Synthesis And Anti-proliferative Activity Of Fluoroquinolone-pyrazolone Chalcone-like Derivatives

Malignant tumor is a major disease threatening human life and health and chemical treatment is still the main means in the clinic.However,conventional therapeutic drugs are poor selectivity leading to cell toxicity,poor tolerance of the patient or tumor cells resistance resulting in low therapeutic index.Therefore,synthetisizing novel anti-tumor drugs is the urgent problems in the anti-tumor drug research by finding the new structure of the anti-tumor lead compounds,promoting its druggability.Drug innovation is a multidisciplinary intelligence creation project,and based on the structure or mechanism of rational drug design principles,making full use of the advantage pharmacophore of the existing drugs to build a new drug chemical molecules is the most economical and effective strategy.Fluoroquinolone,as a wholly synthetic drug,works as topoisomerase inhibitor and its advantage pharmacophore skeleton—quinoline is also important structural units of a lot of drugs and natural active ingredients.Because of the similar molecular structure and function with DNA-TOPO in animal cells,fluoroquinolone can be used as antitumor drugs by a series of structural modification.At present,based on the antimicrobial fluoroquinolone"quinolin-4-one-3-carboxylic acid"skeleton,the modification is mainly focused on the substitution of C-3 carboxyl bioisosteres,it is still a new challenge in the field to discover new structural modifications,further improve antitumor activity,improve its pharmacokinetic properties and bioavailability.Chalcone is a kind of compound composed ofα,β-unsaturated ketone skeleton,which exists widely in natural products and has many kinds of pharmacological activities,and has attracted much attention in drug molecule design.Therefore,how to convert the structure of"quinolin-4-one-3-carboxylic acid"of fluoroquinolone into"quinolin-4-one-3-unsaturated ketone"of chalcone is worthy of attention.At the same time,pyrazolone ring also has a variety of pharmacological activity,butα,β-unsaturated ketone skeleton constructed by quinoline and pyrazolone ring has not been reported.Thus,the"quinolin-4-one-3-carboxylic acid"of fluoroquinolones is converted to the"quinolin-4-one-3-carbaldehyde"structure and then condensed withα-active methylene of pyrazolone to get C=C double bond,to realize the combination of"fluoroquinolone—α,β-unsaturated ketone—pyrazolone",eventually to find promising anti-tumor fluoroquinolone compounds.Fluoroquinolones C-3 aldehydes were prepared by methylation,hydrazinolysis and oxidation of fluoroquinolones as raw material.And then condensed with pyrazolone to obtain21 fluoroquinolone C-3 pyrazolone chalcone-like derivatives,The structures of 21 title compounds were characterized by ¹H NMR,LC-MS and IR.The antitumor activity of the target compounds against SMMC-7721 cell and Capan-1cell in vitro was screened by a MTT experiment.The results show that the target compounds have potential growth inhibitory activity on the cell line the above.Among them,compounds R1,Q2 exhibited the most potent activity,with IC₅₀ values of 5.8⁷.2μmol.L^-1 against the cell line the above.This shows that the use of active splicing principle and bio-electronic isotope principle,with pyrazolone instead of fluoroquinolone C-3 carboxyl is conducive to improving the anti-tumor activity.