Ferrocenyl Derivatives of the Anthelmintic Praziquantel: Design, Synthesis, and Biological Evaluation

• Published in: Journal of medicinal chemistry 2012-10, Vol.55 (20), p.8790-8798
• Main Authors: Patra, Malay, Ingram, Katrin, Pierroz, Vanessa, Ferrari, Stefano, Spingler, Bernhard, Keiser, Jennifer, Gasser, Gilles
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Crystallography, X-Ray; Ferrous Compounds - chemical synthesis; Ferrous Compounds - pharmacology; Humans; Metallocenes; Models, Molecular; Molecular Structure; Praziquantel - analogs & derivatives; Praziquantel - chemical synthesis; Praziquantel - pharmacology; Schistosoma mansoni - drug effects; Schistosomicides - chemical synthesis; Schistosomicides - pharmacology; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm301077m

The design, synthesis, and biological evaluation of 18 ferrocenyl derivatives (4A–12A and 4B–12B) of the most well-known drug against schistosomiasis, namely praziquantel (PZQ), are reported. These compounds, which have been all isolated as racemates, were unambiguously characterized by 1H and 13C NMR spectroscopy, mass spectrometry, and elemental analysis as well as by X-ray crystallography for 4A, 5A, and 7A. Cytotoxicity studies revealed that the complexes were moderately toxic toward a cervical cancer cell line (HeLa) and, importantly, significantly less active toward a noncancerous cell line (MRC-5). The in vitro anthelmintic activity of the 18 ferrocenyl PZQ derivatives was tested against adult Schistosoma mansoni, and values in the micromolar range (26–68 μM) were determined for the four most active compounds. It was also demonstrated using two compounds of the series as models (8A and 8B) that the complexes were stable when incubated for 24 h at 37 °C in human plasma.