The Synthesis And Antiviral Effects Of Quinolone/tenofovir Derivatives, As Well As The Synthesis Of Nitrofuranamides And The Role Of Anti-drug Resistant TB

Infection with the Human cytomegalovirus(HCMV)and Herpes simplex virus type 1(HSV-1)can lead to severe disease,and threaten to human health.Quinolones,one of the classical first-line anti-infective drugs,were reported displaying multi "non-classical"biological activity.Among them,Voreloxin and Elvitegravir were approved by FDA as the first anti-tumor and anti-AIDs quinolones in 2009 and 2012,respectively.Recently,it was reported that the 6-aminoquinolone WC5 exhibited good activity and selectivity to HCMV In this study,a series of compounds containing aromatic heterocyclic fragments was designed and synthesized by modifying at the 1,6,7 and 8-postion of MC5.Our primary objective was to discovery new compounds with more potent anti-HCMV activity,and facilitate for further study of these quinolones.Infection of Hepatitis B virus(HBV)can cause acute and chronic hepatitis,has a close relationship with liver cirrhosis and liver cancer.Tenofovir,the first-line anti-hepatitis B drug,has the oral bioavailability and nephrotoxic issues which limited its clinical use.In recent years,tenofovir disoproxil and tenofovir alafenamide,are prodrugs of tenofovir,have been widely used in clinical.Inspired by the successful designing tactics of anti-HSC amino acid prodrugs,a series of tenofovir prodrugs containing bis-L-amino acid was designed and synthesized by introduction of L-amino acid fragments to the phosphonic acid hydroxyl groups of tenofovir.It was expected to find compounds which are worthy for further study,and provide the leads for further structural modifications.The rising incidence of tuberculosis(TB)infection especially multi-drug resistant TB(MDR-TB)as well as the association of TB and HIV/AIDS presents a global health problem.Therefore,it is imminent to find and develop new drugs which can control and treatment of TB especially MDR-TB effectively.The study of nitroimidazole compounds with a new anti-tuberculosis mechanism has aroused great interest in recent years.Delamanid was approved by EMA in 2014,and its modifications,PA-824 and TBA-354,are currently under clinical trials.Recently,nitrofuran amides were reported displaying excellent broad spectrum in vitro anti-mycobacterial activity.However,the efficacy of their in vivo activity was far weaker than expected.In this study,the most potent nitrofuran amide Lee0504 was employed as our lead compound,a series of nitrofuran amides was designed and synthesized by avoiding the structural fragments with potent poor metabolic stability.It is expected to find compounds with good activity and metabolic stability,which will lay a foundation for the further study.The research work in this paper could be divided into three parts as follows:Firstly,twenty-one novel quinolone compounds which contain aromatic heterocyclic fragment were designed,synthesized and evaluated for their in vitro antiviral activity.Only part of the targets exhibited anti-HCMV and/or HSV-1 activity.The activity of L9f on HSV-1 was only slightly weaker than the leading compound WC5.According to this,in order to screen out anti-HSV-1 more active and less toxic compounds,it is necessary to modify the C6,C7 and C8 positions of 1-[(1S,2R)-2-fluorocyclopropyl]quinolone/nalidone corresponding to L9f.The results of the study have already been published in the Chin Med Biotechnol,April 2017,Vol.12,No.2.Secondly,a series of novel tenofovir L-bis-amino acid prodrugs was designed and synthesized,and evaluated for their in vitro anti-HBV activity.The valine prodrug L5A displayed more potent activity than tenofovir,and slightly superior activity comparing to tenofovir disoproxil.Besides,L5A also shown low toxicity,and a good selectivity.Thereby,L5A is worth for further study.Thirdly,a series of nitrofuran amide derivatives were designed and synthesized.The in vitro anti-tuberculosis activity of these target compounds is under evaluation.In this dissertation,108 compounds were synthesized,57(including 49 target compounds)of which have been not reported in the literature yet.All of the new compounds were characterized by MS,1H NMR spectra,and some target compounds were further confirmed by 13C NMR,and HRMS spectra.