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

Abstract

The design, synthesis, and biological evaluation of 18 ferrocenyl derivatives (<b>4A</b>–<b>12A</b> and <b>4B</b>–<b>12B</b>) 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 <b>4A</b>, <b>5A</b>, and <b>7A</b>. 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 <i>in vitro</i> anthelmintic activity of the 18 ferrocenyl PZQ derivatives was tested against adult <i>Schistosoma mansoni</i>, 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 (<b>8A</b> and <b>8B</b>) that the complexes were stable when incubated for 24 h at 37 °C in human plasma