Study On Synthesis Of Febrifugine Analogues

Febrifugine and isofebrifugine,which are quinazolinone alkaloids with high antimalarial activities,were isolated from a Chinese medicinal plant,Chang Shan(Dichroa febrifuga).Febrifugine and its derivatives possess extensive biological activities,such as halofuginone has been widely used to prevent and treat chicken coccidiosis with advantages of high efficiency,broad spectrum,low cross resistance and low toxicity.It was found that halofuginone showed good antitumor activities in inhibiting the process of angiogenesis and neovascularization,inhibiting proliferation of uncontrolled cells and inducing apoptosis of them with obvious inhibitory effects for cancer models in liver,brain,bladder,breast and prostate as the deepening of the research on it.These structures with high pharmacological activity can provide a reference for the design and development of new drugs,such as changroline is used in the treatment of arrhythmia,which is the transformation of febrifugine.Because the structure differences between febrifugine and halofuginone is only different at6-,7-sites on quinazolone moiety,the coupling reaction of 4(3H)-quinazolone derivatives with different substituents at 6-,7-sites was conducted with the key intermediate of piperidine ring of febrifugine in this paper.Therefore a series of febrifugine analogues were obtained and their antibacterial activities were tested.During the synthesis of piperidine ring key intermediates of febrifugine,the introduction of α-Allyl moiety on the piperidine ring is the key step of the all synthesis process,which is one of the reasons why industrialization of halofuginone has not been achieved so far.On the basis of the synthesis routes of piperidine ring intermediates reported in the literature,the synthesis method of Takeuchi group was selected,improved and optimized in this paper.α-Allyl was successfully introduced to piperidine ring,and then the key intermediate with piperidine ring,2-h was obtained under mild conditions.The intermediates were characterized and confirmed by ~1H NMR and ESI-MS.The improved work includes:1.During the synthesis of 2-c,KI was added as a catalyst for Williamson etherification,which reduced the reaction time from 16 h to 12 h.2.In the synthesis of 2-d,one pot method was adopted for the exchange protection and Claisen rearrangement,which simplified the post-processing of the reaction and avoided the use of the toxic Lewis acid,boron trifluoride diethyl etherate.The above improvements and optimization provide references for large-scale production of piperidine ring moieties,the key intermediate of febrifugine analogue.After the early multistep synthesis,the produced key intermediates with piperidine ring,2-f and 2-h,were coupled with different 6,7-disubstituted quinazolin 1a~e respectively,and5 febrifugine analogues were obtained.The protective groups were removed to get 4febrifugine analogues.The 8 compounds in the above 9 compounds are the new febrifugine analogues synthesized in this paper.The suitable catalyst for deprotection reaction of different analogues was investigated during the study,and the yields was between 30%~55%.In addition,the antibacterial activities of the above 8 novel febrifugine analogues and other 10 other Analogues synthesized by the research group,to Escherichia coli,Staphylococcus aureus and Bacillus subtilis were preliminarily investigated.And their control experiments were carried out with vancomycin,penicillin and ciprofloxacin.The results showed that the antibacterial effects of this series of Analogues was not as good as expected.Based on the related antibacterial mechanism,the next step is to transform some nitrogenous groups in the Analogues into positively charged quaternary ammonium groups.