male mice, po), 7.43 (rats, ip), and 28.60 (rats, po). Thermal analysis proved that its hydrochloride (4a) can exist in polymorphic forms. The compound binds to σ, 5-HT1A, and α2 receptors as well as 5-HT transporter and it does not exhibit mutagenic properties.

Studies on Novel Pyridine and 2-pyridone Derivatives of N-arylpiperazine as α-adrenoceptor Ligands

This paper describes the synthesis of a series of new N-arylpiperazine derivatives of pyridine and 2-pyridone. The in vitro pharmacological study indicated that all of the compounds possess affinity towards α1-adrenoceptors, with exception of 6d, and are selective over α2 receptor. The most potent compound 5f displayed 62-fold α2/α1 selectivity with Ki value of 27.3 nM for α1 receptor. Selectivity of other ligands ranged from 6 to more than 146-fold. Hydrochlorides of selected compounds with the best α1-adrenoceptor affinity (7b, 7e, 7f, 8b) were tested in vivo (hypotensive activity test in rats) and the results proved their α-adrenoreceptor antagonistic activity. Furthermore, the lipophilicity of the investigated compounds has been assessed experimentally and in silico.

Fluorescent 1,2,3-triazole derivative of 3′-deoxy-3-azidothymidine: synthesis and absorption/emission spectra

Abstract 3′-Deoxy-3-azidothymidine (AZT, zidovudine) is a nucleoside-analog reverse transcriptase inhibitor, successfully used against the human immunodeficiency virus (HIV). Its structure contains an azide function, which makes it a useful substrate for 1,2,3-triazole synthesis, using the copper-catalyzed azide-alkyne cycloaddition, the flagship reaction of ‘click chemistry’. Herein we present the synthesis and spectral characterization of its 1,2,3-triazole derivative containing a fluorenylmethyloxycarbonyl (fmoc) fluorescent fragment. The preparation and characteristics of a novel fluorescent probe, 9H-fluoren-9-ylmethyl prop-2-yn-1-yl carbonate (propargyl-fmoc) is also presented.

Kinetics of Hydrolysis of N-Methyl-2,4-dithiophenobarbital

The rate of hydrolytic degradation of N-methyl-2,4-dithiophenobarbital by spectrophotometric and separation methods was studied. The rate constants, order of reaction, activation energy, and pKa values were calculated based on the measurements of absorbance in the UV range. The changes in the absorbance values ​​over time for solutions of different pH were analysed. Based on the obtained results, it was found that the hydrolysis of N-methyl-2,4-dithiophenobarbital followed the kinetics of a pseudo-first order reaction. Plots illustrating dependences, log k, and pH indicate the catalytic effect of OH– ions on the occurring process. The results show that in an alkaline environment the pyrimidine ring undergoes cleavage in the 1–6 position, and gradual desulfurization. The obtained results were compared with data for phenobarbital, 2-thiophenobarbital, and 2,4-dithiophenobarbital. It can be concluded that the change of an oxygen atom to a sulfur atom in the ring of a barbituric acid derivative causes an easier decomposition of the compound. However, the insertion of a methyl group on the nitrogen atom increases the durability of the compound.