Synthesis And Biological Evaluation Of Pyrazole And Condensed Pyrazole Derivatives

As an important N-containing five-membered heterocyclic compounds, pyrazole derivatives have been widely applied in bio-pharmaceutical and pesticides. As in bio-pharmaceutical and clinical applications, pyrazoles have been used for the treatment of ulcerative colitis, arteriosclerosis, senile dementia, anticancer, anti-parasitic, anti-hypertension, anti-tuberculosis and anti-diabetes etc. As in pesticides fields, pyrazoles have been utilized as antibacterial, herbicide and insecticide. Based on the excellent bioactivities of pyrazole-containing compounds, the introduction of other bioactive units to obtain more small molecular pyrazoles with better biological activities has attracted considerable attention of people.The design and synthesis of pyrazoles have always been the research emphasis of our lab, and several series of pyrazole derivatives have been synthesized and demonstrated as anti-proliferation agents of lung cancer A549cells. The inhibitory mechanisms mainly include inducing cell apoptosis, autophagy or necrocytosis. Here we designed and synthesized three series of pyrazole derivatives and the structures of the compounds have been characterized by IR, NMR, HRMS and X-ray single crystal diffraction, and preliminary evaluation of their anti-proliferation activity against lung cancer A549cells have been carried out.This paper involves the following three parts:1. Synthesis and biological evaluation of1-aryl-N-hydroxy-3-aryl-1H-pyrazole-5-carboxamide derivativesHydroxamic acid functional group is known as good Zn2+chelating agent, and is a key pharmacophore of matrix metalloproteases inhibitors. Based on the synthesis experience of pyrazole derivatives of our lab, we here designed and synthesized a novel series of pyrazolyl hydroxamic acid derivatives as inhibitors against human lung cancer cell line A549. All the compounds have been characterized by IR,1H NMR,13C NMR and HRMS, and the molecular structure has been confirmed by X-ray single crystal diffraction. According to the preliminary biological evaluation, most compounds exhibit anti-proliferation activity by inducing cell autophagy and some also through inducing necrocytosis.2. Synthesis of ethyl1-(2-hydroxy-2-arylethyl)-3-aryl-1H-pyrazole-5-carboxylate derivativesHydroxy-containing pyrazole derivatives have been demonstrated as another kind of effective bioactive compounds, and have been developed as anti-HIV, anti-cancer and antalgic agents. With the employment of NaBH4, the reduction of carbonyl group was realized with the retaining of ester and a novel series of hydroxyl-containing pyrazole derivatives were obtained. All the compounds have been characterized by IR,1H NMR and HRMS, and the molecular structure has been confirmed by X-ray single crystal diffraction.3. Synthesis of2,6-diaryl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-4-one derivativesCondensed pyrazole derivatives also exhibit notable biological activities, and compounds containing oxazine ring, such as benzoxazines and imidazo-oxazines have been demonstrated with excellent biological activities. With the catalyzation of TsOH or NaH, we synthesized a novel series of pyrazolo[5,1-c][1,4]oxazin-4-one derivatives and all the compounds have been characterized by IR,1H NMR and HRMS, and the molecular structure has been confirmed by X-ray single crystal diffraction.In conclusion, we synthesized three series of pyrazole derivatives, and the pyrazolyl hydroxamic acid derivatives have been demonstrated as effective inhibitors against lung cancer cell line A549with the inhibitory mechanism of inducing cell autophagy or necrocytosis. The synthesized compounds not only expand the molecular diversity of candidates for anticancer agent, but also laid foundations for the further discussion of structure-activity relationship.