Synthesis, Characterization, and Biological Activity of Ferrocenyl Analogues of the Anthelmintic Drug Monepantel

There is major demand for the development of structurally new anti-infectives using innovative approaches to circumvent multidrug resistance in parasites. Herein, we describe the synthesis and characterization of ferrocenyl precursors and derivatives (2-8) of an anthelmintic drug, monepantel. All compounds were isolated as their racemates and characterized by ¹H, ¹³C, and ¹⁹F NMR spectroscopy, mass spectrometry, and IR spectroscopy. The purity of individual compounds was confirmed by elemental microanalysis. The molecular structures of three of the organometallic compounds (5-7) were also established by X-ray crystallography. The biological activities of these compounds were then evaluated in vitro on various important eukaryotic parasites, including H. contortus, T. colubriformis, and D. immitis. The potencies against D. immitis (canine heartworm) of two compounds, a ferrocene-containing precursor (4) and the final ferrocene-based monepantel derivative (8), were shown to be moderate (EC₅₀ = 3.70 μg/mL for 4 and 5.60 μg/mL for 8) and were comparable with those of the controls AAD85 (EC₅₀ = 2.20 μg/mL) and a commercial drug, ivermectin (EC₅₀ = 1.00-3.00 μg/mL). The assessment of the cytotoxicity using cancerous HeLa and noncancerous MRC-5 cell lines revealed that these compounds have moderate to low toxicities in mammalian cells, thereby showing selective activity on parasites.