title: A molecular modeling approach to in vivo efficacy of triclabendazole.
abstract: The structural and electronic features of a narrow-spectrum benzimidazole anthelmintic triclabendazole (TCZ, 6-chloro-5-[2,3-dichlorophenoxy]-2-methylthio-benzimidazole) and its 2 main metabolites triclabendazole sulfoxide (TCZ sulfoxide, 6-chloro-5-[2,3-dichlorophenoxyl]-2-methylsulfonyl-benzimidazole) and triclabendazole sulfone (TCZ sulfone, 6-chloro-5-[2,3-dichlorophenoxy]-2-methylsulfonyl-benzimidazole) have been determined using a combination of quantum mechanics, molecular graphics, and molecular modeling techniques. Using conformational analyses and quantum mechanics, 2 important differences were found between TCZ sulfoxide, the purported active species, and the broad-spectrum benzimidazole anthelmintics. The first distinguishing feature is the shape of the molecule; the substituent at the 2 position of TCZ sulfoxide is nonplanar. All other broad-spectrum benzimidazole anthelmintics, regardless of substituent at the 2 position (methyl carbamate or thiazolyl group), are flat. The second distinguishing feature is the net atomic charge on the substituent at the 2 position of TCZ sulfoxide; it is an order of magnitude larger than the net atomic charges on the other anthelmintics. Thus the nonplanar shape of the methysulfinyl group at the 2 position of TCZ sulfoxide is different (as is its net charge), suggesting that this may be the origin of its narrow spectrum of activity.
authors.affiliation: Department of Chemistry, Indiana University-Purdue University, Indianapolis 46205.
authors.forename: K B
authors.initials: KB
authors.lastname: Lipkowitz
authors.forename: R O
authors.initials: RO
authors.lastname: McCracken
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000737:chemistry* / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000737:chemistry* / Q000493:pharmacokinetics; D001693:Biological Transport, Active; D016166:Free Radical Scavengers; D008958:Models, Molecular; D008968:Molecular Conformation; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D000077682:Triclabendazole
chemical_list: D000871:Anthelmintics; D001562:Benzimidazoles; D016166:Free Radical Scavengers; D000077682:Triclabendazole