Assessment of the nematocidal activity of metallocenyl analogues of monepantel.

In this study, we present the design, synthesis, characterization and biological evaluation of structurally new ferrocenyl and ruthenocenyl derivatives of the organic anthelmintic monepantel (Zolvix®). All seven metallocenyl derivatives prepared (4a/b, 5a/b, 6a/b and 7) were isolated as racemates and characterized by 1H, 13C and 19F NMR spectroscopies, mass spectrometry, IR spectroscopy and elemental microanalysis. The molecular structures of four compounds (4a/b, 6a and 7) were further confirmed by X-ray crystallography. The biological activities of the organometallic intermediates (4a/b) and organometallic derivatives of monepantel (5a/b, 6a/b and 7) were evaluated in vitro using parasitic nematodes of major importance in livestock, namely Haemonchus contortus and Trichostrongylus colubriformis. Two ferrocenyl compounds (4a and 6a) showed nematocidal activity, while the analogous ruthenocenyl compounds (4b and 6b) were not active at the highest concentration tested (10 µg mL-1). In order to obtain insight into the difference in activity between ferrocenyl and ruthenocenyl derivatives, the potential of the compounds for reactive oxidative species (ROS) production in live cells was assessed. Interestingly, neither the ferrocenyl nor the ruthenocenyl compounds (4a/b and 6a/b) produced significant ROS in HeLa cells when checked after 22 h, potentially indicating a redox-independent activity of 4a and 6a on the parasites. The selectivity of the compounds on parasites was confirmed by investigating their cytotoxicity profiles. None of these compounds was toxic either to HeLa or MRC-5 cells. Thus, 4a and 6a could be considered as interesting leads for further development of new classes of anti-parasitic agents.

Organometallic Derivatization of the Nematocidal Drug Monepantel Leads to Promising Antiparasitic Drug Candidates.

The discovery of novel drugs against animal parasites is in high demand due to drug-resistance problems encountered around the world. Herein, the synthesis and characterization of 27 organic and organometallic derivatives of the recently launched nematocidal drug monepantel (Zolvix® ) are described. The compounds were isolated as racemates and were characterized by 1 H, 13 C, and 19 F NMR spectroscopy, mass spectrometry, and IR spectroscopy, and their purity was verified by microanalysis. The molecular structures of nine compounds were confirmed by X-ray crystallography. The anthelmintic activity of the newly designed analogues was evaluated in vitro against the economically important parasites Haemonchus contortus and Trichostrongylus colubriformis. Moderate nematocidal activity was observed for nine of the 27 compounds. Three compounds were confirmed as potentiators of a known monepantel target, the ACR-23 ion channel. Production of reactive oxygen species may confer secondary activity to the organometallic analogues. Two compounds, namely, an organic precursor (3 a) and a cymantrene analogue (9 a), showed activities against microfilariae of Dirofilaria immitis in the low microgram per milliliter range.

Novel, mercury-free synthetic pathway for trifluoromethylthio-substituted metallocenes.

A novel synthetic pathway for trifluoromethylthioferrocene (3), which does not involve the use of toxic mercury(II)-based reagents, is described. The novel approach involves first the treatment of the commercially available bromoferrocene (1a) with NaSCN in the presence of copper(+I) to yield thiocyanatoferrocene (1), and then the reaction of 1 with the Rupper-Prakash reagent and tetrabutylammonium fluoride (TBAF) to give 3 in an overall yield of 60%. This approach could be extended for the preparation of thiocyanato-(4) and trifluoromethylthio-ruthenocene (7), which are herein both reported for the first time. Interestingly, diferrocenyl disulfide (2a) and diruthenocenyl disulfide (5) could be isolated as side-products during the synthesis of 3 and 7, respectively. All new compounds were unambiguously characterized by (1)H, (13)C, and (19)F NMR spectroscopy, mass spectrometry, cyclic voltammetry, elemental analysis, as well by X-ray crystallography for 1, 4, 4b, 5, 6, and 7. 1-7 were further tested for their toxic activity on cervical cancer (HeLa) and noncancerous (MRC-5) cell lines. All organometallic compounds were found either to be nontoxic or to have a moderate toxicity toward the cell lines used in this study.