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.