Header

UZH-Logo

Maintenance Infos

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


Hess, Jeannine; Patra, Malay; Pierroz, Vanessa; Spingler, Bernhard; Jabbar, Abdul; Ferrari, Stefano; Gasser, Robin B; Gasser, Gilles (2016). Synthesis, Characterization, and Biological Activity of Ferrocenyl Analogues of the Anthelmintic Drug Monepantel. Organometallics, 35(19):3369-3377.

Abstract

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.

Abstract

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.

Statistics

Citations

6 citations in Web of Science®
4 citations in Scopus®
Google Scholar™

Altmetrics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research

07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:2016
Deposited On:09 Feb 2017 13:34
Last Modified:09 Feb 2017 13:35
Publisher:American Chemical Society (ACS)
ISSN:0276-7333
Publisher DOI:https://doi.org/10.1021/acs.organomet.6b00577

Download

Full text not available from this repository.
View at publisher