Synthesis, antichagasic in vitro evaluation, cytotoxicity assays, molecular modeling and SAR/QSAR studies of a 2-phenyl-3-(1-phenyl-1 H-pyrazol-4-yl)-acrylic acid benzylidene-carbohydrazide series

• Published in: Bioorganic & medicinal chemistry 2009, Vol.17 (1), p.295-302
• Main Authors: Vera-DiVaio, Maria A.F., Freitas, Antônio C.C., Castro, Helena C., de Albuquerque, Sérgio, Cabral, Lucio M., Rodrigues, Carlos R., Albuquerque, Magaly G., Martins, Rita C.A., Henriques, Maria G.M.O., Dias, Luiza R.S.
• Format: Article
• Language: English
• Subjects: 1-Phenyl-1 H-pyrazol; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Antiprotozoal Agents - chemical synthesis; Benzylidene Compounds - chemical synthesis; Benzylidene Compounds - pharmacology; Benzylidene-carbohydrazides; Biological and medical sciences; Cell Death - drug effects; Chagas disease; Chagas Disease - drug therapy; Hydrazines - chemical synthesis; Hydrazines - pharmacology; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Quantitative Structure-Activity Relationship; Trypanocidal evaluation; Trypanosoma cruzi - drug effects
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.10.085

The 6k (X = H, Y = NO 2, pIC 50 = 4.55 M) and 6l (X = F, Y = CN, pIC 50 = 4.27 M) are the most potent trypanocidal agents. However, 6l showed the most promising overall profile, with low toxicity (0% of cell death). 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-NO 2, 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.