title: Structure-activity relationships from in vitro efficacies of the thiazolide series against the intracellular apicomplexan protozoan Neospora caninum.
abstract: Nitazoxanide (2-acetolyloxy-N-(5-nitro 2-thiazolyl) benzamide; NTZ) represents the parent compound of a novel class of broad-spectrum anti-parasitic compounds named thiazolides. NTZ is active against a wide variety of intestinal and tissue-dwelling helminths, protozoa, enteric bacteria and a number of viruses infecting animals and humans. While potent, this poses a problem in practice, since this obvious non-selectivity can lead to undesired side effects in both humans and animals. In this study, we used real time PCR to determine the in vitro activities of 29 different thiazolides (NTZ-derivatives), which carry distinct modifications on both the thiazole- and the benzene moieties, against the tachyzoite stage of the intracellular protozoan Neospora caninum. The goal was to identify a highly active compound lacking the undesirable nitro group, which would have a more specific applicability, such as in food animals. By applying self-organizing molecular field analysis (SOMFA), these data were used to develop a predictive model for future drug design. SOMFA performs self-alignment of the molecules, and takes into account the steric and electrostatic properties, in order to determine 3D-quantitative structure activity relationship models. The best model was obtained by overlay of the thiazole moieties. Plotting of predicted versus experimentally determined activity produced an r2 value of 0.8052 and cross-validation using the "leave one out" methodology resulted in a q2 value of 0.7987. A master grid map showed that large steric groups at the R2 position, the nitrogen of the amide bond and position Y could greatly reduce activity, and the presence of large steric groups placed at positions X, R4 and surrounding the oxygen atom of the amide bond, may increase the activity of thiazolides against Neospora caninum tachyzoites. The model obtained here will be an important predictive tool for future development of this important class of drugs.
authors.affiliation: Institute of Parasitology, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Esposito
authors.forename: Norbert
authors.initials: N
authors.lastname: Müller
authors.forename: Andrew
authors.initials: A
authors.lastname: Hemphill
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002417:Cattle; D004285:Dogs; D015195:Drug Design; D018688:Neospora / Q000187:drug effects*; D009574:Nitro Compounds; D016133:Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines / Q000494:pharmacology*; D046509:Tissue Culture Techniques
chemical_list: D000981:Antiprotozoal Agents; D009574:Nitro Compounds; D013844:Thiazoles; D053778:Thiazolidines; C041747:nitazoxanide