New potent 5-substituted benzofuroxans as inhibitors of Trypanosoma cruzi growth: Quantitative structure–activity relationship studies Original Research Article

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, image) was generated using multiple regression analysis of tabulated substituents’ physicochemical properties and indicator variables. In addition, a 3D-QSAR model (r2 = 0.997, q2 = 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 α-atom as a requirement for activity. Further support was found using a density functional theory (DFT) approach.