Design Synthesis And Biological Evaluation Of Novel Phthalazione Dengue Virus Small Molecule Inhibitors

Dengue virus(DV),also referred to as dengue virus,belongs to the genus Flaviviridae.This virus contains four serotypes,DENV1,DENV2,DENV3 and DENV4.DV is mainly produced by Aedes aegypti and Aedes albopictus bites,the infection with dengue virus can produce a series of different diseases.At present,there is no listed drugs aganist dengue virus in the world.Research and development of anti-dengue virus drugs have become very urgent.In addition,since dengue virus and West Nile virus,Japanese encephalitis virus and yellow fever virus belong to the genus of Flaviviridae,research and development of anti-Dengue virus drugs also contribute to the further study of other anti-Flaviviridae viruses.Phenotype-based high-throughput screening,due to the complexity of the virus infection process,is a powerful tool to find anti-virus compound.This paper is based on the phenotypic screening to get new anti dengue virus active compounds,improve the activity and reduce the toxicity of compounds as the criterion,design and synthesis phthalazine ketones anti dengue virus compounds,carry out the study of the structure-activity relationship,find lead compound,and explore the possible mechanism of compound.The specific research results are as follows:Through high-throughput screening of pyridazinone compounds in our group,we obtained a class of DV small molecule inhibitors with phthalazinone nucleus 1805(CC50=8.51μM,IC50 = 0.64μM,SI = 13.30).It has novel chemical structure,and is different from the DV inhibitors which have been reported so far.We systematically modify the active compound 1805,synthesized a total of 76 new compounds,and obtained several compounds more than 1805 in activity and selectivity.Result of Structure-activity relationship:the counterpoint to replace is superior to the interposition replace on 2-benzyl ketone carbamate of phthalein oxazine,In addition,N,N-dimethyl carbamate side chains is essential to keep activity,Hetero cyclic substituent on 8 is not conducive to activity,Benzene ring substituent is conducive to activity,In addition,the benzene ring replaced on interposition is good to improve the activity.Through the preliminary investigation of the structure-activity relationship,using the virus phenotype screening,we changed the side chain of the carbamate to the para position,and changed the para-fluorophenyl group on the 4-position of the phthalazinone to m-trifluorobenzene.And gave a more active and less toxic 1-27(IC50 =0.14μM,CC50=5.06μM).Subsequently,a fractional metabolism test was carried out to obtain a bioavailability of 34.9%.To sum up,I-27 has the advantages of novel chemical structure,excellent active toxicity,stable metabolic property,convenient synthesis route,and potential as a potential drug candidate for DV small molecule inhibitor.