Cyclohexadepsipeptides (CHDPs) with improved anthelmintical efficacy against the gastrointestinal nematode (Haemonchus contortus) in sheep.
Besides 24-membered cyclooctadepsipeptides (CODPs) with the most prominent member of this class emodepside, the structurally related 18-membered cyclohexadepsipeptides (CHDPs) were of interest with regard to their efficacy against the nematode H. contortus in sheep.The CHDPs prepared by a simple total synthesis represent enniatin derivatives with strong in vivo activity against H. contortus in sheep. The correlation between the nature of the CHDP major conformers and their anthelmintic activities was studied in detail. All CHDPs with strong in vivo activity exists in deuterochloroform solution as conformers with restricted flexibility which was found by 2D-NMR spectroscopic analysis. This reduced flexibility of the major conformer can be exemplified by CHDPs containing e.g.: (i) an unsymmetrically folded conformation with no cis-amide bound, (ii) an internal hydrogen bond or (iii) one cis-amide bond, respectively.The strong in vivo anthelmintic activity against H. contortus in sheep indicates that the stereochemistry in 2-position of CHDPs is less important for their high inding affinity. It may be assumed that the identified inflexible region of the major conformers might mimic the active conformation of these CHDPs, which could be helpful for rational design of anthelmintics with less complicated structures.
Jeschke
P
P
Bayer CropScience AG, Research and Development Chemistry Insecticides, Alfred-Nobel-Str. 50, 40789, Monheim am Rhein, Germany. peter.jeschke@bayercropscience.com.
Harder
A
A
Bayer HealthCare AG, Animal Health Division, Research and Development Parasiticides, Leverkusen, Germany.
Schindler
M
M
Bayer CropScience AG, Research and Development Chemistry Insecticides, Alfred-Nobel-Str. 50, 40789, Monheim am Rhein, Germany.
Etzel
W
W
Bayer CropScience AG, Research and Development Chemistry Insecticides, Alfred-Nobel-Str. 50, 40789, Monheim am Rhein, Germany.
D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D047630:Depsipeptides / Q000737:chemistry / Q000494:pharmacology*; D006188:Haemonchiasis / Q000188:drug therapy / Q000662:veterinary*; D006189:Haemonchus / Q000187:drug effects*; D008958:Models, Molecular; D015394:Molecular Structure; D012756:Sheep; D012757:Sheep Diseases / Q000188:drug therapy* / Q000469:parasitology; D013329:Structure-Activity Relationship
D000871:Anthelmintics; D047630:Depsipeptides