DIRECTED SEARCH FOR COMPOUNDS THAT AFFECT THE EXCRETORY FUNCTION OF RAT KIDNEYS, AMONG NEW CYCLOALKYLCARBONYL THIOUREAS AND THIOSEMICARBAZIDES DERIVATIVES
DOI:
https://doi.org/10.11603/mcch.2410-681X.2020.v.i2.11351Keywords:
synthesis, cycloalkylcarbonyl thioureas and thiosemicarbazides, spectral data, molecular docking, carbonic anhydrase II, diuretic activityAbstract
Introduction. Prolonged usage of diuretics, especially in large doses, the number and severity of side effects (water-electrolyte and metabolic disorders), as well as the relatively limited range of existing diuretics dictate the need to find new compounds that would have diuretic effects, simple production technology and would be safer.
The aim of the study – directed search for diuretics among unknown disubstituted thioureas and thiosemicarbazides using the molecular docking methodology as the way to explain the probable mechanism of action.
Research Methods. The structures of the target compounds have been proposed using drug-design approaches, namely the introduction of structural fragments into thioureas and thiosemicarbazides, which are characteristic of known diuretics. The synthesis of substituted cycloalkylcarbonylthioureas or thiosemicarbazides was carried out by a single-reactor method using cycloalkylcarbonyl chlorides, ammonium isothiocyanate and substituted anilines or carboxylic acid hydrazides. The structure of the synthesized compounds was proved by IR, 1H NMR spectroscopy, chromato-mass spectrometry and elemental analysis. Probable molecular mechanisms of activity were predicted due to molecular docking. Directed search for compounds that affect the excretory function of the kidneys of rats was conducted by the conventional method of E.B. Berkhin with water load.
Results and Discussion. It has been found that the single-reaction of cycloalkylcarbonyl chlorides with an equimolecular amount of ammonium isothiocyanate and substituted anilines or carboxylic acid hydrazides resulted in formation of substituted cycloalkylcarbonylthioureas or thiosemicarbazides. The structure of the synthesized compounds was discussed using IR, 1H NMR and chromato-mass spectra. Studies of the effect of the synthesized compounds on the excretory function of rats kidneys under water load have revealed several compounds that exceed the diuretic effect of “Furosemide” and compete with “Hydrochlorothiazide”. Molecular docking results have shown that the test compounds demonstrated a high affinity for carbonic anhydrase II and similar binding sites to reference drugs. This indicates their probable mechanism of action.
Conclusion. The developed and implemented strategy for searching of diuretics among cycloalkylcarbonyl thioureas and thiosemicarbazides derivatives has allowed to identify an effective compound (3.2), which is close to the reference drug “Hydrochlorothiazide” in terms of diuretic effect. Importantly, according to the results of molecular docking, the synthesized compounds as well as the reference drugs have a similar mechanism of action (carbonic anhydrase II inhibitors). It is likely, that the expressed diuretic effect of several compounds is related to the ability of substituted thioureas to form coordination bonds with the zinc cation in the active site of CA II. The obtained results substantiate the further purposeful search for potential diuretics among this class of compounds.
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