Document Detail


Comparison of nodulisporic acid analogs in a Lucilia sericata in vitro assay and a Ctenocephalides felis membrane feeding system.
MedLine Citation:
PMID:  12053989     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A medicinal chemistry program on the nodulisporic acid chemical class, guided by an artificial membrane flea-feeding assay, has recently identified permissive and nonpermissive regions of the pharmacophore for exploitation against fleas. This pathway was validated when several promising compounds from this program were administered orally to dogs at 15.0 mg/kg and found to have >90% flea activity for 2 wk. To determine if a surrogate insect assay would have provided the same guidance, a nodulisporic acid analog series was examined in both a Lucilia sericata larval assay and an artificial membrane flea-feeding assay using Ctenocephalides felis. Results from both insect assays were concordant in that even subtle chemical modification or substitution to the left-hand side of the nodulisporic acid pharmacophore resulted in substantial loss of insecticidal activity. Both assays were also in general agreement that the only modifications to the pharmacophore that did not result in loss of activity occurred to the C-8 side chain on the right-hand side of the molecule. Although there was good agreement between the 2 assays on the general regions of the pharmacophore, there was variance on individual compounds in the mono- and disubstituted amide series from the C-8 side chain. For example, the L. sericata assay showed several analogs from this subclass to possess similar activity to the parent acid, whereas the membrane assay indicated superior activity against fleas relative to the same parent. Consequently, although there was substantial general agreement between the assays, it was concluded that finer optimization of a lead compound should be done against the target parasite, even if it is ex vivo, as early as possible in a medicinal chemistry program.
Authors:
T Felcetto; J Ondeyka; S L Colletti; P T Meinke; W L Shoop
Related Documents :
18798209 - Synthesis and biological properties of cylindramide derivatives: evidence for calcium-d...
17591549 - Preparation and biological evaluation of 111in-, 177lu- and 90y-labeled dota analogues ...
16875829 - Design, synthesis and molecular modeling study of iminodiacetyl monohydroxamic acid der...
6318729 - The semisynthesis of analogues of cytochrome c. modifications of arginine residues 38 a...
6438319 - Pyridonecarboxylic acids as antibacterial agents. 4. synthesis and antibacterial activi...
3994839 - Biological activity of 4-hydroxyisophthalic acid derivatives. iii. variously substitute...
6129289 - Inhibiton of diazepam and gamma-aminobutyric acid of depolarization-induced release of ...
10930899 - Helicobacter pylori infection influences nocturnal gastric acid breakthrough.
21917129 - Effect of polyunsaturated fatty acids on drug-sensitive and resistant tumor cells in vi...
Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  The Journal of parasitology     Volume:  88     ISSN:  0022-3395     ISO Abbreviation:  J. Parasitol.     Publication Date:  2002 Apr 
Date Detail:
Created Date:  2002-06-10     Completed Date:  2002-06-27     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7803124     Medline TA:  J Parasitol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  223-6     Citation Subset:  IM    
Affiliation:
Merck Research Laboratories, Merck and Co., Inc., Rahway, New Jersey 07065, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Diptera / metabolism*
Dogs
Fleas / metabolism*
Indoles*
Insecticides*
Membranes, Artificial
Structure-Activity Relationship
Chemical
Reg. No./Substance:
0/Indoles; 0/Insecticides; 0/Membranes, Artificial; 0/nodulisporic acid A

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Decreased hemoglobin concentrations, hyperparasitemia, and severe malaria are associated with increa...
Next Document:  Partial characterization of a tapeworm-secreted signal factor inducing sustained spike potentials in...