Synthesis and biological activity of 2-arylidene-5,6-dihydroimidazo[2,1-b]thiazoles and 6,7-dihydro-5h-[1,3]thiazolo[3,2-a]pyrimidines

Authors

DOI:

https://doi.org/10.15587/2519-4852.2025.326521

Keywords:

imidazo[2,1-b]thiazoles, thiazolo[3,2-a]pyrimidines, Knoevenagel condensation, antimicrobial activity, antioxidant activity, DPPH

Abstract

The aim. The present study is devoted to searching for potential biologically active agents among functionalized imidazo[2,1-b]thiazoles and thiazolo[3,2-a]pyrimidines.

Materials and methods. The interaction of preparatively available 5,6-dihydroimidazo[2,1-b]thiazolone and 6,7-dihydro-2H-thiazolo[3,2-a]pyrimidinone with several substituted benzaldehydes in boiling acetic acid in the presence of anhydrous sodium acetate leads to new 2-arylidene-substituted 5,6-dihydroimidazo[2,1-b]thiazoles and 6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidines as potential pharmacological agents. Their antimicrobial activity was studied using the micromethod of two-fold serial dilutions in a liquid nutrient medium. The antioxidant activity of the synthesized compounds was evaluated using a DPPH assay.

Results. A library of 2-arylidene-5,6-dihydroimidazo[2,1-b]thiazolone and 6,7-dihydro-2H-thiazolo[3,2-a]pyrimidinone was synthesized by condensation of 5,6-dihydroimidazo[2,1-b]thiazoles and 6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidines with series of aromatic aldehydes. Pharmacological in vitro screening results revealed that synthesized compounds possess moderate antimicrobial activity with MBC and MFC values of 31.25-62.5 mg/mL. While studying the antioxidant activity, it was found that all derivatives effectively inhibited DPPH radicals with an inhibition rate of 42.3-94.4 %. The best antiradical effect was observed for the molecule's derivatives containing 3-methoxy-4-hydroxy- or 2-hydroxyphenylmethylidene fragments.

Conclusions. It was found that the Knevenagel condensation of 5,6-dihydroimidazo[2,1-b]thiazolone and 6,7-dihydro-2H-thiazolo[3,2-a]pyrimidinone with aromatic aldehydes is a convenient approach for structure modification and optimization using pharmacophore fragments for these types of heterocycle. The synthesized arylidene derivatives are characterized by moderate antimicrobial and good antioxidant activity in vitro models

