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

Abstract

The design, synthesis and biological evaluation of eighteen 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 1 H and 13 C 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 towards a cervical cancer cell line (HeLa) and, importantly, significantly less active towards a noncancerous cell line (MRC-5). The in vitro anthelmintic activity of the eighteen ferrocenyl PZQ derivatives was tested against 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. 3Introduction.

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

“…Using organometallic moieties such as ferrocenyl (already present in anticancer, antibacterial, and antimalarial drugs [56][57][58]) Fc-PZQ derivatives (types A and B, Fig. 4) displayed anthelmintic activity in the micromolar range but were considerably less active than PZQ1 (59). Upon alteration of the organometallic moiety to Cr(CO) 3 (CrPZQ16, CrPZQ17, Fig.…”

Toward Organometallic Antischistosomal Drug Candidates

“…This encouraged us to actively engage in this research field and hence two years ago we started a project on organometallic modifications of PZQ. Initially, 18 ferrocenyl derivatives of PZQ were synthesized, which are divided into two structural classes (Figure 3 Type A & Type B) [49]. Type-A class of compounds lacks the cyclohexane ring of PZQ, which might avoid the transformation to a hydroxylated metabolite with reduced activity.…”

Metal Complexes and Medicine: A Successful Combination

“…Out of the 18 ferrocenyl derivatives in our hands, only four compounds were found to have an antischistosomal activity at 30 µg/mL in vitro against S. mansoni. [33] We then evaluated the antischistosomal potential of two new chromium tricarbonyl derivatives of PZQ (1 and 2, Fig. 4).…”

“…4. a) Structures of a) ferrocenyl derivatives [33] and b) of chromium tricarbonyl derivatives [34] of the antischistosomal drug praziquantel. Scheme 2.…”