Design, Synthesis And Activity Evaluation Of New Anti-HIV-1 Agents

Acquired immune deficiency syndrome (AIDS) is a disease resulting from infection with human immunodeficiency virus (HIV). Since the first case of AIDS was reported in 1981 in the United States, AIDS has become a world concerned epidemic disease, more than 33.2 million people have been infected worldwide, and 25 million people died. The advent of HAART significantly reduces HIV-1 infection mortality. However, HIV-1 infection cannot be controled fully because HIV-1 can acquire resistance against all currently available antiretroviral drugs. In addition, the side-effects of anti-HIV drugs is still high. Thus, it is still an arduous task to discover and develop new anti-HIV drugs with exact mechanism of action and novel structure type.CCR5 is a major co-receptor for HIV-1 entry into human cells and is also a good target for anti-HIV-1 drug design. Up till now, one CCR5 antagonist has been aproved by FDA and several CCR5 antagonist have entered into clinical trial.Based on the structural information of CCR5 receptor and the structure-activity relationship analyses of reported CCR5 inhibitors, two series of CCR5 inhibitors were designed and synthesized using the classical drug design theory. In addition, based on the stucture of ST-246, which is a potent inhibitor of smallpox, 17 new ST-246 derivatives were synthesized and evaluated in the anti-HIV-1 assays. Major studies were finished in this thesis:1. N-benzyl-N-{(3R) -1-[1- (2,6-dimethylbenzoyl) piperidin-4-yl] pyrrolidin-3-yl}-cyclopropane carboxamide was used as a lead compound, a convergent synthetic route for the preparation of bicyclic piperidine derivatives was designed. Using the modification strategy, such as open loop, substitution, 15 target compounds were parepared.2. 1-acetyl-N-[3-(4-benzylpiperidin-1-yl)propyl]-N-(3-chloro-4-methylphenyl) piperidine-4-formamide was used as a lead compound, a simple synthetic route for preparation of single chain piperidine derivatives was designed. Using the isostrism, splicing and other design strategy, 15 new compounds were synthesized. 3. Based on the stucture of ST-246, which is a potent inhibitor of smallpox, 17 new ST-246 derivatives were synthesized ans evaluated in the anti-HIV-1 assays.4. In this study, a total of 47 target compounds including three series were synthesized. Their structure were confirmed by nuclear magnetic resonance (1H-NMR, 13C-NMR), mass spectrometry (MS). CA Online (SciFinder) search confirmed that these target compounds are novel and first synthesized.5. All synthesized compounds were evaluated for their in vitro antiviral activity against HIV-1 R5 strain Bal infection in CEMX174 5.25M7 cells and cell cytotoxicity. The results showed that most of our compounds exhibited potent inhibitory activities. The anti-HIV activities of compound DMX-B06, DMX-B07 and DMX-B08 were equivalent to the positive control (IC50= 10 nM), and their selectivity index were greater than 10,000 and twe fold higer than that of the highest positive compound of this type. DMX-C07 , a dervative of ST-246, exhibited inhibitory activity with a IC50 of 0.41μM, selectivity index was as high as 291.68, suggesting this compound could be used as new lead compound for further HIV-1 inhibitor design.6. The structure-activity relationship of bicyclic piperidines and single chain piperidine inhibitors were discussed based on the effects of substitutional and configurational changes, positional isomerism and Bio-isostere on activities, and consistent with the prediction of biological activity.7. Using comparative molecular field analysis, the three-dimensional quantitative structure activity relationship of the tropane inhibitors were established. The main score of the best model was 4, cross-validation coefficient q2 was 0.582, non cross- validation regression coefficient r2 is 0.921. This model not only explained the existing relationship between structures and suppression, but also provided a theoretical basis foe the next round inhibitors design.