Synthesis And Antiviral Activity Of Quinoline Compounds And Research On Synthesis And Anti-G~-bacteria Activity Of LpxC Inhibitors

Over the course of human civilization and globalization,viral infections have caused millions of human casualties worldwide,and the prevention and treatment of viral diseases are a global public health challenge.Respiratory syncytial virus(RSV)is a leading viral cause of hospitalization due to acute lower respiratory infection especially in infants and young children.It is also a critical cause of morbidity and mortality in the elderly people and those adults with cardiopulmonary diseases or immunocompromised.Influenza viruses could also cause acute respiratory infectious diseases and remains serious public health problems worldwide.It possesses high pathogenicity and is the main cause of seasonal epidemics and occasional pandemics of respiratory diseases worldwide.However,there is no effective drug for the treatment of respiratory syncytial virus in the world,and the drugs for the treatment of influenza infections in the clinic are also very limited.Safe and effective therapy for RSV or IAV infection is still a high unmet medical need.Therefore,we are constantly required to develop new antiviral agents with new scaffolds and novel mechanism of action.Compound 6344B-E6 was identified as potent RSV inhibitors from an rRSV-mGFP high-throughput screening assay.It exhibited considerable anti-RSV activity(IC50:55.75?M)and low toxicity(CC50:539.5 ?M).Inspired by the results,it was decided to design and synthesize a series of 6344B-E6 derivatives to optimize its potency of these compounds.Base on their anti-RSV and IAV activity,the simple structure-activity(SAR)was explored and the primary mechanisms of action study against IAV were also investigated.Besides,we also synthesized a series of 2,4-disubstitued quinazoline derivatives using the bio-isosterism and scaffold hopping strategies,and evaluated their anti-IAV activity and primary mechanisms of action,aiming at finding new quinazoline derivatives with potent anti-IAV activity and facilitate the further development of these compounds.The emerge of Gram-negative bacteria resistance has become one of the major threats to public health,which has led to an increased morbidity and mortality.The UDP-3-O-(R-hydroxyacyl)-N-acetylglucosamine deacetylase(LpxC)is an essential enzyme in the biosynthesis of lipid A in Gram-negative bacteria,which displays no sequence homology with any mammalian protein,but is highly conserved in Gram-negative bacteria.Either enhance levels or lack of LpxC expression is lethal for Gram-negative bacteria.Therefore,it may become a promising target in the research of anti-Gram-negative agents.Based on the mode of action of CHIR-090 or ACHN-975 with LpxC protein,we decided to design and synthesize a series of novel LpxC inhibitors by rational design.Our primary object was to screen promising candidates and explore the structure-activity relationshipsThe research of this dissertation is composed by the following three chapters:Firstly,a series of novel quinoline derivatives containing O-acetamide moiety at C-8 position were designed and synthesized.Based on the anti-RSV and anti-IAV activities in vitro,their SAR were explored.Compounds ?-6b,?-6g,-6h,?-13f and ?-13h(IC50:3.10-6.93 ?M)had good in vitro activity against RSV,which were better than the lead ?-6a and ribavirin.In addition,we found that compound I-6g displayed the lower cytotoxicity(CC50:2490.33 ?M)and the highest selective index(SI=673.06),suggesting its promising potential as a candidate for further development.On the other hand,compounds ?-6a,?-6m,?-6v,?-13d-?-13f and ?-13h-?-13i(IC50s:1.87-14.28 ?M)were more active against IAV than or comparable to ribavirin.Particularly,the most active compound ?-13e(IC50:1.87±0.58?M)was found to be 8.2-fold more potent than the reference drug,which could inhibit the virus transcription and replication cycle at an early stage.Secondly,a series of 2,4-disubstitued quinazoline derivatives were designed,synthesized and evaluated for their anti-influenza A virus activity in vitro.The NH-acetamide derivatives(?-23)are more active than the O/S-acetamides.Many of them exhibit potent and low cytotoxicity(CC50:>100 ?M)in vitro.Particularly,compounds ?-10a5 and ?-17a show a better activity(IC50:3.70-4.19 ?M)and higher selective index(SI:>27.03,>23.87,respectively)against influenza A/WSN/33 virus(H1N1).Nine compounds(?-10b2,?-23a,?-23e,?-23i,?-23j,?-23n,?-23o,?-23p and ?-23r)showed much stronger anti-influenza A activities with IC50s at the low-micromole level(1.29-9.04 ?M).Particularly,?-23e and ?-23r exhibited excellent anti-IAV activity(EC50:1.29 ?M and 3.43 ?M,respectively)and displayed acceptable cytotoxicity.In addition,they also displayed good drug like properties,which also may inhibit the virus transcription and replication cycle at an early stage,suggesting their promising potential as candidates for further development.Thirdly,a series of novel LpxC inhibitors were designed and synthesized,and some synthetic routes were developed.Although the target compounds did not show antibacterial activity against Gram-negative bacteria,all the work lays a foundation for the related studies in the future.In this dissertation,175 compounds(including 111 target compounds)were synthesized,which have not been reported in literature yet.Their structures were characterized by 1H NMR,MS,HRMS and 13C NMR spectra.Parts of the work were published on Bioorg Med Chem Lett.