Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Aug;28(4):2667-2680.
doi: 10.1007/s11030-023-10704-9. Epub 2023 Jul 23.

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

Helena D Janse van Rensburg  1 , Keisuke Suganuma  2 , David D N'Da  1
Affiliations

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

Helena D Janse van Rensburg et al. Mol Divers. 2024 Aug.

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.

Keywords: 1,2,3-Triazole; African trypanosomes; Ciprofloxacin; Trypanocidal activity.

PubMed Disclaimer

References

    1. Altamura F, Rajesh R, Catta-Preta CM, Moretti NS, Cestari I (2022) The current drug discovery landscape for trypanosomiasis and leishmaniasis: challenges and strategies to identify drug targets. Drug Dev Res 83(2):225–252. https://doi.org/10.1002/ddr.21664 - DOI - PubMed
    1. Brun R, Blum J, Chappuis F, Burri C (2010) Human African trypanosomiasis. Lancet 375(9709):148–159. https://doi.org/10.1016/S0140-6736(09)60829-1 - DOI - PubMed
    1. Büscher P, Cecchi G, Jamonneau V, Priotto G (2017) Human African trypanosomiasis. Lancet 390(10110):2397–2409. https://doi.org/10.1016/S0140-6736(17)31510-6 - DOI - PubMed
    1. Cayla M, Rojas F, Silvester E, Venter F, Matthews KR (2019) African trypanosomes. Parasit Vectors 12(1):1–8. https://doi.org/10.1186/s13071-019-3355-5 - DOI
    1. Desquesnes M, Gonzatti M, Sazmand A, Thévenon S, Bossard G, Boulangé A, Gimonneau G, Truc P, Herder S, Ravel S (2022) A review on the diagnosis of animal trypanosomoses. Parasit Vectors 15(1):1–24. https://doi.org/10.1186/s13071-022-05190-1 - DOI