Influence of the cyclooctadepsipeptides PF1022A and PF1022E as natural products on the design of semi-synthetic anthelmintics such as emodepside.
The 24-membered cyclooctadepsipeptide (CODP) PF1022A, the active metabolite of the fungus imperfectus Mycelia sterilia (Rosellinia sp.) isolated from the plant Camellia japonica in Japan, is described as a powerful broad-spectrum anthelmintic natural product with low toxicity in animals. Further CODPs such as PF1022B, C, D and E have been isolated from the same culture and their structures have been established. Both PF1022A and PF1022E serve as valuable starting materials for the synthesis of semi-synthetic CODP derivatives with improved intrinsic anthelmintic potency and broad-spectrum activity. It was found that in most cases the di-substituted PF1022A derivatives showed a greater (or equal) activity by oral application against the gastrointestinal nematode Haemonchus contortus compared to the corresponding mono-substituted PF1022A analogues as exemplified by emodepside. In order to get additional information on the bioactive conformation, emodepside was transformed into its mono- and tetra-thionated derivatives by isosteric replacement. In the light of the increased efficacy of these derivatives against H. contortus or Trichostrongylus colubriformis, it has been suggested that the asymmetric conformation clearly influences the anthelmintic activity of CODPs. Although useful synthetic pathways are available today for the preparation of the semi-synthetic CODP emodepside, the fermentative production of its bis-para-nitro and bis-para-amino precursors could be the process used for its industrial-scale production in the future.
Jeschke
R
R
Bayer CropScience AG, Research and Development, Chemistry lnsecticides, Alfred-Nobel-Strasse 50, 40789, Monheim am Rhein, Germany. peter.jeschke@bayercropscience.com.
Iinuma
K
K
Fuji Amide Chemical Company Limited, 8-18,5-chome, Ukima, Kita-ku, Tokyo 115-0051, Japan.
Harder
A
A
Bayer HealthCare AG, Animal Health Division, Research and Development Parasiticides, 51368, Leverkusen, Germany.
Schindler
M
M
Bayer CropScience AG, Research and Development, Chemistry lnsecticides, Alfred-Nobel-Strasse 50, 40789, Monheim am Rhein, Germany.
Murakami
T
T
Microbiological Resources and Technology Laboratories, Meiji Seika Kaisha, Ltd., 788 Kayama, Odawara-shi, Kanagawa 250-0852, Japan.
D000818:Animals; D000871:Anthelmintics / Q000737:chemistry*; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006189:Haemonchus / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000871:Anthelmintics; D047630:Depsipeptides; C542265:PF1022E peptide, Rosellinia; D010456:Peptides, Cyclic; C075544:PF 1022A; C468987:emodepside