Synthesis And Activity Study Of Nitazoxanide Derivatives

Nitazoxanide(NTZ)is a nitrothiazole benzamide compound.It is a safe,efficient,and broad-spectrum antiparasitic drug with various biological activities,such as antiviral,antibacterial,anti-inflammatory,Antioxidant,etc.The study found that NTZ not only has a good antibacterial effect on anaerobic bacteria,but also has a certain inhibitory effect on common bacteria such as E.coli and Staphylococcus aureus.The new compounds obtained by structural modification of NTZ may also have better antibacterial effect.To further explore the structural advantages of NTZ and explore the biological value of its derivatives,it is possible to obtain compounds with better biological activity,so it has great pharmaceutical development value.In this paper,a series of NTZ derivatives were synthesized using acid chloride and amine as raw materials,tetrahydrofuran or dichloromethane as reaction solvent,triethylamine as acid binding agent,and 4-dimethylaminopyridine(DMAP)as catalyst.The structure identification and analysis of these derivative molecules were performed by ~1HNMR,MS and IR.The results showed that 22 new derivatives were successfully synthesized,which laid the foundation for the next activity screening study.The minimum inhibition concentration(MIC)and minimum bactericidal concentration(MBC)of 22 kinds of NTZ derivatives,prototype drugs NTZ and tizoxanide and commonly used antibacterial drugs against standard quality control strains E.coli ATCC25922 and Staphylococcus aureus ATCC25923 and various clinical isolates was determined by using micro broth dilution method.The results showed that the prototype drugs NTZ,tizoxanide,and most of the synthesized derivatives showed no antibacterial effect on these strains.However,the derivative 2showed a good inhibitory effect on most strains,especially the MIC value of Bacillus cereus CVCC2002 and Streptococcus equi infection CVCC556 reached 1?g/m L.In addition,derivative 2 also showed good antibacterial effects on clinically isolated strains that were resistant to meropenem,polymyxin B and other clinically commonly used antibacterial drugs.By monitoring the antibacterial growth curve of derivative 2on clinically isolated strains of Bacillus cereus and Staphylococcus aureus.The results further confirmed the antibacterial effect of derivative 2.Further prediction of absorption,distribution,metabolism,excretion and toxicity of newly synthesized compounds through admet SARV 2.0 software The results show that the relevant parameters of most of the derivative compounds are not ideal,and the number of hydrogen bond donors of derivative 2 is only 0,and the number of hydrogen bond acceptors is 6,indicating that the distribution of electron clouds in their structural molecules has been rearranged,so it may have Special chemical and biological properties.In this paper,the pseudorabies virus infection of Vero cells was used as a model to study the inhibitory effect of NTZ on DNA viruses.The results showed that 12.5?M nitazoxanide can significantly inhibit the growth and reproduction of pseudorabies virus on Vero cells,indicating that it has the potential to be developed as a DNA virus inhibitor.In conclusion,this paper carried out structural modification and modification of NTZ,and obtained a series of derivatives of NTZ,which proved the antibacterial activity of derivative 2 and the in vitro viral inhibitory activity of NTZ,indicating its potential for further development.