Discovery of Piperidine-linked Quinazoline Derivatives as Potent HIV-1 NNRTIs and HIV-1 Latent Reservoir Activators

作     者：Samuel Desta 

作者单位：山东大学 

学位级别：硕士

导师姓名：Xinyong Liu

授予年度：2019年

学科分类：1007[医学-药学(可授医学、理学学位)] 100701[医学-药物化学] 10[医学] 

主      题：NNRTIs Quinazoline Drug resistance HIV-1 Latent reservoirs LRAs HDACIs 

摘      要：Acquired immune deficiency syndrome（AIDS）,mainly caused by human immunodeficiency virus type-1（HIV-1）,is still one of the leading causes of death *** highly active antiretroviral therapy（HAART）regimens,a combination of three or more HIV-1 antiretroviral targeting different steps of active viral replication,is used as the most efficient treatment regimen in controlling HIV-1 replication in infected ***-nucleoside reverse transcriptase inhibitors（NNRTIs）comprise an important component of HAART,owing to their potent antiviral activity,high selectivity and generally good ***,the efficacy of NNRTIs is compromised by the emergence of drug-resistant mutations,poor pharmacokinetic properties and severe toxic side effects over long-term *** impose the development of new NNRTIs with broader antiviral spectrum and better pharmacokinetic *** induce conformational change of the active site by binding to HIV-1 reverse transcriptase at a site distinct from the DNA polymerase active site of the enzyme,and inhibit retroviral reverse transcription step of HIV-1 replication in a non-competitive *** the past few years,diarylpyrimidine（DAPY）-based NNRTIs,represented by etravirine（ETR）and rilpivirine（RPV）,have attracted considerable attention because of their exceptional characteristics such as positional adaptability and conformational flexibility,which might serve to minimize the loss of binding stabilization caused by *** addition,the key hydrogen bonds and specifically targeting conserved residues of reverse transcriptase provide important avenues for further optimization and development of anti-HIV drug *** thesis has two *** Ⅰ.Design,Synthesis and Biological Evaluation of Piperidine-linked Quinazoline Derivatives as Potent HIV-1 NNRTIsBy employing molecular hybridization and scaffold hopping strategy,the two tolerant regions of non-nucleoside inhibitory binding pocket（NNIBP）were explor