Design, Synthesis And Antitumor Activity Of 3,5-disubstituted Pyrazolo[1,5-a]pyridine Compound

Pyrazolo[1,5-a]pyridine derivatives have now received considerable attention,and this structure is the key structure of a variety of active compounds,and its biological activities are mainly manifested in:dopamine receptor antagonists,p38 protein kinase inhibitors,adenosine receptor antagonists,etc.However,there are few studies on the antitumor activity of pyrazolo[1,5-a]pyridine series compounds,so we will focus on pyrazolo[1,5-a]pyridine series compounds studies on antitumor activity.Sulfonamides are compounds with a wide range of biological applications,many of which have been reported to have antitumor activity,and the presence of sulfonamide structures is a key factor for the antitumor activity of these compounds.This paper utilizes the principle of active splicing to introduce a sulfonamide structure into the pyrazolo[1,5-a]pyridine ring to enhance the antitumor activity of these compounds.Using 4-aminopyridine as raw material,25 N-substituted-5-sulfonamide-substituted pyrazolo[1,5-a]pyridine-3-methanes amide compounds were designed and synthesized through substitution,cyclohydrolysis,amidation and other reactions.The structure of the target compound was confirmed by HRMS,¹H NMR and ¹³C NMR.Using 5-fluorouracil and paclitaxel as positive control drugs,the in vitro antiproliferative activities of 25 compounds against human lung cancer cells（A549）and human prostate cancer cells（PC-3）were detected by MTT assay.The experimental results show that compound A7 has excellent tumor cell inhibitory activity.Structure-activity analysis showed that the activity of the A-series aliphatic sulfonamide-substituted compounds was better than that of the B-series aromatic sulfonamide-substituted compounds.The activity of the 3-secondary amine-substituted compound was lower than that of the primary amide-substituted compound,indicating that the hydrogen atom on the N atom of the amide is crucial to the activity of the compound.When there is a disubstituted compound on the benzene ring of the aniline substituent,the inhibition rate of the compound is significantly lower than that of the monosubstituted compound.At low concentrations,the compound has almost no activity on A549 cells,and still has a certain inhibitory activity on PC-3 cells.This paper further enriched the structures of 3,5-disubstituted pyrazolo[1,5-a]pyridines,and tested the antitumor activity of the compounds,laying a foundation for further research in the future.