Фармацевтичний журнал (May 2019)
Synthesis, diuretic activity research and QSAR-analysis of N-(1,3,4-tiadiazol-2-il)substituted amides of alkanecarboxylic acids
Abstract
Diuretics are effective drugs that are widely used in medicine, but have unwanted side effects. The derivative of thiadiazole – acetozolamide is a known diuretic. Therefore, the search for diuretics in this series and the establishment of quantitative «structure–activity» (QSAR) dependencies is appropriate. The aim of the work was to synthesis N-(1,3,4-thiadiazol-2-yl)substituted alkanes of alkanecarboxylic acids, study their diuretic activity, and QSAR analysis. The objects of the study were N-(1,3,4-thiadiazol-2-yl)substituted alkanes of alkanecarboxylic acids, obtained by the interaction of 2-amino-5-alkyl-1,3,4-thiadiazole with the corresponding acylchlorides. Investigation of diuretic activity of synthesized compounds was carried out by the method of Berchin. Hyper-Chem and BuildQSAR software were used for calculation of molecular descriptors and QSAR-models. Synthesis of 12 N-(1,3,4-thiadiazol-2-yl)substituted amides of alkanecarboxylic acids, the structure of which was confirmed by PMR spectroscopy and elemental analysis. Studies of diuretic activity showed that the synthesized compounds had pronounced diuretic properties, and some of them according to activity indicators were approaching or exceeding comparative preparations. Compound N-(5-methyl-[1,3,4]thiadiazol-2-yl) propionamide showed the best diuretic effect: increased daily diuresis in white rats, in comparison with intact control, in 2.47 times (p ≤ 0,001), in comparison with hydrochlorothiazide was in 1,6 times and acetazolamide was 1,75 times. The calculation of the molecular descriptors of N-(1,3,4-thiadiazol-2-yl)substituted amides of alkanecarboxylic acids was conducted. Based on the calculated values of molecular descriptors and diuretic activity values of 12 synthesized compounds, a QSAR analysis was performed. Analysis of structure-diuretic activity showed the greatest influence of lipophilicity, energy parameters, spatial structure and size of the molecule. Moreover, diuretic activity increases with increasing logP, decreasing the refractive, volume and area of the molecule, increasing the energy of the higher occupied molecular orbital. Increasing the charge on the Sulfur atom of the thiadiazole ring and the Оxygen atom of the carbonyl group, reducing the angle between the Sulfur atoms, the Nitrogen of the amide group and the Oxygen, and increasing the angle between the Nitrogene atoms of the thiadiazole ring, the Oxygen and the Nitrogen of the amide group, also increases diuretic activity. The results of the diuretic activity of the synthesized compounds N-(1,3,4-thiadiazol-2-yl)substituted amides of alkanecarboxylic acids show the potential for the search for diuretic agents among 1,3,4-thiadiazole derivatives. The resulting QSAR models will be used to modelling and prediction the activity of new potential diuretics.
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