New Potent 5-Substituted Benzofuroxans as Inhibitors of Trypanosoma cruzi Growth. Quantitative Structure-Activity Relationship Studies

G. AGUIRRE; L. BOIANI; M. BOIANI; H. CERECETTO; R. DI MAIO; M. GONZALEZ; W. PORCAL; A. DENICOLA; OSCAR ENRIQUE PIRO; CASTELLANO, EE

Bioorganic & Medicinal Chemistry

Elsevier

Año: 2005 vol. 13 p. 6336 - 6346

0968-0896

Benzofuroxan derivatives have been shown to inhibit the growth of Trypanosoma cruzi, the etiological agent of Chagas´ disease. Therefore, 2D- and 3D-QSAR models of their in vitro antichagasic activity were developed. Six new derivatives were synthesized to complete a final set of 26 structurally diverse benzofuroxans. The 2D-QSAR model (r = 0.939, r^2_adj=0.849) was generated using multiple regression analysis of tabulated substituents´ physicochemical properties and indicator variables. In addition, a 3D-QSAR model (r^2 = 0.997, q^2 = 0.802) was obtained using a comparative molecular field analysis (CoMFA). Due to the well-known benzofuroxan tautomerism, in both approaches (2D- and 3D-QSAR) it was necessary to include an indicator variable to consider the N-oxide position (I6). This parameter was established using low-temperature NMR experiments. Both QSAR models identified the electrophilic character of the substituent a-atom as a requirement for activity. Further support was found using a density functional theory (DFT) approach.