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

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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Milišiūnaitė, V., Kadlecová, A., Žukauskaitė, A. et al. Synthesis and anthelmintic activity of benzopyrano[2,3-c]pyrazol-4(2H)-one derivatives. Mol Divers (2019). https://doi.org/10.1007/s11030-019-10010-3

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Keywords

  • Anthelmintic activity
  • Caenorhabditis elegans
  • Cytotoxicity
  • Pyrazole
  • Benzopyrano[2,3-c]pyrazol-4(2H)-ones