Design, Synthesis And Activity Study Of Target-based HIV-1Non-nucleoside Reverse Transcriptase Inhibitors

The human immunodeficiency virus type1(HIV-1) is the main cause of the acquired immunodeficiency syndrome (AIDS), which was first identified in the Western world in1981. Since then, AIDS has developed into a worldwide pandemic of disastrous proportions. Considerable progress has been made in treating HIV-infected patients using highly active antiretroviral therapy (HAART) involving multidrug combinations. However, the increasing incidence of drug resistant viruses along with the drug toxicity among treated people calls for continuous efforts of developing anti-HIV-1drugs.HIV-1reverse transcriptase (RT) is one of the main targets for the action of anti-AIDS drugs. Drugs targeted at HIV RT can be divided into two categories:(ⅰ) nucleoside and nucleotide analogue RT inhibitors (NRTIs/NtRTIs), which, following activation to their triphosphate forms, compete with the RT substrate and also act as terminators of DNA synthesis after incorporation into the primer strand; and (ⅱ) nonnucleoside RT inhibitors (NNRTIs), including the approved drugs nevirapine, delavirdine, efavirenz and etravirine, which, although having wide structural variation, all bind at a similar site distal to the active site within RT. NNRTIs currently in clinical use have a low genetic barrier to resistance and therefore, the need for novel NNRTIs active against drug-resistant mutants selected by current therapies is of paramount importance.In recent year, in spite of the rapid growth of HFV-1RT3D-structural information, the difficulty in structure-based de novo design of NNRTIs scaffolds and docking based virtual screening approach lies in the following two aspects:i) The flexibility of NNIBP, formed by conformational changes in the RT on binding of the NNRTI ligand; ii) The NNRTI resistance mutations located in and around the NNIBP. Therefore, structure-based and ligand-based combined drug design methodology was carried out to facilitate both drug lead generation and lead optimization. And considerable cases illustrated the benefits for NNRTIs design of closely coupled traditional medicinal chemistry, structural biology, computational chemistry methodology, and many others.As a continuation of our efforts to discover and develop back-up analogs of DAPYs, novel substituted nitropyridine derivatives were designed via a structure-based core refining approach, synthesized and evaluated for their in vitro HIV-1activity in MT-4cells. Preliminary biological evaluation indicated that most of the compounds exhibited marked inhibitory activity against wild-type HIV-1IIIB. Most notably, the compound7b was identified as the most promising candidate in inhibiting HIV-1replication with an EC50value of0.056μM and a selective index (SI) of1251,7k (EC50=0.034μM, SI=691), compound7c (EC50=0.11μM, SI=339) and compound7h (EC50=0.17μM, SI=97) were more active than reference drugs NVP(EC50=0.23μM) and DLV(EC5o=0.51μM) against wt HIV-1(ⅢB). Some antivirally active compounds also showed moderate inhibitory activity against RT. Preliminary structure-activity relationships (SARs) and molecular modeling of these new analogs provide valuable avenues for future molecular optimization.Substituted2,3-diaryl-1,3-thiazolidin-4-one derivatives represented a new class of specific HIV-1NNRTIs. Thiocarboxanilide derivatives UC781,(N-[4-chloro-3-(3-methyl-2-butenyloxy)pheny1]-2-methyl-3-furancarbothiomide), is a extremely potent inhibitor of human immunodeficiency virus type1(HIV-1) reverse transcriptase (RT) with a favorable resistance spectrum. The EC50and SI of UC781inhibited of HIV-1replication in cell culture were0.002μM and50000, respectively. UC781targeted HIV-1RT and had extremely low and almost similar EC50values against wild-type HIV-1and a series of mutant viruses in their RT and restored the anti viral activity of AZT to AZT resistant HIV-1strains. Based on the general crystal structure of the HIV-1RT complexed with NNRTIs, which is like a "butterfly"type, and furthermore,2,3-diaryl-1,3-thiazolidin-4-one and UC-781are served as templates, and according to the general principle of bioisosteric replacement in medicinal chemistry, we designed and synthesized a series of novel2,3-diaryl-1,3-thiazolidin-4-one derivatives in which the2,6-dihalophenyl ring at C-2was retained as an essential moiety, whereas the pyridine ring was replaced by a suitably substituted benzene ring. All the newly compounds are screened for anti-HIV activity in vitro. The results showed that some compunds exhibited inhibition against HIV-1replication, Structure-activity relationship analysis revealed that the different substitute aromatic ring played an important role in affecting the anti-HIV activities. Structure-activity relation was discussed and some useful information was obtained in the design and development of new HIV-1NNRTIs.Among the most representative classes of NNRTIs, DABOs (dihydro-alkylthio-benzyl-oxopyrimidines) occupy a relevant position. Owing to their structures, DABOs can adapt to changes in the binding pocket due to mutations. So DABOs can inhibit the mutation of the target and also inhibit the emergence of drug resistance. Based on computer aided drug design (CADD), we have designed and synthesized novel DABOs derivatives:piperidine-linked S-DABO analogues. We have also used molecular docking to study the relationship between compounds and HIV-1RT, which provide clear guideline and actual activity predicitions for novel HIV-1RT inhibitors. The selected target molecules based on docking results of virtual screening were synthesized. The preliminary activity and cytotoxicity screening of the newly designed and synthesized target compounds S-DABOs for inhibition of HIV-1(strain IIIB), HIV-2(strain ROD) and HIV-1mutant virus strains are in progress.In summary, taking the DAPYs,2,3-Diaryl-1,3-thiazolidin-4-one derivatives and DABOs NNRTIs as leads, four series of novel NNRTIs were designed and synthesized in this dissertation according to bioisosterism principle. The new, simple, and convenient synthetic approaches to the title compounds were developed, or improved and optimized. Lastly, through biological evaluation, we find many high potent antiviral agents, which are worth further investigation and development. We hope that the knowledge and insight on the NNRTIs research learnt from the work will help a lot on the battle against the virus and benefit human health and life.