The thesis is composed of two correspondingly independent parts: the activity and the mechanism of S-DABO derivatives on HIV-1 in vitro; anti-HIV-1 activities and the mechanism of AZT-fluoroquinolones conjugates. The study on the inhibitors of HIV-1 reverse transcriptase is a hot area in anti-HIV drugs research. Because of the severious side-effect, the frequently changing of the HIV virus and the arising of drug resistance et al., we need more compounds of this kind, although there already have several reverse transcriptase inhibitors permitted by FDA. Our study tested the anti-HIV-activities and mechanisms of 23 S-DABO derivatives and 8 AZT-Fluoroquinolones conjugates. Through the primary screen, we found that all the 23 S-DABO derivatives showed low cytotoxicity on different cell lines, and 22 of them had anti-HIV-1 activities. The RZK-4 and RZK-5 showed anti-HIV-activites with the selective index (SI) of syncytium formation inhibition of >16666 and >38462 respectivly; and the selective index of protection on HIV-1 infected MT-4 cell were 2667 and 2150. The values of SIs were similar to the NVP’s. 20 of these compounds could decrease the production of HIV-1 p24 antigen, of which the 50% effective concentration (EC50) of RZK-4 and RZK-5 were 5.93 and 5.74ng/ml, the values were lower than the NVP’s（27.3ng/ml）. The activites against another 3 strains of HIV-1 were also determined. There were laboratory-derived virus (HIV-1MN), low-passage clinical isolated virus (HIV-1KM018) and drug-resistant virus of NNRTIs(HIV-1ⅢB A17). These S-DABO derivatives also showed very good anti-HIV-1 effect on these three strains. But all the 23 S-DABO derivatives had no inhibition effect on HIV-2 replication. We tried to find the anti-HIV-1 mechanism of the 23 compounds. Through fusion inhibition assay, RT and PR assay, and inhibition on HIV replication in persistant infected H9 cell assay et al., we found that: 20 compounds showed inhibition effect on the HIV-1 proteinase(PR), and 17 of them had effect on the reverse transcriptase (RT). Whereas, all the compounds could not inhibit fusion in coculture and they had no effect on the HIV replication in persistant infected H9 cell. All the results suggest that the S-DABO derivatives are classic NNRTIs. In 8 AZT-Fluoroquinolones conjugates, SRLZ and SROZ significantly inhibited HIV-1 syncytium formation. Their SI were >416667 and >105263 respectivly. They also had the ability to protect MT-4 cells from HIV-1 infection, the SI were 30162 and 6368. The values were similar to the AZT’s. Both of the two compounds could decrease the production of HIV-1 p24 antigen, and the 50% effective concentration (EC50) were 0.71 and 2.1ng/ml, which were lower than the value of the AZT(3.5 ng/ml). SRLZ and SROZ were also found to be active against HIV-1KM018 (EC50=1.4 and 22ng/ml) infection. The mechanism study showed that the SRLZ and SROZ could not inhibit the HIV-1 replication in persistant infected H9 cell. However, the SRLZ and SROZ showed inhibition effect on the St. aureus growth, the MIC（Minimum inhibitory concentration）value were 14.65 and 7.32μg/ml, which were equal to the positive control drugs. All the results show that, this chemical modification method will not change the drug target of the AZT-Fluoroquinolones conjugates, but it will also not much affect the anti-HIV activities and anti-microbial activities of AZT-Fluoroquinolones conjugates.
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