Dependence of anticonvulsant activity of 1-aryl-1, 5-dihydro-4H-pyrazole (3,4-d) pyrimidine-4-one derivatives on biopharmaceutical factors

Abstract

Background: We have synthesized three 5-R-1-aryl-1,5-dihydro-4Н-pyrazole(3,4-d)pyrimidine-4-one derivatives that previously have demonstrated powerful anticonvulsant activity. A great number of physicochemical factors are known to influence on bioavailability and stability of active pharmaceutical ingredients. Therefore the purpose of research was to determine the effect of purification technology and dispersibility of 5-R-1-aryl-1, 5-dihydro-4Н-pyrazole (3,4-d) pyrimidine-4-one derivatives on their anticonvulsant activity.Methods: The anticonvulsant effect of this compounds was studied in a model of pentylenetetrazole-induced seizure in mice.Results: The results obtained revealed the optimal solvent for recrystallization of compounds to be isopropanol: compounds, purified by recrystallization from isopropanol, had higher solubility in water and tween; also, they had a tendency to increase anticonvulsant activity. It was found that there is a significant dependence of the latter on compound’s dispersion - the smaller the size of crystals the higher anticonvulsant activity.Conclusions: The dependence of anticonvulsant activity of compounds on the degree of dispersion was proved: the smaller particle size the higher anticonvulsant activity. This can be explained by fast dissolution of fine-dispersed substances, thus increasing the bioavailability if the compounds studied.

Synthesis, docking study, and pharmacological evaluation of S-acetamide derivatives of 4,6-dimethyl-2-thiopyrimidine as anticonvulsant agents

“…The NH proton of compound 1j with the cyclohexyl substituent resonates in the form of a doublet and in a stronger field (7.32 ppm). The protons of the methylene SCH 2 group of the synthesized compounds 1a-k shifted slightly to the strong field (4.00-3.67 ppm), compared to the similar signals synthesized by us earlier (4-oxo-6-methyl-2-pyrimidinyl)thio-N-acetamides (4.12-4.00 ppm) (Severina et al, 2019) due to the absence of electronwithdrawing effects of the carbonyl group at the fourth position of the pyrimidine cycle. The singlet signal of the proton in the fifth position of the pyrimidine cycle was observed at 6.88-6.67 ppm, and the compounds 1b, c were overlaid with the aromatic proton signals.…”

“…As with the thiopyrimidine-4(3H)-one acetamides (Severina et al, 2019), the compound with the 4-bromophenyl radical 1e was the most active: it statistically significantly prolonged the latency period and the duration of the seizure by 3.4 and 2.2 times, respectively, and by 80% reduced the lethality of animals; the severity of seizure was 2.0 points against 4.96 in the control group. However, the anticonvulsant action of N-(4bromophenyl)-2-((4,6-dimethylpyrimidin-2-yl)thio)acetamide 1e was significantly weaker than that of its structural analogue: N-(4-bromophenyl)-2-[(4-methyl-6-oxo-1H-pyrimidin-2-yl) thio]acetamide.…”

“…The choice of alkylating agents was based on the literature and own research findings on the effect of substituent in the amide moiety on anticonvulsant activity (Matias et al, 2017;Severina et al, 2019). As can be seen from Scheme 1, the modification of the scaffold 4,6-dimethyl-2-thiopyrimidine occurred by introducing an acetamide moiety with various biologically active substituents: aryl, cyclohexyl, and 2,3-dihydro-1,4-benzodioxin.…”

“…Our previous studies identified a number of substances with pronounced anticonvulsant properties and a sufficient profile among pyrimidine derivatives (Severina et al, 2019), its annelated (El Kayal et al, 2019) and condensed derivatives (Severina et al, 2017). In each of the study groups, promising anticonvulsants were found and significant patterns of "structureanticonvulsant activity" were established.…”

Molecular docking, ADMET study and in vivo pharmacological research of N-(3,4-dimetoxyphenyl)-2-{[2-methyl-6-(pyridine-2-yl)-pyrimidin-4-yl]thio}acetamide as a promising anticonvulsant

“…It is known that various biopharmaceutical aspects, including purity, concomitant impurities, crystal form, etc., influence the manifestation of the pharmacological activity (Severina et al 2017). As the synthesis conditions of the test substance Epirimil were changed, its anticonvulsant activity was examined, using the PTZ-induced seizures in rats to obtain more reliable results.…”