DIRECTED SEARCH FOR COMPOUNDS THAT AFFECT THE EXCRETORY FUNCTION OF RAT KIDNEYS, AMONG NEW CYCLOALKYLCARBONYL THIOUREAS AND THIOSEMICARBAZIDES DERIVATIVES

Authors

  • O. V. Kholodniak ZAPORIZHZHIA STATE MEDICAL UNIVERSITY
  • K. V. Sokolova DNIPROPETROVSK MEDICAL ACADEMY
  • S. I. Kovalenko ZAPORIZHZHIA STATE MEDICAL UNIVERSITY
  • O. A. Pidpletnya DNIPROPETROVSK MEDICAL ACADEMY

DOI:

https://doi.org/10.11603/mcch.2410-681X.2020.v.i2.11351

Keywords:

synthesis, cycloalkylcarbonyl thioureas and thiosemicarbazides, spectral data, molecular docking, carbonic anhydrase II, diuretic activity

Abstract

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.

References

Moskvichev, Yu.A., & Feldblyum, V.Sh. (2007). Chemistry in our lives (products of organic synthesis and their use): Monograph.Yaroslavl: Publishing House of the Nuclear Technology University.

Feng, M., Tang, B., Liang, S.H., & Jiang, X. (2016). Sulfur containing scaffolds in drugs: Synthesis and application in medicinal chemistry. Curr. Top. Med. Chem., 16 (11), 1200-1216. DOI: https://doi.org/10.2174/1568026615666150915111741

Roush, G.C., Kaur, R., & Ernst, M.E. (2013). Diuretics: A review and update. J. Cardiovasc. Pharmacol. Ther., 19 (1), 5-13.

Temperini, C., Cecchi, A., Scozzafava, A., & Supuran, C.T. (2008.) Carbonic anhydrase inhibitors. Interaction of indapamide and related diuretics with 12 mammalian isozymes and X-ray crystallographic studies for the indapamide-isozyme II adduct. Bioorg. Med. Chem. Lett., 18 (8), 2567-2573. DOI: https://doi.org/10.1016/j.bmcl.2008.03.051

Radchenko, O.M. (2016). Pobichni efekty diure­tychnoi terapii ta shliakhy yikh podolannia [Particular effects of diuretic therapy and hats]. Ratsionalna far­makoterapiia – Regional Pharmacotherapy, 3 (40), 5-10 [in Ukrainian].

Bedane, K.G., & Singh, G.S. (2015). Reactivity and diverse synthetic applications of acyl isothiocyanates. ARKIVOC, 6, 206-245. DOI: https://doi.org/10.3998/ark.5550190.p009.052

Dawood, K.M. (2019). Bisthiourea derivatives and their utility in synthesis of monoheterocyclic, bishetero­cyclic, and fused heterocyclic systems. J. Heterocycl. Chem., 56 (6), 1701-1721. DOI: https://doi.org/10.1002/jhet.3540

The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug data with comprehensive drug target information. Retrieved from: https://www.drugbank.ca/

Shakeel, A., Altaf, A.A., Qureshi, A.M., & Bad­shah, A. (2016). Thiourea derivatives in drug design and medicinal chemistry: A short review. Journal of Drug Design and Medicinal Chemistry, 2 (1), 10-20. DOI: https://doi.org/10.11648/j.jddmc.20160201.12

Viana, G.M., Soares, D.C., Santana, M.V., & do Amaral, L.H. (2017). Antileishmanial thioureas: synthesis, biological activity and in silico evaluations of new pro­mising derivatives. Chem. Pharm. Bull., 65 (10), 911-919. DOI: https://doi.org/10.1248/cpb.c17-00293

Limban, C., Marutescu, L., & Chifiriuc, M.C. (2011). Synthesis, spectroscopic properties and anti­pathogenic activity of new thiourea derivatives. Molecules, 16 (9), 7593-7607. DOI: https://doi.org/10.3390/molecules16097593

Choi, J., & Jee, J.G. (2015). Repositioning of thiourea-containing drugs as tyrosinase inhibitors. Int. J. Mol. Sci., 16 (12), 28534-28548. DOI: https://doi.org/10.3390/ijms161226114

