ABSTRACT
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.
Subject(s)
Anthelmintics/pharmacology , Depsipeptides/pharmacology , Haemonchiasis/veterinary , Haemonchus/drug effects , Sheep Diseases/drug therapy , Animals , Depsipeptides/chemistry , Haemonchiasis/drug therapy , Models, Molecular , Molecular Structure , Sheep , Sheep Diseases/parasitology , Structure-Activity RelationshipABSTRACT
The tetra- and mono-thionated cyclic octadepsipeptides represent novel cyclic octadepsipeptide derivatives with broad-spectrum activity against parasitic nematodes in mice and sheep. Some of these show better activity than the potent natural anthelmintic cyclic octadepsipeptide PF1022A against Hymenolepis nana, Heterakis spumosa and Trichinella spiralis larvae in mice. In particular, they show improved efficacy against Haemonchus contortus and Trichostrongylus colubriformis in sheep compared with PF1022A. Here we report on two different and simple synthetic pathways for this new class of thionated cyclic octadepsipeptides.
Subject(s)
Anthelmintics/chemical synthesis , Depsipeptides , Helminths/drug effects , Peptides, Cyclic/chemical synthesis , Thioamides/chemical synthesis , Animals , Anthelmintics/metabolism , Anthelmintics/pharmacology , Helminthiasis, Animal/drug therapy , Magnetic Resonance Spectroscopy , Male , Mice , Mice, Inbred Strains , Molecular Structure , Peptides, Cyclic/metabolism , Peptides, Cyclic/pharmacology , Sheep , Structure-Activity Relationship , Thioamides/metabolism , Thioamides/pharmacologyABSTRACT
New cyclohexadepsipeptides of the enniatin type with potential anthelmintic properties were produced by two different strategies: 1. In vitro synthesis by use of the multienzyme enniatin synthetase, and 2. in vivo precursor feeding of enniatin producing strains Fusarium scirpi and Fusarium sambucinum. The compounds were analyzed by HPLC, various NMR measurements and mass spectrometry. The three N-methyl L-amino acid positions in the enniatin B molecule could be gradually replaced by other (N-methyl) L-amino acids, e.g. alanine, cysteine, threonine and serine. The latter two amino acids yield new enniatins with functional groups in the hydrophobic side chains. Similarly the three D-2-hydroxyisovalerate residues, present in all naturally occuring enniatins, could be substituted by D-2-hydroxybutyric acid and D-lactic acid. Despite its lower yield the in vitro synthesis has the advantage of a broader variety of products formed.
