| Acquired immune deficiency syndrome (AIDS), which has developed into a global pandemic disease, is mainly caused by the human immunodeficiency virus type 1 (HIV-1). HIV-1 virus is a kind of retro virus, which replicate by reverse transcristion, integration and transcriptional elongation. The transcription process of HIV-1 virus must be completed by the specific reverse transcription. Though the reverse transcriptase (RT) doesn’t exist in human cells, it is responsible for the conversion of single-stranded viral RNA into double-stranded priviral DNA, a prerequisite for integration into host DNA.So design and synthesis of virus transcription inhibitors become a research hotspot RT inhibitors can be divided into two different classes:nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). NNRTIs have been widely used for their high selectivity, relatively low toxicity and potent activity, which are also an important component of Highly Active Anti-Retroviral Therapy (HAART).However, anti-HIV therapy is challenged by inevitable emergence of drug resistant virul strains because of the rapid mutations of the residues in RT. Therefore, further development of novel NNRTIs with improved pharmacological and anti-resistance profile is crucial for a more successful application of NNRTIs in anti-HIV therapy.The Chinese medicinal herb Schisandra chinensis can be used to protect liver and antitumor. In recently research, a kind of dibenzocyclooctadiene lignan isolated firstly from Schisandra chinensis showed significant anti-HIV activity. In previous research, a lead compound which was similar to dibenzocyclooctadiene but with simpler structure, namely SJP-L-5 was synthesized by our research group. Although SJP-L-5 has stroug bioactivity toward HIV-1, the water solubility of SJP-L-5 is poor, and its metabolic speed is too fast to detect in pharmacokinetic research. Therefore, we plan to synthesize a number of new compounds based on the structure of SJP-L-5. In this thesis,40 new compounds based on biphenyl structure of SJP-L-5 were designed and synthesized, and their anti-HIV bioassays were conducted. All the compounds and derivatives showed low therapeutic index in anti-HIV bioactivity research.This dissertation is composed of four chapters.The current AIDS situation and anti-HIV medicinal research progress were described in Chapter One.Studies on the synthesis and bioactivities of the derivatives of SJP-L-5 were described in Chapter Two. We completed the following three aspects:Firstly, the esfer group of SJP-L-5 was hydrolysed and the resulted acid was condensed with amines. Secondly, modification of amine part of SJP-L-5 were carried out with acids. Thirdly, starting from 3,4-(methylenedioxy)phenylacetic acid,3,4,5-trimethoxyphenylacetic acid, 4-bromo-N,N-dimethylaniline and 4-bromoaniline analogues similar to SJP-L-5 were synthesized.Experiment procedure, physical and spectral data for all compounds, which described in Chapter Two are recorded in Chapter Three.The summary of this work was described in Chapter Four. |