Mohapatra, R.K., Das, P.K., Pradhan, M.K., El-Ajaily, M.M., Das, D., Salem, H.F., & E-Zahan, M.K. (2019). Recent advances in urea- and thiourea-based metal complexes: biological, sensor, optical, and corroson inhibition studies. Comments on Inorganic Chemistry, 1–61. DOI: https://doi.org/10.1080/02603594.2019.1594204

Sippel, K.H., Robbins, A.H., Domsic, J., Genis, C., Agbandje-McKenna, M., & McKenna, R. (2009). High-resolution structure of human carbonic anhydrase II complexed with acetazolamide reveals insights into inhibitor drug design. Acta Cryst. F., 65 (10), 992-995. DOI: https://doi.org/10.1107/S1744309109036665

Coldham, C.I. (2004). Modern Methods of Organic Synthesis (4th edition). Cambridge University Press.

Protein Data Bank. Retrieved from: http://www.rcsb.org/pdb/home/home.do.

ChemAxon MarvinSketch version 19.24. Retrieved from: http://www.chemaxon.com.

Trott, O., & Olson, A.J. (2010). AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J. Comput. Chem., 31, 455-461. DOI: https://doi.org/10.1002/jcc.21334

Discovery Studio Visualizer v19.1.018287. Accelrys Software Inc.

(1986). European convention for the protection of vertebrate animal used for experimental and other scientific purposes. Council of Europe, Strasbourg

Berkhin, Ye.B. (1970). Metody izuchenyya vliyaniya novykh khimicheskikh soyedineniy na funktsiyu pochek [Methods of studying the effect of new chemical compounds on renal function]. Khim.-farmats. zhurn. – Chem. farm. Journal, 11 (5), 311 [in Russian].

Bryukhanov, V.M., Zverev, Y.F., Lampatov, V.V., & Zharikov, A.Yu. (2009). Metodologycheskiye podkhody k yzucheniyu funktsyy pochek v eksperimentye na zhy­votnykh [Methodological approaches to the study of renal function in an animal experiment]. Nefrologiya – Ne­phro­logy, 13 (3), 52-62 [in Russian].

Stefanova, O.V. (2001). Doklinicheskiye issle­dovaniya lekarstvennykh sredstv [Preclinical studies of drugs]. Kyiv: Avi-Cena Publishing House [in Ukrainian].

Lapach, S.N., Chubenko, A.V., & Babich, P.N. (2000). Statisticheskiye metody v biomeditsinskikh issledovaniyakh s ispolzovaniyem EXCEL [Statistical methods in biomedical research using EXCEL]. Kyiv: Morion [in Russian].

Antypenko, L., Meyer, F., Kholodniak, O., Jirás­ková, T., Troianova, A., Buhaiova, V., …, & Steffens, K. (2019). Novel acyl thiourea derivatives: synthesis, anti­fungal activity, gene toxicity, drug-like screening and molecular docking. Arch. Pharm. (Weinheim)., 352 (2), e1800275. DOI: https://doi.org/10.1002/ardp.201800275

Breitmaier, E. (Ed.). (2002). Structure elucidation by NMR in organic chemistry: a pract. Guide. 3rd rev. edn. Wiley. DOI: https://doi.org/10.1002/0470853069

Stuart, B.H. (2004). Infrared spectroscopy: fundamentals and applications. Wiley, DOI: https://doi.org/10.1002/0470011149

Published

2020-08-21

How to Cite

Kholodniak, O. V., Sokolova, K. V., Kovalenko, S. I., & Pidpletnya, O. A. (2020). DIRECTED SEARCH FOR COMPOUNDS THAT AFFECT THE EXCRETORY FUNCTION OF RAT KIDNEYS, AMONG NEW CYCLOALKYLCARBONYL THIOUREAS AND THIOSEMICARBAZIDES DERIVATIVES. Medical and Clinical Chemistry, (2), 5–16. https://doi.org/10.11603/mcch.2410-681X.2020.v.i2.11351

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Section

ORIGINAL INVESTIGATIONS