Author Biographies

Vasyl Zhylko, Lesya Ukrainka Volyn National University

PhD Student

Lesya Saliyeva, Lesya Ukrainka Volyn National University

PhD

Department of Organic and Pharmaceutical Chemistry

Nataliia Slyvka, Lesya Ukrainka Volyn National University

Doctor of Chemical Sciences, Associate Professor

Department of Organic and Pharmaceutical Chemistry

Serhii Holota, Danylo Halystsky Lviv National Medical University

PhD, Associate Professor

Department of Pharmaceutical, Organic and Bioorganic Chemistry

Alina Grozav, Bukovinian State Medical University

PhD, Associate Professor

Department of Medical and Pharmaceutical Chemistry

Nina Yakovychuk, Bukovinian State Medical University

PhD, Associate Professor

Department of Microbiology, Virology and Immunology

Mykhailo Vovk, Institute of Organic Chemistry of NAS of Ukraine

Doctor of Chemical Sciences, Professor

Department of Functional Heterocyclic Systems

References

  1. Tojo, S., Kohno, T., Tanaka, T., Kamioka, S., Ota, Y., Ishii, T. et al. (2014). Crystal Structures and Structure–Activity Relationships of Imidazothiazole Derivatives as IDO1 Inhibitors. ACS Medicinal Chemistry Letters, 5 (10), 1119–1123. https://doi.org/10.1021/ml500247w
  2. Fascio, M. L., Errea, M. I., D’Accorso, N. B. (2015). Imidazothiazole and related heterocyclic systems. Synthesis, chemical and biological properties. European Journal of Medicinal Chemistry, 90, 666–683. https://doi.org/10.1016/j.ejmech.2014.12.012
  3. Kamal, A., Kashi Reddy, M., Viswanath, A. (2013). The design and development of imidazothiazole–chalcone derivatives as potential anticancer drugs. Expert Opinion on Drug Discovery, 8 (3), 289–304. https://doi.org/10.1517/17460441.2013.758630
  4. Keshari, A. K., Singh, A. K., Saha, S. (2017). Bridgehead Nitrogen Thiazolo[3,2-a]pyrimidine: A Privileged Structural Framework in Drug Discovery. Mini-Reviews in Medicinal Chemistry, 17 (15), 1488–1499. https://doi.org/10.2174/1389557517666170216142113
  5. Wu, F. Y., Luo, Y., Hu, C. B. (2018). Recent progress in the synthesis of thiazolo[3,2-a]pyrimidine compounds. IOP Conference Series: Materials Science and Engineering, 292, 012038. https://doi.org/10.1088/1757-899x/292/1/012038
  6. Amarouch, H., Loiseau, P. R., Bacha, C., Caujolle, R., Payard, M. et al. (1987). Imidazo[2,1-b]thiazoles: analogues du lévamisole. European Journal of Medicinal Chemistry, 22 (5), 463–466. https://doi.org/10.1016/0223-5234(87)90037-7
  7. Montalban-Bravo, G., Jabbour, E., Chien, K., Hammond, D., Short, N., Ravandi, F. et al. (2024). Phase 1 study of azacitidine in combination with quizartinib in patients with FLT3 or CBL mutated MDS and MDS/MPN. Leukemia Research, 142, 107518. https://doi.org/10.1016/j.leukres.2024.107518
  8. Leysen, J. E., Van Gompel, P., Gommeren, W., Woestenborghs, R., & Janssen, P. A. J. (1986). Down regulation of serotonin-S2 receptor sites in rat brain by chronic treatment with the serotonin-S2 antagonists: ritanserin and setoperone. Psychopharmacology, 88 (4), 434–444. https://doi.org/10.1007/bf00178504
  9. Cole, D. C., Stock, J. R., Lennox, W. J., Bernotas, R. C., Ellingboe, J. W., Boikess, S. et al. (2007). Discovery of N1-(6-Chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine as a Potent, Selective, and Orally Active 5-HT6Receptor Agonist. Journal of Medicinal Chemistry, 50 (23), 5535–5538. https://doi.org/10.1021/jm070521y
  10. Da Pozzo, E., La Pietra, V., Cosimelli, B., Da Settimo, F., Giacomelli, C., Marinelli, L. et al. (2014). p53 Functional Inhibitors Behaving Like Pifithrin-β Counteract the Alzheimer Peptide Non-β-amyloid Component Effects in Human SH-SY5Y Cells. ACS Chemical Neuroscience, 5 (5), 390–399. https://doi.org/10.1021/cn4002208
