title: CoMFA-SIMCA model for antichagasic nitrofurazone derivatives.
abstract: The physico-chemical properties of some 5-nitro-2-furaldehyde semicarbazones (nitrofurazones) and thiophene analogues were compared with their in vitro and in vivo trypanocidal activity against Trypanosoma cruzi (Tulahuen strain). 3D-QSAR models were obtained by applying the SIMCA methodology to the electrostatic and steric fields (CoMFA fields) of the molecules. Nitrofurazones bearing N4 substituents. which cover a range of 14-17 A from the nitro group with a thickness of about 6 A when considering the extended conformer. produced complete survival in infected mice. The in vitro model allows larger N4 substituents than the SURVival model, but they must not bear positive centres in the region 15-16 A from the nitro group. Moreover, the in vitro model is in agreement with the active site of trypanothione reductase (TR). Both models can be of use in the design of novel drugs bearing an amide-like group at a distance of 7-9 A from an easily reducible group.
authors.affiliation: Departamento de Química Aplicada, Universidad Pública de Navarra, Pamplona, Spain. merino@unavarra.es
authors.forename: V
authors.initials: V
authors.lastname: Martinez-Merino
authors.forename: H
authors.initials: H
authors.lastname: Cerecetto
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D009583:Nitrofurazone / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D014344:Trypanocidal Agents; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D009583:Nitrofurazone