Abstract
Objective. Mixed organometallic complexes containing amino acids and water-soluble vitamins as ligands are promising research subjects in organic and physical chemistry. The practical applications of these compounds may include medicine, where they are considered sources of biologically active substances (essential amino acids, vitamins, and essential microelements).
The aim of this study is to synthesize and characterize a ternary chelate complex of iron with folic acid and L-valine.
Material and methods. The obtained samples were analyzed using IR spectroscopy, UV-visible spectroscopy, and X-ray diffraction analysis.
Results. IR spectral analysis revealed that the spectrum of the triple chelate complex of the essential element iron with vitamin B9 and the essential amino acid L-valine significantly reduced the bands of the carboxyl group of folic acid, as well as the deformation vibrations of the amino group and carboxyl group of L-valine, compared to pure substances, and also revealed bands at 619 cm-1, which is characteristic of the Fe-O bond. Analysis of UV-visible spectroscopy data revealed that the distribution spectrum of the triple chelate complex of iron with folic acid and L-valine exhibited maximum concentrations at λ = 343 nm, λ = 281 nm, λ = 215 nm.
Conclusion. Acute toxicity study analysis revealed that the LD50 was greater than 5000 mg/kg for the triple chelate complex of the essential trace element iron with vitamin B9 and the essential amino acid L-valine. Further studies will be aimed at investigating proanemic activity in conditions of iron deficiency anemia in vivo
Authors and affiliations
A.A. Gvozdenko(1), М.А. Yasnaya(2), A.A. Blinova(1), А.А. Vlasov(1), M.A. Kolodkin(1),
1-Federal State Autonomous Educational Institution of Higher Education “North Caucasian Federal University”,
Pushkin St., 1, Stavropol, 355017, Russian Federation; 2-JSC NPO “Mikrogen” in Stavropol –
Branch of “Allergen” Enterprise, Biologicheskaya St., 20, Stavropol, 355019, Russia
References
Mengesha A.M. The study of antimicrobial activities of various transition metal mixed ligand complexes containing 1, 10-phenanthroline with any other ligands. Biol Activ Some Kinds. 2022; 7: 1–9. DOI: 10.11648/j.ijbc.20220701.11.
2. Kartikeyan R., Murugan D., Ajaykamal T., Varadhan M., Rangasamy L., Velusamy M., Palaniandavar M. et al. Mixed ligand copper (II)-diimine complexes of 2-formylpyridine-N 4-phenylthiosemicarbazone: diimine co-ligands tune the in vitro nanomolar cytotoxicity. Dalton Transactions. 2023; 52 (26): 9148–69. DOI: 10.1039/D3DT00213F.
3. Pal S. Pyridine: A useful ligand in transition metal complexes. Pyridine. 2018; 57: 57–74. DOI: 10.5772/intechopen.76986.
4. Safin D.A., Mitoraj M.P., Robeyns K., Filinchuk Y., Vande Velde C.M. Luminescent mononuclear mixed ligand complexes of copper (I) with 5-phenyl-2, 2’-bipyridine and triphenylphosphine. Dalton Transactions. 2015; 44 (38): 16824–32. DOI: 10.1039/C5DT02755A.
5. Khan T., Raza S., Lawrence A. J. Medicinal utility of thiosemicarbazones with special reference to mixed ligand and mixed metal complexes: A Review. Russian J. of Coordination Chemistry. 2022; 48 (12): 877–95. DOI: 10.1134/S1070328422600280.
6. Amolegbe S.A., Adewuyi S., Akinremi C.A., Adediji J.F., Lawal A., Atayese A.O., Obaleye J.A. Iron (III) and copper (II) complexes bearing 8-quinolinol with amino-acids mixed ligands: Synthesis, characterization and antibacterial investigation. Arabian J. of Chemistry. 2015; 8 (5): 742–7. DOI: 10.1016/j.arabjc.2014.11.040.
7. Martin R.B. Complexes of α-amino acids with chelatable side chain donor atoms. Metal ions in biological systems. CRC Press. 2024; 1–39. DOI: 10.1201/9781003573586.
