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Benzo[b]thiophene-thiazoles as potent anti-Toxoplasma gondii agents: Design, synthesis, tyrosinase/tyrosine hydroxylase inhibitors, molecular docking study, and antioxidant activity.
Eur J Med Chem 2019; 184:111765EJ

Abstract

Synthesis and investigation of anti-Toxoplasma gondii activity of novel thiazoles containing benzo [b]thiophene moiety are presented. Among the derivatives, compound 3k with adamantyl group shows exceptionally high potency against Me49 strain with IC50 (8.74 μM) value which is significantly lower than the activity of trimethoprim (IC50 39.23 μM). In addition, compounds 3a, 3b and 3k showed significant activity against RH strain (IC50 51.88-83.49 μM). The results of the cytotoxicity evaluation showed that Toxoplasma gondii growth was inhibited at non-cytotoxic concentrations for the mammalian L929 fibroblast (CC30 ∼ 880 μM). The most active compound 3k showed tyrosinase inhibition effect, with IC50 value of 328.5 μM. The binding energies calculated for compounds 3a-3e, 3k are strongly correlated with the experimentally determined values of tyrosinase inhibition activity. Moreover, the binding energies corresponding to the same ligands and calculated for both tyrosinase and tyrosine hydroxylase are also correlated with each other, suggesting that tyrosinase inhibitors may also have an inhibitory effect on tyrosine hydroxylase. Compounds 3j and 3k have also very strong antioxidant activity (IC50 15.9 and 15.5 μM), respectively, which is ten times higher than well-known antioxidant BHT.

Authors+Show Affiliations

Department of Chemical Technology and Pharmaceuticals, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089, Bydgoszcz, Poland.Department of Immunoparasitology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237, Lodz, Poland.Department of Chemical Technology and Pharmaceuticals, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089, Bydgoszcz, Poland.Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Niezapominajek 8, 30-239, Cracow, Poland.Department of Chemical Technology and Pharmaceuticals, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089, Bydgoszcz, Poland.Department of Medicinal Chemistry, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089, Bydgoszcz, Poland.Department of Immunoparasitology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237, Lodz, Poland. Electronic address: katarzyna.dzitko@biol.uni.lodz.pl.Department of Chemical Technology and Pharmaceuticals, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089, Bydgoszcz, Poland. Electronic address: krzysztof.laczkowski@cm.umk.pl.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31629163

Citation

Rosada, Beata, et al. "Benzo[b]thiophene-thiazoles as Potent anti-Toxoplasma Gondii Agents: Design, Synthesis, Tyrosinase/tyrosine Hydroxylase Inhibitors, Molecular Docking Study, and Antioxidant Activity." European Journal of Medicinal Chemistry, vol. 184, 2019, p. 111765.
Rosada B, Bekier A, Cytarska J, et al. Benzo[b]thiophene-thiazoles as potent anti-Toxoplasma gondii agents: Design, synthesis, tyrosinase/tyrosine hydroxylase inhibitors, molecular docking study, and antioxidant activity. Eur J Med Chem. 2019;184:111765.
Rosada, B., Bekier, A., Cytarska, J., Płaziński, W., Zavyalova, O., Sikora, A., ... Łączkowski, K. Z. (2019). Benzo[b]thiophene-thiazoles as potent anti-Toxoplasma gondii agents: Design, synthesis, tyrosinase/tyrosine hydroxylase inhibitors, molecular docking study, and antioxidant activity. European Journal of Medicinal Chemistry, 184, p. 111765. doi:10.1016/j.ejmech.2019.111765.
Rosada B, et al. Benzo[b]thiophene-thiazoles as Potent anti-Toxoplasma Gondii Agents: Design, Synthesis, Tyrosinase/tyrosine Hydroxylase Inhibitors, Molecular Docking Study, and Antioxidant Activity. Eur J Med Chem. 2019 Oct 10;184:111765. PubMed PMID: 31629163.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Benzo[b]thiophene-thiazoles as potent anti-Toxoplasma gondii agents: Design, synthesis, tyrosinase/tyrosine hydroxylase inhibitors, molecular docking study, and antioxidant activity. AU - Rosada,Beata, AU - Bekier,Adrian, AU - Cytarska,Joanna, AU - Płaziński,Wojciech, AU - Zavyalova,Olga, AU - Sikora,Adam, AU - Dzitko,Katarzyna, AU - Łączkowski,Krzysztof Z, Y1 - 2019/10/10/ PY - 2019/08/27/received PY - 2019/09/21/revised PY - 2019/10/06/accepted PY - 2019/10/20/pubmed PY - 2019/10/20/medline PY - 2019/10/20/entrez KW - Antioxidant KW - Benzothiophene KW - Molecular docking KW - Thiazole KW - Toxoplasma gondii KW - Tyrosinase SP - 111765 EP - 111765 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 184 N2 - Synthesis and investigation of anti-Toxoplasma gondii activity of novel thiazoles containing benzo [b]thiophene moiety are presented. Among the derivatives, compound 3k with adamantyl group shows exceptionally high potency against Me49 strain with IC50 (8.74 μM) value which is significantly lower than the activity of trimethoprim (IC50 39.23 μM). In addition, compounds 3a, 3b and 3k showed significant activity against RH strain (IC50 51.88-83.49 μM). The results of the cytotoxicity evaluation showed that Toxoplasma gondii growth was inhibited at non-cytotoxic concentrations for the mammalian L929 fibroblast (CC30 ∼ 880 μM). The most active compound 3k showed tyrosinase inhibition effect, with IC50 value of 328.5 μM. The binding energies calculated for compounds 3a-3e, 3k are strongly correlated with the experimentally determined values of tyrosinase inhibition activity. Moreover, the binding energies corresponding to the same ligands and calculated for both tyrosinase and tyrosine hydroxylase are also correlated with each other, suggesting that tyrosinase inhibitors may also have an inhibitory effect on tyrosine hydroxylase. Compounds 3j and 3k have also very strong antioxidant activity (IC50 15.9 and 15.5 μM), respectively, which is ten times higher than well-known antioxidant BHT. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/31629163/Benzo[b]thiophene-thiazoles_as_potent_anti-Toxoplasma_gondii_agents:_Design,_synthesis,_tyrosinase/tyrosine_hydroxylase_inhibitors,_molecular_docking_study,_and_antioxidant_activity L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(19)30917-1 DB - PRIME DP - Unbound Medicine ER -