Nitrogen-containing Heterocycles-Design, Synthesis, And Biological Activity Of Novel Pyrazole Derivatives

The pyrazole unit is one of the core structure in a number of natural products. Many pyrazole derivatives are known to exhibit a wide range of biological properties such as anti-hyperglycemic, analgesic, anti-inflammatory, anti-pyretic, anti-bacterial, antifungal hypoglycemic, sedative-hypnotic activity, antitumor and anticoagulant activity. Due to the importance of pyrazole in organic synthesis and drug synthesis, much attention has been paid to the application in many fields.Using the nucleophilic opening reaction of epoxides by pyrazoles, we intend to explore new conditions for the ring opening reaction, synthesize novel compounds with potent bioactivity and study the bioactivity of the obtained products.Four aspects were included in this paper:1. Using 3-aryl-1H-pyrazole-5-carboxylate and 2-aryloxymethyl-epoxide as starting materials, 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate derivatives were synthesized region-selectively by the base catalyzed ring opening reaction in 62～93% yields. The structure of 3-(4-chlorophenyl)-1-(2-hydroxy-3-(2-nitro-phenoxy)propyl)-1H-pyrazole-5-carboxylate was characterized by ¹³C NMR, ¹H NMR, IR and HRMS spectral data. The structures of other compounds were confirmed by ¹H NMR, IR and HRMS.2. We studied the bioactivity of 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate derivatives, and the biological evaluation results showed that fifteen compounds could suppress A549 lung cancer cell growth. Among of them, compound 3i was the most effective small molecule in inhibiting A549 cell growth; Compound 3f might most effectively induce A549 cell differentiation; Compound 3g remarkably induced cellular vacuolation.3. Based on the obtained 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate derivatives, 6-(aroxymethyl)-2-aryl-6, 7-dihydropyrazolo[5, 1-c] [1, 4]-oxazin-4-one derivatives were synthesized more efficiently in two steps. The hydrolysis reaction of 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate derivatives with alcoholic KOH afforded 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylic add derivatives in 84-99% yields. Then the ring-closure reaction of the isolated carboxylic add in the presence of p-TsOH yielded the desired 6-(aroxymethyl)-2-aryl-6, 7-dihydropyrazolo[5, 1-c][1, 4]oxazin-4-one derivatives in 54-98% yields. The structures of 15 compounds were characterized by ¹H NMR, IR and MS spectral data.4. The reaction of 3-aryl-1H-pyrazole-5-carboxylate with 2-aryloxy- methylepoxide under solvent free conditions and microwave irradiation afforded 15 6-(aroxymethyl)-2-aryl-6, 7-dihydropyrazolo[5, 1-c][1, 4]-oxazin-4-one derivatives. The reaction was carried rapidly and regioselectively in 53-78% yields. The structures of the products were confirmed by IR, MS and ¹H NMR.In conclusion, we synthesized a series of useful intermediates and many important products with bioactivity by the nudeophilic ring-opening reaction of epoxides and substituted pyrazoles,. Furthermore, we proposed a novel and effident method that is friendly to environment for the synthesis of 6-(aroxymethyl)-2-aryl-6, 7-dihydro-pyrazolo[5, 1-c][1, 4]oxazin-4-one derivatives. Moreover, we synthesized a series of novel 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate derivatives that paves the way for studying the structure-activity relationship of this class of drugs and builds up basis for research and development of novel agents with inhibitory activity against cancer cell growth.