  11. Krueger, J. G., Suárez-Fariñas, M., Cueto, I., Khacherian, A., Matheson, R., Parish, L. C. et al. (2015). A Randomized, Placebo-Controlled Study of SRT2104, a SIRT1 Activator, in Patients with Moderate to Severe Psoriasis. PLOS ONE, 10 (11), e0142081. https://doi.org/10.1371/journal.pone.0142081
  12. Dianat, S., Moghimi, S., Mahdavi, M., Nadri, H., Moradi, A., Firoozpour, L. et al. (2016). Quinoline-based imidazole-fused heterocycles as new inhibitors of 15-lipoxygenase. Journal of Enzyme Inhibition and Medicinal Chemistry, 31 (sup3), 205–209. https://doi.org/10.1080/14756366.2016.1206087
  13. Serafini, M., Torre, E., Aprile, S., Massarotti, A., Fallarini, S., Pirali, T. (2019). Synthesis, Docking and Biological Evaluation of a Novel Class of Imidazothiazoles as IDO1 Inhibitors. Molecules, 24 (10), 1874. https://doi.org/10.3390/molecules24101874
  14. Jin, C.-H., Jun, K.-Y., Lee, E., Kim, S., Kwon, Y., Kim, K., Na, Y. (2014). Ethyl 2-(benzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate analogues as a new scaffold for protein kinase casein kinase 2 inhibitor. Bioorganic & Medicinal Chemistry, 22 (17), 4553–4565. https://doi.org/10.1016/j.bmc.2014.07.037
  15. Nobe, K., Miyatake, M., Nobe, H., Sakai, Y., Takashima, J., Momose, K. (2004). Novel diacylglycerol kinase inhibitor selectively suppressed an U46619‐induced enhancement of mouse portal vein contraction under high glucose conditions. British Journal of Pharmacology, 143 (1), 166–178. https://doi.org/10.1038/sj.bjp.0705910
  16. Saliyeva, L., Holota, S., Grozav, G., Yakovychuk, N., Litvinchuk, M., Slyvka, N., Vovk, M. (2022). Synthesis and Evaluation of Antimicrobial and Anti-inflammatory Activity of 6-aryliden-2-methyl-2,3-dihydroimidazo[2,1-b][1,3]thiazoles. Biointerface Research in Applied Chemistry, 12 (1), 292–303. https://doi.org/10.33263/BRIAC121.292303
  17. Ye, X., Zhou, W., Li, Y., Sun, Y., Zhang, Y., Ji, H., Lai, Y. (2010). Darbufelone, a novel anti-inflammatory drug, induces growth inhibition of lung cancer cells both in vitro and in vivo. Cancer Chemotherapy and Pharmacology, 66 (2), 277–285. https://doi.org/10.1007/s00280-009-1161-z
  18. Kouzi, O., Pontiki, E., Hadjipavlou-Litina, D. (2019). 2-Arylidene-1-indandiones as Pleiotropic Agents with Antioxidant and Inhibitory Enzymes Activities. Molecules, 24 (23), 4411. https://doi.org/10.3390/molecules24234411
  19. Jain, S., Kumar, A., Saini, D. (2018). Novel arylidene derivatives of quinoline based thiazolidinones: Synthesis, in vitro, in vivo and in silico study as antimalarials. Experimental Parasitology, 185, 107–114. https://doi.org/10.1016/j.exppara.2018.01.015
  20. Rajagopalan, P., Dera, A., Abdalsamad, M. R., C. Chandramoorthy, H. (2019). Rational combinations of indirubin and arylidene derivatives exhibit synergism in human non‐small cell lung carcinoma cells. Journal of Food Biochemistry, 43 (7), e12861. https://doi.org/10.1111/jfbc.12861
  21. Yakovychuk, N. D., Deyneka, S. Y., Grozav, A. M., Humenna, A. V., Popovych, V. B., Djuiriak, V. S. (2018). Аntifungal activity of 5-(2-nitrovinyl) imidazoles and their derivatives against the causative agents of vulvovaginal candidiasis. Regulatory Mechanisms in Biosystems, 9 (3), 369–373. https://doi.org/10.15421/021854
  22. Brand-Williams, W., Cuvelier, M. E., Berset, C. (1995). Use of a free radical method to evaluate antioxidant activity. LWT – Food Science and Technology, 28 (1), 25–30. https://doi.org/10.1016/s0023-6438(95)80008-5
  23. Urbano, M., Guerrero, M., Velaparthi, S., Crisp, M., Chase, P., Hodder, P., Schaeffer, M.-T. et al. (2011). Discovery, synthesis and SAR analysis of novel selective small molecule S1P4-R agonists based on a (2Z,5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolidin-4-one chemotype. Bioorganic & Medicinal Chemistry Letters, 21 (22), 6739–6745. https://doi.org/10.1016/j.bmcl.2011.09.049
