Design, Synthesis, Biological Activity And In Vitro Metabolism Evaluation Of Novel NNRTIs Diaryl Anilines And HIV Mature Inhibitor Bevirimat Dual Target Compounds

Human immunodeficiency virus(HIV)-caused HIV infectionand acquired immunodeficiency syndrome(AIDS)were first identified over 30 years ago.Global AIDS statistics from 2016 estimated that 36.7 million people were living with HIV in 2015.Among them,two million were newly infected with HIV and 1.1 million died from AIDS-related illnesses.Although over 30 drugs targeted at different steps of the viral life have been approved or are in experimental stages for treatment of HIV,acure for HIV infection has not yet been found.HIV therapy suffers from the rapid emergence of drug-resistant viral strainsand detrimental side effects caused by long term drug treatment.Therefore,the discovery of new innovative anti-HIV agents is a research priority.In our prior studies of novel HIV-1 NNRTI agents,we discovered two series of extremely potent anti-HIV NNRTI agents,diarylanilines(DAANs)and diarylpyridiamines(DAPAs).The new chemotypes caffolds have topologic shape and molecular flexibility similar to those of new-generation NNRTI drugs Etravirine(TMC125)and Riplivirne(TMC278).The initialleads(DAANs)exhibited high anti-HIV potency against wild-type and multiple drug-resistant strains HIV-1 replication.Bevirimat(3-O-(3`,3`-dimethylsuccinyl)-betulinic acid,BVM)is the first-in--maturation inhibitor.BVM interferes with the processing of P25(CA-SP1)to CA,leading to the accumulation of P25 and producing immature HIV-1 particles.In 2009,BVM succeeded in phase IIa clinical trials,thus proving it`s clinical efficacy and safety.Based on the study of DAANs and BVM,our group modified the diarylsubstituted anilines and linked to BVM.The aim is to synthesize double ligands which are easy to metabolize.Two target compounds have an effect on different targets to anti-HIV virus.In this paper,the coupling method and the linkage chain were explored,and different types of linker were attached to the 2-or 4-position of DAAN.We synthesized a series of novel DAAN derivatives,a total of 20 new compounds,of which 16 active compounds,the novel DAAN derivatives were tested for anti-HIV activity,metabolic stability and pharmacological evaluation.We can know the structure-activity relationship as follow:1)If R2 increase thelength or the polarity of the linking group,the activity of anti-HIV will be reduced.R2 substituted by a short chain can maintain or improve the anti-HIV activity.In the metabolic stability,the ester side chain is more metabolizable than the amide bond side chain.2)Compared with substituted in the B-ring 4-position of the diarylanilide compounds,the B-ring 2-position amide-substituted compounds are easy to metabo-lizable in the metabolic stability test of human liver microsomes,in vitro.3)After linking the aliphatic chainat the 2-position of the B-ring of DAANs,it was found that the shorter the R1 was,the better the anti-HIV activity was.There was consistent with the previous study,which is the site of 2-position play a key role in anti-HIV activity.3 double-ligand compounds were synthesized.While double-ligand compounds with a low activity to anti HIV were metabolized quite quickly in HLM assay,with t1/2 values of 37.1min,47.1min and 42.8 min,respectively.The double-ligand drug combained DAAN and BVM is ease to metabolize in HLM assay.The results of this study are expected to provide a new double-target compound to anti-HIV.