Synthesis And Bioactivities Of Benzothiazin-4-one-3-(Rhodanine Unsaturated Ketone) Amine Derivatives

Cancer and inflammation are common diseases which have threatened human life. Due to the poor selectivity, great toxicity and prone to resistance of existing drugs, millions of people worldwide die from cancer and many other people suffer from inflammation each year.Therefore,the study of high-efficient and low-toxic anti-cancer,anti-inflammatory drugs is very important.On the one hand, chalcone is a kind of unsaturated ketone structure of natural active ingredients, with anti-bacterial, anti-viral, anti-cancer, anti-inflammatory, anti-parasitic and other broad biological activity. Structure modification on its molecular struture has received much concern. On the other hand, oxicam drugs, which are a kind of non-steroidal anti-inflammatory drugs have the structure of benzothiazine amide, act on the COX enzyme and play the anti-inflammatory effect by inhibiting the synthesis of arachidonic acid. Besides, owing to thiazolidinone five-heterocyclic structure, rhodanine has been as the dominant pharmacophore and widely been used to build new drug chemical skeleton. Threrfore, based on the design of the drug molecule pharmacophore split principle, this article attempts to put advantage pharmacophore of benzothiazine amides and rhodanine unsaturated ketone together, and then build a benzothizine(rhothanine unsaturated ketone)amide target compound, in order to achieve superposion of pharmacophore activity, finally finding the anti-cancer or anti-inflammatory lead compounds to provide guidance for further study.Methods: Piroxicam front ester as raw materials, obtain benzothiazine-4-one-3-hydrazide1,1-dioxide by hydrazine solution, and obtain the corresponding dithiocarbamate salt by carbondisulfide condensation, then obtain the key intermediate benzothiazine-4-one-3-(rhodinine)carboxamide 1,1-dioxide by condensation with sodium chloroacetate cyclization. Rhodanine reacts with an aromatic aldehyde by claisen-schmidt condensation reaction, thereby synthesizing a series of benzothiazine-4-one-3-(rhodinine-unsaturated ketone) carboxamide 1,1-dioxide. The structures of these compounds have been characterized by MS H-NMR and IR. The in vitro anticancer activity against human hepotoma SMMC-7721 and MCF-7 cells of human breast cancer have been evaluated by MTT assay. The ELISA kit method was used to evaluate target compounds to inhibit the activity of cyclooxygenase-2.Results: Preliminary pharmacological results showed that the target compounds have good inhibition on SMMC-7721 cell lines and MCF-7 cell llines. Besides, the proliferation rate of MCF-7 cell lines was higher than SMMC-7721 cell lines. Under 10umol/L concentration, the inhibition rate compound P13 on human hepatoma SMMC-7721 cells was 37.50% and the inhibition rate of compound P5 on human breast cancer cells was 58.4%, which was equivalent to or better than the control piroxicam activity. At the same time, the target compounds have good inhibitory activity on COX-2, wherein the inhibition rate of compound P5 was 2 times as much as referance substitute.Conclutions: In this paper, eighteen novel compounds with the structure of benzothiazine-4-one-3-(rhodanine unsaturated ketone) were synthesized and their structures were confirmed.Preliminary pharmacological results showed that target compounds express inhibition on SMMC-7721 and MCF-7 cell lines and the inhibition rate is equivalent to piroxicam. Based on the advantage structures of benzothiazine and rhodanine-unsaturated ketone,benzothiazine-4-one-3-(rhodinine-unsaturated ketone) carboxamide 1,1-dioxide was synthesized and deserved to be further studied.