  24. Kushakova, P. M., Yulisova, A. I., Ramsh, S. M., Garabadgiu, A. V. (2006). New data on the alkylation of cyclic thioureas with á-halocarboxylic acids and their esters. 2. Alkylation of tetrahydropyrimidine-2(1h)-thione and 5,5-dimethyltetrahydropyrimidine-2(1h)-thione. Chemistry of Heterocyclic Compounds, 42 (4), 520–529. https://doi.org/10.1007/s10593-006-0120-4
  25. Li, X., Zheng, A., Liu, B., Yu, X., Yi, P. (2010). Synthesis of Novel Spiro Pyrrolidine and Pyrrolizine Derivatives by 1,3‐Dipolar Cycloaddition. Chinese Journal of Chemistry, 28 (7), 1207–1211. https://doi.org/10.1002/cjoc.201090209
  26. Yan, J., Fu, X., Li, W. (2017). Synthesis of Spiro Thiazolo[3,2-a]Pyrimidine-Tetrahydrothiophenes via Sulfa-Michael/Aldol Cascade Reactions. Journal of Chemical Research, 41 (12), 722–724. https://doi.org/10.3184/174751917x15125690124282
  27. Hecht, D. W. (2004). Prevalence of Antibiotic Resistance in Anaerobic Bacteria: Worrisome Developments. Clinical Infectious Diseases, 39 (1), 92–97. https://doi.org/10.1086/421558
  28. Moore, B. S., Carter, G. T., Brönstrup, M. (2017). Editorial: Are natural products the solution to antimicrobial resistance? Natural Product Reports, 34 (7), 685–686. https://doi.org/10.1039/c7np90026k
  29. Battin, E. E., Brumaghim, J. L. (2009). Antioxidant Activity of Sulfur and Selenium: A Review of Reactive Oxygen Species Scavenging, Glutathione Peroxidase, and Metal-Binding Antioxidant Mechanisms. Cell Biochemistry and Biophysics, 55 (1), 1–23. https://doi.org/10.1007/s12013-009-9054-7
  30. Djukic, M., Fesatidou, M., Xenikakis, I., Geronikaki, A., Angelova, V. T., Savic, V. et al. (2018). In vitro antioxidant activity of thiazolidinone derivatives of 1,3-thiazole and 1,3,4-thiadiazole. Chemico-Biological Interactions, 286, 119–131. https://doi.org/10.1016/j.cbi.2018.03.013
  31. Chaban, T. I., Ogurtsov, V. V., Chaban, I. G., Klenina, O. V., Komarytsia, J. D. (2013). Synthesis and Antioxidant Activity Evaluation of Novel 5,7-dimethyl-3H-Thiazolo[4,5-B]Pyridines. Phosphorus, Sulfur, and Silicon and the Related Elements, 188 (11), 1611–1620. https://doi.org/10.1080/10426507.2013.777723
  32. Pokorný, J. (2007). Are natural antioxidants better – and safer – than synthetic antioxidants? European Journal of Lipid Science and Technology, 109(6), 629–642. Portico. https://doi.org/10.1002/ejlt.200700064
  33. Stoia, M., Oancea, S. (2022). Low-Molecular-Weight Synthetic Antioxidants: Classification, Pharmacological Profile, Effectiveness and Trends. Antioxidants, 11 (4), 638. https://doi.org/10.3390/antiox11040638
  34. Jones, G. (1967). The Knoevenagel Condensation. Organic Reactions, 15, 204–599.
  35. He, J., Qiao, W., An, Q., Yang, T., Luo, Y. (2020). Dihydrofolate reductase inhibitors for use as antimicrobial agents. European Journal of Medicinal Chemistry, 195, 112268. https://doi.org/10.1016/j.ejmech.2020.112268
Synthesis and biological activity of 2-arylidene-5,6-dihydroimidazo[2,1-b]thiazoles and 6,7-dihydro-5h-[1,3]thiazolo[3,2-a]pyrimidines

Downloads

Published

2025-04-30

How to Cite

Borysiuk, O., Zhylko, V., Saliyeva, L., Slyvka, N., Holota, S., Grozav, A., Yakovychuk, N., & Vovk, M. (2025). Synthesis and biological activity of 2-arylidene-5,6-dihydroimidazo[2,1-b]thiazoles and 6,7-dihydro-5h-[1,3]thiazolo[3,2-a]pyrimidines. ScienceRise: Pharmaceutical Science, (2 (54), 22–28. https://doi.org/10.15587/2519-4852.2025.326521

Issue

No. 2 (54) (2025)

Section

Pharmaceutical Science

License

Copyright (c) 2025 Olha Borysiuk, Vasyl Zhylko, Lesya Saliyeva, Nataliia Slyvka, Serhii Holota, Alina Grozav, Nina Yakovychuk, Mykhailo Vovk

Creative Commons License

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

Our journal abides by the Creative Commons CC BY copyright rights and permissions for open access journals.