title: Norcantharidin analogues with nematocidal activity in Haemonchus contortus.
abstract: With the major problems with resistance in parasitic nematodes of livestock to anthelmintic drugs, there is an urgent need to develop new nematocides. In the present study, we employed a targeted approach for the design of a series of norcantharidin analogues (n=54) for activity testing against the barber's pole worm (Haemonchus contortus) of small ruminants in a larval development assay (LDA) and also for toxicity testing on nine distinct human cell lines. Although none of the 54 analogues synthesized were toxic to any of these cell lines, three of them (N-octyl-7-oxabicyclo(2.2.1)heptane-2,3-dicarboximide (B2), N-decyl-7-oxabicyclo(2.2.1)heptane-2,3-dicarboximide (B3) and 4-[(4-methyl)-3-ethyl-2-methyl-5-phenylfuran-10-oxa-4-azatricyclo[5.2.1]decane-3,5-dione (B21) reproducibly displayed 99-100% lethality to H. contortus in LDA, with LD(50s) of 25-40 μM. The high 'hit rate' (5.6%) indicates that the approach taken here has advantages over conventional drug screening methods. A major advantage of norcantharidin analogues over some other currently available anthelmintics is that they can be produced in one to two steps in large amounts at low cost and high purity, and do not require any additional steps for the isolation of the active isomer. This positions them well for commercial development.
authors.affiliation: Department of Veterinary Science, The University of Melbourne, Parkville, Vic. 3052, Australia.
authors.forename: Bronwyn E
authors.initials: BE
authors.lastname: Campbell
authors.forename: Mark
authors.initials: M
authors.lastname: Tarleton
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Gordon
authors.forename: Jennette A
authors.initials: JA
authors.lastname: Sakoff
authors.forename: Jayne
authors.initials: J
authors.lastname: Gilbert
authors.forename: Adam
authors.initials: A
authors.lastname: McCluskey
authors.forename: Robin B
authors.initials: RB
authors.lastname: Gasser
mesh_terms: D000818:Animals; D000969:Antinematodal Agents / Q000737:chemistry* / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D015195:Drug Design; D006189:Haemonchus / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms
chemical_list: D000969:Antinematodal Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C069741:norcantharidin