Synthesis, antichagasic in vitro evaluation, cytotoxicity assays, molecular modeling and SAR/QSAR studies of a 2-phenyl-3-(1-phenyl-1H-pyrazol-4-yl)-acrylic acid benzylidene-carbohydrazide series.
Chagas disease (American trypanosomiasis) is one of the most important parasitic diseases with serious social and economic impacts mainly on Latin America. This work reports the synthesis, in vitro trypanocidal evaluation, cytotoxicity assays, and molecular modeling and SAR/QSAR studies of a new series of N-phenylpyrazole benzylidene-carbohydrazides. The results pointed 6k (X=H, Y=p-NO2, pIC(50)=4.55 M) and 6l (X=F, Y=p-CN, pIC(50)=4.27 M) as the most potent derivatives compared to crystal violet (pIC(50)=3.77 M). The halogen-benzylidene-carbohydrazide presented the lowest potency whereas 6l showed the most promising profile with low toxicity (0% of cell death). The best equation from the 4D-QSAR analysis (Model 1) was able to explain 85% of the activity variability. The QSAR graphical representation revealed that bulky X-substituents decreased the potency whereas hydrophobic and hydrogen bond acceptor Y-substituents increased it.
Vera-Divaio
Maria A F
MA
Laboratório de Química Medicinal (LQMed)-Faculdade de Farmácia, Universidade Federal Fluminense, Rua Mário Viana 523, Santa Rosa, 24241-000 Niterói, RJ, Brazil.
Freitas
Antônio C C
AC
Castro
Helena C
HC
de Albuquerque
Sérgio
S
Cabral
Lucio M
LM
Rodrigues
Carlos R
CR
Albuquerque
Magaly G
MG
Martins
Rita C A
RC
Henriques
Maria G M O
MG
Dias
Luiza R S
LR
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis*; D001597:Benzylidene Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D014355:Chagas Disease / Q000188:drug therapy*; D006834:Hydrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects
D000981:Antiprotozoal Agents; D001597:Benzylidene Compounds; D006834:Hydrazines; C019289:carbohydrazide