Synthesis, Bioactivity Evaluation And SAR Of Novel Pyrazole Derivatives As Potential Antitumor Agents

The pyrazole unit is one of the core structure in a number of natural products and biologically active compounds.As an active member of heterocyclic compounds, pyrazole derivatives showing broad spectrum activity have attracted many attentions. Many pyrazole derivatives have been found to exhibit a wide range of pharmaceutical properties such as anti-hyperglycemic,analgesic,anti-inflammatory,anti-pyretic, anti-bacterial,antifungal hypoglycemic,sedative-hypnotic activity,antitumor and anticoagulant activity.Recently,many attentions from scientists have been paid to synthesize pyrazole compounds modified different groups to find out new and effective antitumor drugs.We thus intend to synthesize a series of novel pyrazole derivatives,investigate the biological activities in A549 lung cancer cell growth and study the structure-activity relationship of novel classes of compounds to find out the novel potent agents with inhibitory activity against cancer cell growth.Four aspects were included in this paper:1.We synthesized a series of novel 1-arylmethyl-3-aryl-1H -pyrazole-5-carbohydrazide derivatives 4(4a-4i)in 72-93%yields from ethyl 1-arylmethyl-3 -aryl-1H- pyrazole-5-carb-oxylate derivatives 3(3a-3i)and hydrazine hydrate.The structures of compounds 4 were characterized by ~1HNMR,IR and MS spectral data. Furthermore,the structures of compounds 3a,3c,3d,3e,4b,and 4f were confirmed by the X-ray diffraction.2.We studied the bioactivity of 1-arylmethyl-3-aryl-1H-pyrazole-5-carbohydrazide derivatives 4(4a-4i)and the structure-activity relationship(SAR).The biological evaluation results showed that compounds 4b-4f and 4h could inhibit the cell growth obviously in the concentrations of 20-80μM after 48 h of the treatment.Among of them,compound 4b,4e,and 4h were more effective to inhibit A549 cell growth.SAR exhibited that the cytotoxic potency was highly dependent,as expected,on the substitution types and patterns on the aryl ring.The compounds with tert-butyl group 4b, 4e,and 4h were more effective.3.We further synthesized a series of novel 1-arylmethyl-3-aryl-1H-pyrazole-5-carbohydrazide hydrazoneⅡ(1-20)in 82-98%yields from 1-arylmethyl-3-aryl-1H-pyrazole-5-carbohydrazide derivatives 4(4a-4i)and aldehydes.The structures of compoundsⅡ were characterized by ~1HNMR,IR and MS spectral data.Furthermore,the structure of compound 16 was confirmed by the X-ray diffraction.4.We studied the bioactivity of 1-arylmethyl-3-aryl-1H-pyrazole-5-carbohydrazide hydrazoneⅡ(1-20)and the structure-activity relationship(SAR).The biological evaluation results showed that compoundsⅡhad inhibitory effects on the growth of A549 cells in dosage-and time-dependent manners except compounds 1,5,7,9 and 11. SAR exhibited that the antitumor activity of these compounds appears to be closely related to the nature of the Ar group.Compounds 4,8,12 and 15-20 with b group were proved to be the most active member with a unique antitumor potency against A549 cell lines.These results revealed the crucial role of the o-hydroxybenzene moiety in the hydrazone cytotoxic activities.In conclusion,we synthesized 1-arylmethyl-3-aryl-1H-pyrazole-5-carbohydrazide derivatives and 1-arylmethyl-3-aryl-1H-pyrazole-5-carbohydrazide hydrazone and then investigated the biological activity in A549 lung cancer cell growth,studied the structure-activity relationship of novel classes of compounds and the relationship of prediction of lipophilicities of the compounds and activity.Our study paves the way for studying the mechanism of apoptosis inducers and builds up basis for finding out potential new anticancer agents.