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Organometallic Derivatization of the Nematocidal Drug Monepantel Leads to Promising Antiparasitic Drug Candidates
Author(s) -
Hess Jeannine,
Patra Malay,
Rangasamy Loganathan,
Konatschnig Sandro,
Blacque Olivier,
Jabbar Abdul,
Mac Patrick,
Jorgensen Erik M.,
Gasser Robin B.,
Gasser Gilles
Publication year - 2016
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201602851
Subject(s) - anthelmintic , chemistry , antiparasitic , drug , antiparasitic agent , albendazole , avermectin , derivatization , haemonchus contortus , mass spectrometry , combinatorial chemistry , stereochemistry , pharmacology , biology , chromatography , helminths , medicine , ecology , zoology , pathology , anatomy
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 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.