8. Osowole A.A., Wakil S.M., Emmanuel M. O. Synthesis, characterization, antioxidant and antimicrobial activities of some Metal (II) Complexes of the Mixed-Ligands, Vitamin B2 and Benzoic acid. Elixir Appl Chem. 2015; 79: 30370–4.
9. Kayode M., Ayodeji O.E., Yetunde B.B., Joseph O.T., Timothy A.T., Habeeb O., Tochi N.S. et al. Synthesis, Characterization and Antimicrobial Activity of Mixed Antibiotic-Vitamin Metal Complexes Involving Metronidazole and Vitamin B1 (Thiamine). Asian J. of Chemical Sciences. 2024; 14 (6): 46–59. DOI: 10.9734/ajocs/2024/v14i6333.
10. Tabrizi L., Abyar F. De Novo Design of Cu (II) Complex Containing CNC–Pincer–Vitamin B3 and B7 Conjugates for Breast Cancer Application. Molecular Pharmaceutics. 2019; 16 (9): 3802–13. DOI: 10.1021/acs.molpharmaceut.9b00399.
11. Fazary A.E., Ju Y.H., Rajhi A.Q., Alshihri A.S., Alfaifi M.Y., Alshehri M.A., Saleh K.A. et al. Bioactivities of novel metal complexes involving B vitamins and glycine. Open Chemistry. 2016; 14 (1): 287–98. DOI:10.1515/chem-2016-0028.
12. Yu C., Heidari Majd M., Shiri F., Shahraki S., Karimi P. The role of folic acid in inducing of apoptosis by zinc (II) complex in ovary and cervix cancer cells. Molecular Diversity. 2022; 26 (3): 1545–55. DOI: 10.1007/s11030-021-10293-5.
13. Karpagam S., Mamindla A., Sali V.K., Niranjana R.S., Periasamy V.S., Alshatwi A.A., Akbarsha M.A. et al. Folic acid-conjugated mixed-ligand copper (II) complexes as promising cytotoxic agents for triple-negative breast cancers: A case study using MDA-MB-231 cell. Inorganica Chimica Acta. 2022; 531: 120729. DOI: 10.1016/j.ica.2021.120729.
14. Клинические рекомендации «Железодефицитная анемия». Министерство здравоохранения РФ. 2025; 669_2: 56. [Klinicheskie rekomendacii «Zhelezodeficitnaya anemiya». Ministerstvo zdravooxraneniya RF. 2025; 669_2: 56 (in Russian)].
15. Al-Naseem A., Sallam A., Choudhury S., Thachil J. Iron deficiency without anaemia: a diagnosis that matters. Clinical Medicine. 2021; 21 (2): 107–13. DOI: 10.7861/clinmed.2020-0582.
16. Белоконова Н.А., Тихомирова Е.И., Куприянова И.Н. Исследование физико-химических свойств препаратов протеин сукцинилат железа (III) и гидроксид полимальтозат железа (III). Вестник Томского государственного университета. Химия. 2024; 33: 6–23. [Belokonova N.A., Tixomirova E.I., Kupriyanova I.N. Study of the physicochemical properties of the preparations iron (III) protein succinylate and iron (III) polymaltose hydroxide. Vestnik Tomskogo gosudarstvennogo universiteta. Ximiya. 2024; 33: 6–23. DOI: 10.17223/24135542/33/1 (in Russian)].
17. Духанин А.С. Актуальные представления о фармакологической коррекции железодефицитных состояний в гинекологической практике. Гинекология. 2021; 23 (4): 300–6. [Duxanin A.S. Current concepts of pharmacological correction of iron deficiency conditions in gynecological practice. Ginekologiya. 2021; 23 (4): 300–6. DOI: 10.26442/20795696.2021.4.201064 (in Russian)].
18. Gromova O.A., Torshin I.Y., Tetruashvili N.K. Systematic computer analysis of iron fumarate pharmacology in the treatment of iron deficiency and iron deficiency anemia. Obstetrics, Gynecology and Reproduction. 2025; 19 (2): 230–49. DOI: 10.17749/2313-7347/ob.gyn.rep.2025.632.
