Structure-based Design,Synthesis And Antiviral Activity Of Novel Arylthioacetanilide As HIV-1 NNRTIs

Acquired lmmunodeficiency Syndrome（AIDS）,which is caused by the infection of human immunodeficiency virus type 1（HIV-1）,is an infectious disease that seriously threatens human life and health.Due to the high variability of HIV-1 itself,the clinical implementation of "Highly Active Antiretroviral Therapy"（HAART）,in which three or more drugs acting on different targets of the HIV-1 life cycle are used in combination to carry out anti-AIDS treatment.As a functional protein,reverse transcriptase（RT）is responsible for reverse transcription of viral genomic RNA into viral double-stranded DNA,so RT is one of the preferred targets for anti-AIDS drug research.According to the different chemical structure and mechanism of action,RT inhibitors can be divided into nucleos（t）ide reverse transcriptase inhibitors（N（t）RTIs）and non-nucleoside reverse transcriptase inhibitors（NNRTIs）.Among them,HIV-1 NNRTIs act on the allosteric pocket（NNRTI Binding Pocket,NNIBP）,which is 10 A away from the catalytic activity center of RT.NNRTIs,which are important components of HAART,precede in high efficiency,low toxicity,strong selectivity,and diverse structures,but the clinical side effects and drug-resistant virus strains significantly reduce the potency of proved drugs.Arylazolylthioacetanilide platform,which are discovered by High-throughput Screening（HTS）,have been of great interest for the development of novel NNRTIs,owing to their high activities against HIV-1 WT.However,the low inhibition against HIV-1 mutant strains limits their clinical application.In the second chapter,based on the classic "three-point pharmacophore" model of arylthioacetanilide derivatives,the new compounds were designed,synthesized and evaluated for their biological activity by virtue of bioisosterism approach and scaffold hopping strategy（series A,B and series C,D）.Most of the tested compounds（series A and B）inhibited HIV-1（ⅢB）replication at micromolar concentrations.In particular,the most potent compound A-8 had an EC50 value of 0.78 μM and a SI value of 28,which was similar to that of reference drug NVP（EC50=0.258μM,SI>58）.Meanwhile,compound A-8 exhibited moderate inhibition of RT（wide type）with an IC50 value of 6.42 μM,which was slightly lower than the reference drug NVP（IC50=8.78 μM）.Besides,compound B-6 showed moderate activity against L100I mutant（EC50=5.64 μM）and double mutant strain RES056（EC50=22.24 μM）.On the contrary,all of the tested series C and D compounds showed no inhibitory effect to HIV-1.In the third chapter,based on the "three-point pharmacophore" model of NNRTIs,a fourth pharmacophore element was employed to construct a "four-point pharmacophore" model of arylthioacetanilide with the characteristics of "multi-site binding".Under the guidance of this new model,a series of novel pyridinylthiolacetanilides were designed,synthesized and evaluated for their biological activity as potent HIV-1 NNRTIs through molecular hybridization strategy（series E,F,G）.Among the tested compounds（series E,F and G）,F-4（EC50=0.31μM,SI=27）and E-4（EC50=0.33 μM,SI=25.6）exhibited best inhibition of HIV-1（IIIB）,which were 9 times higher than the reference drug NVP（EC50=2.78μM,SI>4.27）.Besides,compounds G-2 and F-1 showed moderate activity against HIV-1（IIIB）.Therefore,the modification of C-5 position of pyridine ring,which based on the "four point pharmacophore model",is a valuable attempt for further optimization.Overall,taking arylthioacetanilides NNRTIs as the lead compounds,three series of novel NNRTIs were designed and synthesized by different drug design strategies.The newly synthesized target compounds were screened for anti-HIV activity,and we found several high potent anti-HIV agents,which deserves further investigation.Additionally,the structure-activity relationship（SAR）and molecular modeling study of each series in the thesis were investigated and discussed in detail for further research.