New potent 5-substituted benzofuroxans as inhibitors of Trypanosoma cruzi growth: quantitative structure-activity relationship studies |
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Authors: | Aguirre Gabriela Boiani Lucía Boiani Mariana Cerecetto Hugo Di Maio Rossanna González Mercedes Porcal Williams Denicola Ana Piro Oscar E Castellano Eduardo E Sant'Anna Carlos Mauricio R Barreiro Eliezer J |
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Institution: | Departamento de Química Orgánica, Facultad de Química-Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay. |
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Abstract: | 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(adj)(2) = 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 (I(6)). This parameter was established using low-temperature NMR experiments. Both QSAR models identified the electrophilic character of the substituent alpha-atom as a requirement for activity. Further support was found using a density functional theory (DFT) approach. |
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