19. Skorik N.A. D-Metal folates and the folic acid–imidazole conjugate. Russian J. of Inorganic Chemistry. 2015; 60 (11): 1402–6. DOI: 10.1134/S0036023615110145.
20. Skorik N.A., Vostretsova E.N. Solubilities of Folic Acid and Selected Synthesized Metal Folates. Russian J. of Inorganic Chemistry. 2019; 64 (12): 1572–8. DOI: 10.1134/S0036023619120179.
21. ГОСТ 34557 – 2019 «Методы испытания по воздействию химической продукции на организм человека. Испытания по оценке острой токсичности при внутрижелудочном поступлении. Метод «вверх и вниз». М.: Стандартинформ, 2019: 35. [GOST 34557 – 2019 «Test methods for the effects of chemical products on the human body. Acute toxicity tests for intragastric administration. The «up and down» method». M.: Standartinform, 2019: 35 (in Russian)].
22. Baibarac M., Smaranda I., Nila A., Serbschi C. Optical properties of folic acid in phosphate buffer solutions: the influence of pH and UV irradiation on the UV-VIS absorption spectra and photoluminescence. Scientific Reports. 2019; 9 (1): 14278. DOI:10.1038/s41598-019-50721-z.
23. Hamed E., Attia M.S., Bassiouny K. Synthesis, spectroscopic and thermal characterization of copper (II) and iron (III) complexes of folic acid and their absorption efficiency in the blood. Bioinorganic chemistry and applications. 2009; 2009 (1): 979680. DOI: 10.1155/2009/979680.
24. Abd El-Wahed M.G., Refat M.S., El-Megharbel S.M. Synthesis, spectroscopic and thermal characterization of some transition metal complexes of folic acid. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 2008; 70 (4): 916–22. DOI: 10.1016/j.saa.2007.10.008.
25. Hernandez B., Pfluger F., Nsangou M., Ghomi M. Vibrational analysis of amino acids and short peptides in hydrated media. IV. amino acids with hydrophobic side chains: L-Alanine, L-Valine, and L-Isoleucine. The J. of Physical Chemistry B. 2009; 113 (10): 3169–78. DOI: 10.1021/jp809204d.
26. Ramachandran E., Natarajan S. Synthesis of L-valine crystals. Crystal Research and Technology: J. of Experimental and Industrial Crystallography. 2009; 44 (6): 641–6. DOI: 10.1002/crat.200900012.
27. Ahmad I., Manzoor K., Aalam G., Amir M., Ali S. W., Ikram S. Facile synthesis of L-tryptophan functionalized magnetic nanophotocatalyst supported by copper nanoparticles for selective reduction of organic pollutants and degradation of azo dyes. Catalysis Letters. 2023; 153 (9): 2604–23. DOI:10.1007/s10562-022-04182-1.
28. Фармакопейная статья. Фолиевая кислота (ФС.2.1.0686): Приказ Министерства Здравоохранения России от 13.03.2024 №120. Государственная фармакопея Российской Федерации. 2024. XV издание: 8. [Pharmacopoeial article. Folic acid (FS.2.1.0686): Prikaz Ministerstva Zdravooxraneniya Rossii ot 13.03.2024 №120. Gosudarstvennaya farmakopeya Rossijskoj Federacii. 2024. XV izdanie: 8 (in Russian)].
29. Matias R., Ribeiro P.R.S., Sarraguça M.C., Lopes J.A. A UV spectrophotometric method for the determination of folic acid in pharmaceutical tablets and dissolution tests. Analytical methods. 2014; 6 (9): 3065–71. DOI:10.1039/c3ay41874j.
30. ГОСТ 32419-2022 «Классификация опасности химической продукции. Общие требования». М.: Российский институт стандартизации, 2023: 43. [GOST 32419-2022 «Chemical Product Hazard Classification. General Requirements». M.: Rossijskij institut standartizacii, 2023: 43 (in Russian)].