Anthelmintic resistance in human and animal pathogenic helminths has been spreading in prevalence and severity to a point where multidrug resistance against the three major classes of anthelmintics--the benzimidazoles, imidazothiazoles and macrocyclic lactones--has become a global phenomenon in gastrointestinal nematodes of farm animals. Hence, there is an urgent need for an anthelmintic with a new mode of action. Here we report the discovery of the amino-acetonitrile derivatives (AADs) as a new chemical class of synthetic anthelmintics and describe the development of drug candidates that are efficacious against various species of livestock-pathogenic nematodes. These drug candidates seem to have a novel mode of action involving a unique, nematode-specific clade of acetylcholine receptor subunits. The AADs are well tolerated and of low toxicity to mammals, and overcome existing resistances to the currently available anthelmintics.
Anthelmintic resistance has become a global phenomenon in gastro-intestinal nematodes of farm animals, including multi-drug resistance against the three major classes of anthelmintics. There is an urgent need for an anthelmintic with a new mode of action. The recently discovered amino-acetonitrile derivatives (AADs) offer a new class of synthetic chemicals with anthelmintic activity. The evaluation of AADs was pursued applying in vitro assays and efficacy and tolerability studies in rodents, sheep, and cattle. Amongst various suitable compounds, AAD 1566 eliminated many tested pathogenic nematode species, both at larval and adult stages, at a dose of 2.5 mg/kg bodyweight in sheep and 5.0 mg/kg bodyweight in cattle. The same doses were sufficient to cure animals infected with resistant or multi-drug-resistant nematode isolates. These findings, complemented by the good tolerability and low toxicity to mammals, suggest that AAD 1566, monepantel, would be a suitable anthelmintic drug development candidate.
Colchicine is a potent antimitotic poison which is well known to prevent microtubule assembly by binding tubulin very tightly. Colchicine also possesses anti-inflammatory properties which are not well understood yet. Here we show that colchicine tightly interacts with lipid layers. The physical and biological properties of three different lipid derivatives of colchicine are investigated parallel to those of membrane lipids in the presence of colchicine. Upon insertion in the fatty alkyl chains, colchicine rigidifies the lipid monolayers in a fluid phase and fluidifies rigid monolayers. Similarly X-ray diffraction data show that lecithin-water phases are destabilized by colchicine. In addition, an unexpectedly drastic enhancement of the photoisomerization rate of colchicine into lumicolchicine in the lipid environment is observed and further supports insertion of the alkaloid in membranes. Finally the interaction of colchicine with lipids makes the drug inaccessible to tubulin. The possible in vivo significance of these results is discussed.
The synthesis of glycero-lipids linked to colchicine derivatives is reported. The lipid structures are designed to perform two-dimensional crystallization experiments with tubulin, the structural subunit protein of microtubules.Introduction. -Colchicine, a plant alkaloid extracted from Colchicum automnale L. in the early thirties, is certainly one of the oldest and the most studied inhibitor of microtubule-mediated processes in vivo [l], and has been used in the treatment of acute gout, familial Mediterranean fever and liver cirrhosis [2]. Colchicine binds to soluble tubulin heterodimer and inhibits microtubule assembly substoichiometrically [3]. It has been shown that incorporation of liganded tubulin into microtubules induces a conformational change that prevents incorporation of additional liganded or unliganded dimers [4]. Actually, three-dimensional structural analyses on tubulin either in microtubules [5], double rings [6], or Zn-induced sheets [7] provide data on functional protein, but no description of conformationally modified colchicine-liganded tubulin is available.To attend a structural analysis of colchicine-liganded tubulin by two-dimensional crystallization and electron crystallography [8], we prepared lipid derivatives of colchicine. Once spread into monolayers at the air/water interface, these derivatives should promote an in-plane concentration of the protein introduced into the sub-phase with further two-dimensional crystallization of the liganded immobilized tubulin. Herein, we describe the synthesis of these specifically designed lipid derivatives of colchicine.Due to its antimitotic properties, colchicine has been extensively studied, and a number of analogs have been synthesized, providing interesting structure-activity-related informations [9]. When aiming to anchor the tubulin molecule at a surface, results of chromatography experiments with the protein are especially valuable and allow pointing out pertinent hypotheses about the way colchicine can be attached to a matrix, mostly preserving its biological properties [lo]. As a matter of fact, results in the literature indicate that the acetamido moiety in colchicine can be chemically modified without substantial loss of activity. Accordingly, colchicine derivatives 3-6 were prepared in order to evaluate their biological properties prior to target any structure of a lipid derivative of 1 he drug.
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