Synthesis, Biological Evaluation Of Novel 4,5-dihydro-2H-pyrazole Derivatives

In today’s world, heterocyclic compounds play an important role in the research and development of pharmaceutical pesticide. Whether it is natural or synthetic heterocyclic pyrazole compounds, they play an important (anticancer, insecticidal, fungicidal) role in medicine.Pyrazole derivatives are kinds of multifunctional compounds, they and their complexes can be used as insecticide, fungicide, herbicide, catalyst, antibacterial. Many pyrazole compounds are the hotspot of the research with their anticancer, antibacterial, antiviral, anti-convulsion and other biological activity. In this paper, two series of new compounds have been synthesized through hydroxyl and methyl phenyl containing three fluoride chalcone derivatives reacted with hydrazine hydrate.Melanoma is a very high malignant tumor, the mortality rate is as high as 80%, is one of the main causes of death in skin cancer. Research shows that, RAF subtype-BRAF kinase kinase pathway is one of the most closely related with melanoma. BRAF as an oncogene, the gene mutation is found in 8% of the cancer cells, and in melanoma mutation rate is 50-70%. The BRAF gene is found in 90% of the mutations in a cancer cell is located on the 600 site is instead of valine glutamate (V600E). The mutations in the MAPK pathway is activated the cancer cell proliferation, survival and metastasis. In recent years, BRAFV600E kinase as a target for the anti-melanoma inhibitor, which inhibits the activity of the vemurafenib, dabrafenib etc. This paper is based on SB2590885 researched by GlaxoSmithKline, design and synthesis a series of hydroxyl containing two hydrogen pyrazole compounds, in order to obtain the a better BRAFV600E kinase inhibitor. All the compounds were test through BRAFV600E kinase inhibitory activity and human melanoma cell line WM226.4 inhibitory activity, the results of IC50 values reached micromolar. Compounds 3d and 3m showed the most potent biological activity with 3d:IC50= 0.22μM,3m:IC50=0.46μM, comparing with Erlotinib:IC50=0.08μM. This paper has also carried on the computer simulation of molecular docking experiments with this series of compounds and BRAFV600E kinase, in order to design more BRAFV600E kinase inhibitors with high activity, low toxicity, and strong theoretical basis.DNA gyrase (DNA gyrase) is a four dimeric protein with two GraA and two GraB subunits. It is a subclass of DNA topoisomerase II and its main function is to introduce negative supercoils and plays an important role in DNA replication.Some pyrazole derivatives used as potent and selective inhibitors against DNA gyrase are capable to cause bacterial cell death. Many selective inhibitors of DNA gyrase contain aryl-pyrazole template. The trifluoromethyl-substituted compounds have also been reported to possess biological activities and are often employed as fungicides, antipyretic agents and analgesic agents. We synthesis a series of pyrazole derivatives containing dinitrobenzotrifluoride moiety to extend the research to achieve new potential antibacterial DNA gyrase inhibitors. All the compounds were test the strains, the results of IC50 values reached micromolar. Among them, compound 4d showed the most potent anti-gram-positive bacterial activity with MIC values of 0.39 μg/mL against the tested gram-positive bacterial strains and exhibited the most potent B.subtilis DNA gynase and S.aureus DNA gynase inhibitory activity with IC50 of 0.125μg/mL. Docking simulation was performed to insert compound 4d into the S.aureus DNA gynase active site to determine the probable binding conformation.