Mono- and Dihydrazones with a 6-Methyluracil Fragment: Synthesis, Cytotoxicity, and Antioxidant Activity

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Abstract

6-Methyluracil is an important compound that plays an active role in cell regeneration processes. Its ability to stimulate cell growth and replication is a key factor in the tissue healing process. Methyluracil accelerates the skin repair process, which makes its use indispensable in dermatology and surgery for the treatment of wounds, ulcers and burns. Carboxylic acid hydrazides are also of interest due to their unique coordination-chemical properties and are used in various industries. In medicine, hydrazides exhibit a wide range of activity: they have anti-tuberculosis, antiviral and antibacterial effects. Some heterocyclic hydrazones have been show to be inhibitors of the main protease of SARS-CoV-2. This highlights the importance of studying the structural and functional features of these compounds. The synthesis of hydrazones with a 6-methyluracil fragment is a promising area in the field of pharmaceutical chemistry and medicine, opening up new opportunities for the development of innovative drugs. In this work, dihydrazones were synthesized based on dihydrazides of carboxylic acids (adipic, azelate, and sebacic) with fragments of 6-methyluracil. Using the online version of the OCHEM expert system, an in silico assessment of the spectrum of biological activity was performed, including cytotoxicity, antioxidant activity, acute toxicity and hematotoxicity of the obtained compounds and comparison drugs. Studies of biological activity have shown that the obtained mono- and dihydrazones do not have cytotoxic effects on the studied tumor cell lines (HepG2, AS49, MCF-7, HCT-116) and the conditionally normal HEK 293 cell line. Moderate selective cytotoxicity of 6-methyl-5-[(2-phenylhydrazono)methyl]pyrimidine-2,4(1H,3H)-dione has been established in relation to human colorectal carcinoma (HCT-116 cell line, IC50 = 71.75 ± 8.29) and the conditionally normal HEK 293 cell line (IC50 = 19.35 ± 2.12). The antioxidant activity of mono- and dihydrazones was studied using methods of reduction of Fe3+ cation radical ABTS and stable radical DPPH in vitro. A leader compound has been identified (3-(2-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)methylene)hydrazinyl)-benzoic acid), comparable in antioxidant activity to ascorbic acid, for in-depth study.

About the authors

I. B Chernikova

Ufa Institute of Chemistry, UFIC RAS

Email: inna.b.chernikova@yandex.ru
Ufa, Russia

R. Yu Khisamutdinova

Ufa Institute of Chemistry, UFIC RAS

Ufa, Russia

N. S Makara

Ufa Institute of Chemistry, UFIC RAS

Ufa, Russia

E. R Sayakhova

Ufa Institute of Chemistry, UFIC RAS

Ufa, Russia

D. V Ishmetova

Institute of Biochemistry and Genetics, UFIC RAS

Ufa, Russia

V. A Vakhitov

Institute of Biochemistry and Genetics, UFIC RAS

Ufa, Russia

References

  1. De Oliveira Carneiro Brum J., França C.C.T., La Plante S.R., Villar J.D.F. // Mini Rev. Med. Chem. 2020. V. 20. P. 342–368. https://doi.org/10.2174/1389557519666191014142448
  2. Mistry S., Singh A.K. // Futur. J. Pharm. Sci. 2022. V. 8. P. 7. https://doi.org/10.1186/s43094-021-00391-4
  3. Jabeen M. // Turkish Chem. Soc. Sec. A: Chemistry. 2022. V. 9. P. 663–698. https://doi.org/10.18596/jotesa.1020357
  4. Verma S., Lal S., Narang R., Sudhakar K. // Chem. Med. Chem. 2023. V. 18. P. e202200571. https://doi.org/10.1002/cmdc.202200571
  5. Sah P.P.T., People S.A. // J. Am. Pharm. Assoc. 1954. V. 43. P. 513–524. https://doi.org/10.1002/jps.3030430902
  6. Althagafy H.S., Abd El-Aziz M.K., Ibrahim I.M., Abd-alhameed E.K., Hassanein E.H.M. // Eur. J. Pharm. 2023. V. 951. P. 175776. https://doi.org/10.1016/j.ejphar.2023.175776
  7. Rollas S., Gülerman N., Erdeniz H. // Farmaco. 2002. V. 57. P. 171–174. https://doi.org/10.1016/s0014-827x(01)01192-2
  8. Rollas S., Küçükşüzel Ş.G. // Molecules. 2007. V. 12. P. 1910–1939. https://doi.org/10.3390/12081910
  9. Tok F., Sağlık B. N., Özkay Y., Ilgın S., Kaplanıcıklı Z.A., Koçviğit-Kaynakçağlu B. // Bioorg. Chem. 2021. V. 114. P. 105038. https://doi.org/10.1016/j.bioorg.2021.105038
  10. Черникова И.Б., Беляева Э.Р., Лобов А.Н. // Изв. АН. Сер. хим. 2023. T. 72. C. 1815–1820.
  11. Chernikova I.B., Belyaeva E.R. // Russ. J. Gen. Chem. 2024. V. 94. P. 337–340. https://doi.org/10.1134/S1070363224020099
  12. Bonachera F., Parent B., Barbosa F., Froloff N., Horvath D. // J. Chem. Inf. Model. 2006. V. 46. P. 2457–2477. https://doi.org/10.1021/cif00241
  13. Лосенкова С.О., Погребняк А.В., Морозов Ю.А., Степанова Э.Ф. // Фармация и фармакология. 2014. T. 2. C. 105–113. https://doi.org/10.19163/2307-9266-2014-2-6(7)-105-113
  14. Debnath A.K. // Mini Rev. Med. Chem. 2001. V. 1. P. 187–195. https://doi.org/10.2174/1389557013407061
  15. Njus D., Kelley P.M., Tu Y.-J., Schlegel H.B. // Free Radic. Bio. Med. 2020. V. 159. P. 37–43. https://doi.org/10.1016/j.freerabionned.2020.07.013
  16. Papagionvannis G., Theodosis-Nobelos P., Rekka E.A. // Molecules. 2024. V. 29. P. 3763. https://doi.org/10.3390/molecules29163763
  17. Adjimani J.P., Asare P. // Toxicol Rep. 2015. V. 2. P. 721–728. https://doi.org/10.1016/j.toxrep.2015.04.005
  18. Re R., Pellegrini N., Proteggente A., Pamala A., Yang M., Rice-Evans C. // Free Radic. Bio. Med. 1999. V. 26. P. 1231–1237. https://doi.org/10.1016/s0891-5849(98)00315-3
  19. Wu Z., Tan B., Liu Y., Dunn J., Martorell Guerola P., Tortajada M., Cao Zh., Ji P. // Molecules. 2019. V. 24. P. 2825. https://doi.org/10.3390/molecules24152825

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