Effect of some compounds from the series of derivatives of cyanothioacetamide with analgesic activity on liver function parameters of rats with chronic administration of paracetamol against the background of alcohol load
DOI:
https://doi.org/10.18413/rrpharmacology.11.555Abstract
Introduction: Derivatives of 1,4-dihydropyridines from a series of α-cyanothioacetamide derivatives are a potentially promising class of compounds with analgesic activity.
Materials and methods: The experiment was carried out on 64 white male rats weighing 220-250 g. The rats were divided into 8 groups: intact, control, comparison (thiotriazoline 50 mg/kg) and 5 experimental groups (derivatives of 1.4-dihydropyridine and thiadiazine 5 mg/kg). Acute paracetamol-alcohol liver damage was modeled after two weeks of taking 1 mL of 400 ethanol and paracetamol at a dose of 500 mg/kg.
Results: The total bilirubin level in the control group, compared to that in the intact, increased by 2.88 times, direct bilirubin – by 37.8%, ALT – by 38.85%, AST – by 51.54%, and alkaline phosphatase – by 163%. In the reference group, compared to the intact, the ALT level increased by 44.76%, AST – by 18.11%, alkaline phosphatase – by 19.4%, and AST reduced by 22.06%. In the Mar-014 group, direct bilirubin reduced by 42.7%. In the CV-150 compound group, total bilirubin reduced by 51.6%, AST – by 18.64%, and alkaline phosphatase – by 272.4%. In the TD-0331 group, the AST index increased by 35.7%, whereas alkaline phosphatase decreased by 43.1%. In the CV-131compound group, when compared with the control group, total bilirubin reduced by 75.3%, direct bilirubin – by 10.1%, and AST – by 12%. In the d02-123 group, no indicators exceeded the values of rats in the intact group.
Conclusion: The most pronounced hepatoprotective properties were shown by the compound with the code d02-123.
Graphical Abstract

Keywords:
hepatotoxicity, hepatoprotectors, non-steroidal anti-inflammatory drugs, paracetamol-alcoholic liver damage, cyanothioacetamide derivativesReferences
Ahmed MH, ElHashash MA, Marzouk MI, ElNaggar AM (2019) Design, synthesis, and biological evaluation of novel pyrazole, oxazole, and pyridine derivatives as potential anticancer agents using mixed chalcone. Journal of Heterocyclic Chemistry 56(1): 114–123. https://doi.org/10.1002/jhet.3380
Antonenko OM (2013) Toxic liver lesions. Medical Council 3: 45–51. https://doi.org/10.21518/2079-701X-2013-6-45-51[in Russian]
Balukova EV, Uspensky JP, Fominykh SA (2018) Liver lesions of different genesis (toxic, drug, dysmetabolic): from etiological heterogeneity to a single unified therapy of patients. RMZ. Medical Review 26(1): 35–40. [in Russian]
Bibik EYu, Saphonova AA, Yeryomin AV, Frolov KA, Dotsenko VV, Krivokolysko SG (2017a) Study of analeptic activity of tetrahydropyrido[2,1-b][1,3,5]thiadiazine derivatives. Research Results in Pharmacology 3(4): 20–25. https://doi.org/10.18413/2313-8971-2017-3-4-20-25
Bibik EYu, Yaroshevskaya OG, Devdera AV, Demenko AV, Zakharov BB, Frolov KA, Dotsenko BB, Krivokolkolsko SG (2017b) Search for agents with anti-inflammatory activity among tetrahydropyrido[2,1-3][1,3,5] thiadiazine derivatives. Chemico-Pharmaceutical Journal [Khimiko-Farmatsevticheskii Zhurnal] 51(8): 16–19. https://doi.org/10.30906/0023-1134-2017-51-8-16-19 [in Russian]
