Second generation of 5-ethenylbenzofuroxan derivatives as inhibitors of Trypanosoma cruzi growth: synthesis, biological evaluation, and structure-activity relationships.
In vitro growth inhibitory activity of 21 new 5-ethenylbenzofuroxan derivatives against the protozoan parasite Trypanosoma cruzi, the causative agent of American trypanosomiasis, was studied. The designed compounds possess the previously described exigencies for optimal anti-parasite activity, the 5-ethenylbenzofuroxanyl moiety with different substituents. The synthetic key for preparing the derivatives was the Wittig procedure, that when 5-formylbenzofuroxan was used as the electrophile the corresponding deoxygenated products were marginally generated. Four of the new derivatives displayed remarkable in vitro activities against the epimastigote form of three strains of T. cruzi, Tulahuen 2, CL Brener, and Y. While the three deoxygenated analogues biologically assayed resulted inactives. Unspecific cytotoxicity was evaluated using human macrophages and active derivatives were not toxic at a concentration at least 13 times that of its IC(50) against T. cruzi (CL Brener strain). From the preliminary structure-activity relationship studies lipophilicity and electronic requirements were found relevant to anti-T. cruzi activity. Active compounds are more lipophilic than inactive ones and it was also identified that an optimum value of R Swain-Lupton's descriptor is required for optimal activity.
Porcal
Williams
W
Departamento de Química Orgánica, Facultad de Química-Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay.
Hernández
Paola
P
Aguirre
Gabriela
G
Boiani
Lucía
L
Boiani
Mariana
M
Merlino
Alicia
A
Ferreira
Ana
A
Maio
Rossanna Di
RD
Castro
Ana
A
González
Mercedes
M
Cerecetto
Hugo
H
D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D008264:Macrophages / Q000187:drug effects; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development*
D001583:Benzoxazoles; D007202:Indicators and Reagents; D014344:Trypanocidal Agents