New potent 5-substituted benzofuroxans as inhibitors of Trypanosoma cruzi growth: quantitative structure-activity relationship studies.
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.
Aguirre
Gabriela
G
Departamento de Química Orgánica, Facultad de Química-Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
Boiani
Lucía
L
Boiani
Mariana
M
Cerecetto
Hugo
H
Di Maio
Rossanna
R
González
Mercedes
M
Porcal
Williams
W
Denicola
Ana
A
Piro
Oscar E
OE
Castellano
Eduardo E
EE
Sant'Anna
Carlos Mauricio R
CM
Barreiro
Eliezer J
EJ
D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004583:Electrons; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009547:Nifurtimox / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D013696:Temperature; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development*; D010069:Oxadiazoles
D001583:Benzoxazoles; D009547:Nifurtimox; D014344:Trypanocidal Agents; C014354:benzofuroxan; D010069:Oxadiazoles