Bibik IV, Bibik EY, Dotsenko BB, Frolov KA, Krivokololsko SG, Aksenov NA, Aksenova IV, Scherbakov SV, Ovcharov SN (2021) Synthesis and analgesic activity of new heterocyclic derivatives of cyanothioacetamide. Russian Journal of General Chemistry [Zhurnal Obshchei Khimii] 91(2): 154–166. https://doi.org/10.31857/S0044460X21020025 [In Russian]
Daina A, Michielin O, Zoete V (2019) Swiss Target Prediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Research 47(1): 357–364. https://doi.org/10.1093/nar/gkz382 [PubMed] [PMC]
Diachenko VD, Diachenko IV, Nenaidenko VG (2018) Cyanothioacetamide – a polyfunctional reagent with great synthetic possibilities. Advances in Chemistry [Uspekhi khimii] 87(1): 1–27. https://doi.org/10.1070/RCR4760 [in Russian]
Dotsenko BB, Frolov KA, Chigorina EA, Khrustaleva AN, Bibik EY, Krivokolkolsko SG (2019) New possibilities of the Mannich reaction in the synthesis of N-, S,N- and Se,N-heterocycles. News of the Academy of Sciences. Chemical series [Izvestiya Akademii Nauk. Seriya Khimicheskaya] 4: 691–707. [in Russian]
Gouda MA, Hussein BH, Helal MH, Salem MA (2018) Synthesis and medicinal importance of nicotinonitriles and their analogous. Journal of Heterocyclic Chemistry 55(7): 1524–1553. https://doi.org/10.1002/jhet.3188
Khan MM, Khan S, Iqbal S (2016) Recent developments in multicomponent synthesis of structurally diversified tetrahydropyridines. RSC Advances 6(48): 42045–42061. https://doi.org/10.1039/c6ra06767k
Khot S, Auti PB, Khedkar SA (2021) Diversified synthetic pathway of 1,4- dihydropyridines: A class of pharmacologically important molecules. Mini-reviews in Medicinal Chemistry 21(2): 135. https://doi.org/10.2174/1389557520666200807130215 [PubMed]
Koroleva MV (2015) Exogenous-toxic hepatitis. Modern view on etiology, pathogenesis, clinical course. Drug Bulletin [Lekarstvennyy Vestnik] 9(2): 18–22. [in Russian]
Marshalko DV, Pchelin IY, Shishkin AN (2018) Nonalcoholic fatty liver disease: comorbidity, clinical significance and methods of fibrosis diagnosis. Medical Sciences [Meditsinskie Nauki] 2: 14–17. [in Russian]
Meldekhanov TT, Kuttybaev AD, Imanbekova JA, Terlikbaeva GA (2019) Toxic drug-induced liver lesions. Bulletin of Kazan State Medical University [Vestnik KazNMU] 1: 63–66. [in Russian]
Shukevich TM, Pomytkina TE, Moses CB (2020) Alcoholic liver disease – key issues of epidemiology and pathogenesis of the disease. Medicine in Kuzbass [Meditsina v Kuzbase] 19(1): 5–10. [in Russian]
Yang J, Kwon S, Bae SH, Park KM, Yoon C, Lee JH, Seok C (2020) Galaxy sagittarius: Structure- and similarity-based prediction of protein targets for drug like compounds. Journal of Chemical Information and Modeling 60(6): 3246–3254. https://doi.org/10.1021/acs.jcim.0c00104 [PubMed]
Zholobova ES, Konopelko OY, Gesheva ZV (2009) Hepatotoxicity of non-steroidal anti-inflammatory drugs used in paediatric rheumatology. Pediatrics [Pediatriya] 88 (5). [in Russian]
Zimmerman JS, Vologzhanina LG (2018) Drug-induced liver injury and liver damage in pregnancy: pathogenesis, diagnosis and treatment. Clinical Pharmacology and Therapeutics [Klinicheskaya Farmakologiya i Terapiya] 27(5): 85–90. https://doi.org/10.32756/0869-5490-2018-5-85-90 [in Russian]
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Elena Yu. Bibik, Daria R. Bukhtoyarova, Sergey G. Krivokolysko

This work is licensed under a Creative Commons Attribution 4.0 International License.