Synthesis of Novel Artemisinin, Ciprofloxacin, and Norfloxacin Hybrids with Potent Antiplasmodial Activity

Vamvoukaki, Georgia; Antoniou, Antonia I.; Baltas, Michel; Mouray, Elisabeth; Charneau, Sebastien; Grellier, Philippe; Athanassopoulos, Constantinos M.

doi:10.3390/antibiotics13020142

Open AccessArticle

Synthesis of Novel Artemisinin, Ciprofloxacin, and Norfloxacin Hybrids with Potent Antiplasmodial Activity

by

Georgia Vamvoukaki

¹,

Antonia I. Antoniou

¹

,

Michel Baltas

^2,*

,

Elisabeth Mouray

³,

Sebastien Charneau

^3,4

,

Philippe Grellier

³ and

Constantinos M. Athanassopoulos

^1,*

¹

Synthetic Organic Chemistry Laboratory, Department of Chemistry, University of Patras, GR-26504 Patras, Greece

²

CNRS, LCC (Laboratoire de Chimie, de Coordination), Université de Toulouse, UPS, INPT, 205 Route de Narbonne, BP 44099, CEDEX 4, F-31077 Toulouse, France

³

MCAM, UMR 7245, Muséum National d’Histoire Naturelle, CNRS, CP52, 63 rue Buffon, F-75005 Paris, France

⁴

Laboratory of Biochemistry and Protein Chemistry, Department of Cell Biology, Institute of Biology, University of Brasilia, Brasilia 70910-900, Brazil

^*

Authors to whom correspondence should be addressed.

Antibiotics 2024, 13(2), 142; https://doi.org/10.3390/antibiotics13020142

Submission received: 9 December 2023 / Revised: 25 January 2024 / Accepted: 27 January 2024 / Published: 1 February 2024

(This article belongs to the Special Issue Antimicrobial Activity of Plant-Derived Products and Synthetic Derivatives, 2nd Edition)

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Abstract

The synthesis and antiplasmodial evaluation of new hybrids combining the pharmacophore structures of artemisinin, ciprofloxacin or norfloxacin, and 7-chloroquinoline are reported in this study. The first step for all of the syntheses is the obtainment of key piperazine esters intermediates bearing the drugs ciprofloxacin and norfloxacin. Using these platforms, 18 final compounds were synthesized through a multistep procedure with overall yields ranging between 8 and 20%. All compounds were screened for their antiplasmodial activity against the chloroquine-resistant Plasmodium falciparum FcB1 strain. Compounds 20, 21, 22, and 28, bearing an artesunate fragment with ciprofloxacin, exhibited IC₅₀ values in the range of 3.5–5.4 nM and excellent selectivity indices. Among the compounds bearing the artesunate moiety on the norfloxacin, two of them, 23 and 24, afforded IC₅₀ values of 1.5 nM and 1.9 nM, respectively. They also showed excellent selectivity indices. The most potent compounds were also evaluated against the CQ-resistant Dd2 strain of Plasmodium falciparum, demonstrating that those compounds incorporating the artesunate fragment were the most potent. Finally, the combination of artesunate with either ciprofloxacin or norfloxacin moieties in a single molecular entity proved to substantially enhance the activity and selectivity when compared to the administration of the unconjugated counterparts artesunate/ciprofloxacin and artesunate/norfloxacin.

Keywords: fluoroquinolones; hybrid; conjugate; structure–activity relationship; antimalarial activity; Pf FcB1 CQ-resistant strain; Pf Dd2 CQ-resistant strain

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MDPI and ACS Style

Vamvoukaki, G.; Antoniou, A.I.; Baltas, M.; Mouray, E.; Charneau, S.; Grellier, P.; Athanassopoulos, C.M. Synthesis of Novel Artemisinin, Ciprofloxacin, and Norfloxacin Hybrids with Potent Antiplasmodial Activity. Antibiotics 2024, 13, 142. https://doi.org/10.3390/antibiotics13020142

AMA Style

Vamvoukaki G, Antoniou AI, Baltas M, Mouray E, Charneau S, Grellier P, Athanassopoulos CM. Synthesis of Novel Artemisinin, Ciprofloxacin, and Norfloxacin Hybrids with Potent Antiplasmodial Activity. Antibiotics. 2024; 13(2):142. https://doi.org/10.3390/antibiotics13020142

Chicago/Turabian Style

Vamvoukaki, Georgia, Antonia I. Antoniou, Michel Baltas, Elisabeth Mouray, Sebastien Charneau, Philippe Grellier, and Constantinos M. Athanassopoulos. 2024. "Synthesis of Novel Artemisinin, Ciprofloxacin, and Norfloxacin Hybrids with Potent Antiplasmodial Activity" Antibiotics 13, no. 2: 142. https://doi.org/10.3390/antibiotics13020142

APA Style

Vamvoukaki, G., Antoniou, A. I., Baltas, M., Mouray, E., Charneau, S., Grellier, P., & Athanassopoulos, C. M. (2024). Synthesis of Novel Artemisinin, Ciprofloxacin, and Norfloxacin Hybrids with Potent Antiplasmodial Activity. Antibiotics, 13(2), 142. https://doi.org/10.3390/antibiotics13020142

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Synthesis of Novel Artemisinin, Ciprofloxacin, and Norfloxacin Hybrids with Potent Antiplasmodial Activity

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