ABSTRACT
Cyclohexadepsipeptides (CHDPs) with cyclohexylmethyl side chains represent novel enniatins with in vivo activity against the parasitic nematode Haemonchus contortus Rudolphi in sheep. It was found that the replacement of benzylic by cyclohexylmethyl side chains on the enniatin skeleton can increase anthelmintic efficacy. Here we report on a simple total synthesis of the precursors for this type of CHDPs and an efficient chemical transformation of the benzylic into the corresponding cyclohexylmethyl side chains.
Subject(s)
Anthelmintics/chemical synthesis , Anthelmintics/pharmacology , Chemistry, Pharmaceutical/methods , Peptides/chemistry , Sheep Diseases/drug therapy , Animals , Catalysis , Drug Design , Haemonchus/metabolism , Humans , Hydrogen/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Chemical , Peptides, Cyclic/chemistry , SheepABSTRACT
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 (S,S,S,R,S,R)-configurated cyclohexadepsipeptides (CHDPs) represent novel enniatin derivatives with strong in vivo activity against the parasitic nematode Haemonchus contortus Rudolphi in sheep. 2D NMR spectroscopic analysis revealed for the major conformation the asymmetric conformer, containing a cis-amide bond between C(alpha) protons of neighbouring 2-hydroxy-(S)-carboxylic acid and N-methyl-(S)-amino acid. The absolute configuration of the novel CHDPs was determined by X-ray crystallography. A correlation between the major conformer and its anthelmintic activity was found. Here, we report on a simple total synthetic pathway for this particular type of CHDPs.
Subject(s)
Anthelmintics/chemical synthesis , Anthelmintics/pharmacology , Haemonchus/drug effects , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/pharmacology , Animals , Haemonchus/growth & development , Sheep , StereoisomerismABSTRACT
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.
