title: Organometallic Derivatization of the Nematocidal Drug Monepantel Leads to Promising Antiparasitic Drug Candidates.
abstract: 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 by1H,13C, and19F 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.
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
authors.forename: Jeannine
authors.initials: J
authors.lastname: Hess
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
authors.forename: Malay
authors.initials: M
authors.lastname: Patra
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
authors.forename: Loganathan
authors.initials: L
authors.lastname: Rangasamy
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
authors.forename: Sandro
authors.initials: S
authors.lastname: Konatschnig
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Blacque
authors.affiliation: Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Abdul
authors.initials: A
authors.lastname: Jabbar
authors.affiliation: Howard Hughes Medical Institute, Department of Biology, University of Utah, Salt Lake City, UT, 84112-0840, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mac
authors.affiliation: Howard Hughes Medical Institute, Department of Biology, University of Utah, Salt Lake City, UT, 84112-0840, USA.
authors.forename: Erik M
authors.initials: EM
authors.lastname: Jorgensen
authors.affiliation: Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, 3010, Australia. robinbg@unimelb.edu.au.
authors.forename: Robin B
authors.initials: RB
authors.lastname: Gasser
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland. gilles.gasser@chem.uzh.ch.
authors.forename: Gilles
authors.identifier: http://orcid.org/0000-0002-4244-5097
authors.initials: G
authors.lastname: Gasser
mesh_terms: D000607:Aminoacetonitrile / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D000969:Antinematodal Agents / Q000737:chemistry* / Q000494:pharmacology; D000977:Antiparasitic Agents / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004351:Drug Resistance / Q000187:drug effects*; D006189:Haemonchus
chemical_list: D000969:Antinematodal Agents; D000977:Antiparasitic Agents; D000607:Aminoacetonitrile; C533978:monepantel
keywords: anthelmintics; bioorganometallic chemistry; drug design; medicinal chemistry; metallocenes