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 |
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| Authors: | Maria AF Vera-DiVaio Antônio CC Freitas Helena C Castro Sérgio de Albuquerque Lucio M Cabral Carlos R Rodrigues Magaly G Albuquerque Rita CA Martins Maria GMO Henriques Luiza RS Dias |
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| Institution: | 1. Laboratório de Química Medicinal (LQMed) - Faculdade de Farmácia, Universidade Federal Fluminense, Rua Mário Viana 523, Santa Rosa, 24241-000 Niterói, RJ, Brazil;2. Laboratório de Antibióticos, Bioquímica e Modelagem Molecular (LABioMol) - Instituto de Biologia, Universidade Federal Fluminense, Outeiro de São João Baptista, 24020-150 Niterói, RJ, Brazil;3. Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, 29020-159 São Paulo, SP, Brazil;4. Laboratório de Modelagem Molecular e QSAR (ModMolQSAR) - Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, 21941-590 Rio de Janeiro, RJ, Brazil;5. Departamento de Química Orgânica - Instituto de Química, Universidade Federal do Rio de Janeiro, 21949-900 Rio de Janeiro, RJ, Brazil;6. Curso de Farmácia, Centro de Ensino Superior do Pará, Av. Nazaré 630, Nazaré, 66035-170 Belém, PA, Brazil;7. Departamento de Farmacologia Aplicada, Instituto de Tecnologia em Fármacos, Fundação Oswaldo Cruz (FIOCRUZ), Rua Sizenando Nabuco 100, Manguinhos, 21041-250, Rio de Janeiro, RJ, Brazil |
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| Abstract: | 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, pIC50 = 4.55 M) and 6l (X = F, Y = p-CN, pIC50 = 4.27 M) as the most potent derivatives compared to crystal violet (pIC50 = 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. |
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