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In vitro trypanocidal activities and structure–activity relationships of ciprofloxacin analogs

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Abstract

Tropical diseases, such as African trypanosomiasis, by their nature and prevalence lack the necessary urgency regarding drug development, despite the increasing need for novel, structurally diverse antitrypanosomal drugs, using different mechanisms of action that would improve drug efficacy and safety. Traditionally antibacterial agents, the fluoroquinolones, reportedly possess in vitro trypanocidal activities against Trypanosoma brucei organisms. During our research, the fluroquinolone, ciprofloxacin (1), and its analogs (2–24) were tested against bloodstream forms of T. brucei brucei, T. b. gambiense, T. b. rhodesiense, T. evansi, T. equiperdum, and T. congolense and Madin-Darby bovine kidney cells (cytotoxicity). Ciprofloxacin [CPX (1)] demonstrated selective trypanocidal activity against T. congolense (IC50 7.79 µM; SI 39.6), whereas the CPX derivatives (2–10) showed weak selective activity (25 < IC50 < 65 µM; 2 < SI < 4). Selectivity and activity of the CPX and 1,2,3-triazole (TZ) hybrids (11–24) were governed by their chemical functionality at C-3 (carboxylic acid, or 4-methylpiperazinyl amide) and their electronic effect (electron-donating or electron-withdrawing para-benzyl substituent), respectively. Trypanocidal hits in the micromolar range were identified against bloodstream forms of T. congolense [CPX (1); CPX amide derivatives 18: IC50 8.95 µM; SI 16.84; 22: IC50 5.42 µM; SI 25.2] and against T. brucei rhodesiense (CPX acid derivative 13: IC50 4.51 µM; SI 10.2), demonstrating more selectivity toward trypanosomes than mammalian cells. Hence, the trypanocidal hit compound 22 may be optimized by retaining the 4-methylpiperazine amide functional group (C-3) and the TZ moiety at position N-15 and introducing other electron-withdrawing ortho-, meta-, and/or para-substituents on the aryl ring in an effort to improve the pharmacokinetic properties and increase the trypanocidal activity.

Graphical abstract

Structure–activity relationships of ciprofloxacin-1,2,3-triazole hybrids were governed by the chemical functionality at C-3 and electronic effect.

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Data availability

Data will be made available upon request.

Materials availability

Samples of the compounds are available from David. D. N’Da.

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Acknowledgements

The authors would like to thank the Japan Society for the Promotion of Science (JSPS) and Ohyama Health Foundation, Inc. for providing financial assistance.

Funding

This work was supported by the Japan Society for the Promotion of Science (JSPS), KAKENHI Grant Number 16K18793 [Grants-in-Aid for Young Scientists (B)], Grant Number 148781 [NRF-JSPS Bilateral Joint Research Program], and Ohyama Health Foundation, Inc. The funders had no role in the study design, data collection, and interpretation, nor the decision to submit the work for publication.

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Authors and Affiliations

  1. Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, 2520, South Africa

    Helena D. Janse van Rensburg & David D. N’Da

  2. National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada, Obihiro, Hokkaido, 080-8555, Japan

    Keisuke Suganuma

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KS and DDN contributed to conceptualization, funding, and bio resources; KS contributed to investigation; HDJR contributed to writing manuscript; and KS, DDN, and HDJR contributed to review and editing . All authors have read and agreed to the published version of the manuscript.

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Correspondence to Keisuke Suganuma.

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The authors declare no conflict of interest. The funders had no role in the design of the study, in the collection, analyses, or interpretation of the data, in the writing of the manuscript, nor in the decision to publish the results.

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Not applicable. MDBK was purchased from JCRB cell bank, National Institute of Biomedical Innovation, Health and Nutrition. T. b. brucei GUTat3.1, T. b. gambiense IL1922, T. b. rhodesiense IL1501, T. congolense IL3000, and T. evansi Tansui were provided by Dr. Hirumi. T. equiperdum IVM-t1 was established by Dr. Suganuma.

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Supplementary file1—Names and structures of test compounds, the predicted physiochemical and pharmacokinetic properties of the test compounds (DOCX 1054 KB)

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Janse van Rensburg, H.D., Suganuma, K. & N’Da, D.D. In vitro trypanocidal activities and structure–activity relationships of ciprofloxacin analogs. Mol Divers (2023). https://doi.org/10.1007/s11030-023-10704-9

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