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Synthesis and anthelmintic activity of benzopyrano[2,3-c]pyrazol-4(2H)-one derivatives

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Abstract

A series of benzopyrano[2,3-c]pyrazol-4(2H)-one derivatives were synthesized from readily available 1-phenyl- and 1-methyl-1H-pyrazol-3-ols by sequentially employing O-acylation, Fries rearrangement and potassium carbonate-induced cyclization. The anthelmintic properties of the obtained compounds were investigated in vivo in a model nematode, Caenorhabditis elegans. Five compounds, namely 2-phenyl[1]benzopyrano[2,3-c]pyrazol-4(2H)-one 33 and its 7-fluoro, 7-chloro-, 7-bromo- and 8-fluoro-analogues, 36, 38, 40 and 43, respectively, altered the development of C. elegans. While the activities of 33 and 43 were rather modest, compounds 36, 38 and 40 inhibited the growth of the worms at concentrations of approximately 1-3 µM. At these concentrations, the compounds did not kill the worms, but they strongly inhibited their development, with the majority of larvae never progressing past the L1 stage. Moreover, testing in non-cancer human cell lines showed that, with exception of 7-bromo derivative 40, the active compounds have favourable toxicity profiles.

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Acknowledgements

This work was supported by the Internal Grant Agency of Palacký University (IGA_PrF_2019_020), by the Ministry of Education, Youth and Sports of the Czech Republic (A Molecular, Cell and Clinical Approach to Healthy Aging (ENOCH), project code CZ.02.1.01/0.0/0.0/16_019/0000868 and INTER-COST (LTC17), project code LTC17072) and by the Research, Development and Innovation Fund of Kaunas University of Technology (project grant No. PP-91B/19). The strains used in this study were provided by the CGC, which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). The authors are grateful to Kateřina Faksová for help with cell culture experiments.

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Authors and Affiliations

  1. Department of Organic Chemistry, Kaunas University of Technology, Radvilėnų pl. 19, 50254, Kaunas, Lithuania

    Vaida Milišiūnaitė & Eglė Arbačiauskienė

  2. Laboratory of Growth Regulators, Institute of Experimental Botany, The Czech Academy of Science, Palacký University, Šlechtitelů 27, 78371, Olomouc, Czech Republic

    Alena Kadlecová, Asta Žukauskaitė, Karel Doležal, Miroslav Strnad & Jiří Voller

  3. Department of Chemical Biology and Genetics, Faculty of Science, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University, Šlechtitelů 27, 78371, Olomouc, Czech Republic

    Karel Doležal

  4. Division of Drug Synthesis, Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090, Vienna, Austria

    Wolfgang Holzer

  5. Institute of Synthetic Chemistry, Kaunas University of Technology, K. Baršausko g. 59, 51423, Kaunas, Lithuania

    Algirdas Šačkus

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Milišiūnaitė, V., Kadlecová, A., Žukauskaitė, A. et al. Synthesis and anthelmintic activity of benzopyrano[2,3-c]pyrazol-4(2H)-one derivatives. Mol Divers 24, 1025–1042 (2020). https://doi.org/10.1007/s11030-019-10010-3

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