ABSTRACT
The substituted (R)-phenyllactic acid containing cyclohexadepsipeptides (CHDPs) represent novel enniatin derivatives with strong in vivo activities against the parasitic nematode Haemonchus contortus Rudolphi in sheep. 2D NMR spectroscopic analysis revealed for the substituted (R)-phenyllactic acid containing CHDPs one major conformer with an unsymmetrically folded conformation lacking a cis-amide bond. A correlation between the substitution pattern and its anthelmintic activity was found. Here we report on a simple total synthetic pathway of the precursor for this particular type of CHDPs and an efficient modification of the benzylic side chain (R-PhLac(2)).
Subject(s)
Anthelmintics/pharmacology , Lactates/chemistry , Lactic Acid/chemistry , Peptides/chemistry , Sheep/parasitology , Animals , Crystallography, X-Ray , Depsipeptides/chemistry , Lactic Acid/pharmacology , Models, Chemical , Models, Molecular , Molecular Conformation , Peptides, Cyclic/chemistry , Protein ConformationABSTRACT
The racemic 7-substituted 3,4a-dimethyl-4a,5a,8a,8b-tetrahydro-6H-pyrrolo[3',4':4,5]furo[3,2-b]pyridine-6,8(7H)-diones represent novel tricyclic compounds with strong in vivo efficacy against the parasitic nematode Haemonchus contortus Rudolphi in sheep. Here we report on the synthesis of tricyclic endo-2,3-dihydro[3,2-b]pyridine-type cycloadducts and describe the separation of the racemic 3,4a-dimethyl-7-ethyl-4a,5a,8a,8b-tetrahydro-6H-pyrrolo[3',4':4,5]furo[3,2]pyridine-6,8(7H)-dione into the enantiomers by HPLC. The absolute configuration of the most anthelmintically active (4aS,5aS,8aS,8bR)-enantiomer was determined by single crystal X-ray analysis using its stable (4aS,5aS,8aS,8bR)-enantiomer-CuCl2 (2:1)-complex.
Subject(s)
Anthelmintics/chemical synthesis , Haemonchus/drug effects , Pyridones/chemical synthesis , Pyrroles/chemical synthesis , Animals , Anthelmintics/pharmacology , Indicators and Reagents , Models, Molecular , Molecular Conformation , Molecular Structure , Pyridones/pharmacology , Pyrroles/pharmacologyABSTRACT
The N-methylated amidoxime analogues of the cyclic octadepsipeptide PF1022A represent novel derivatives with activity against Trichinella spiralis Owen and Nippostrongylus brasiliensis Lane in vitro and against parasitic nematodes in mice and sheep. Some of them show better activity against Hymenolepis nana Siebold, Heterakis spumosa Schneider and Heligmosomoides polygyrus Dujardin in mice than the natural product PF1022A. In particular an improved efficacy against Haemonchus contortus Rudolphi and Trichostrongylus colubriformis Giles in sheep compared to the potent cyclic octadepsipeptide PF1022A and its mono-thionated derivative has been observed. Here we report on a specific modification at the N-methyl amide linkage by using the mono-thionated PF1022A, resulting in novel anthelmintically active backbone analogues of PF 1022A.
