Design, Synthesis And Antiviral Evaluation Of Novel 2,3-Diaryl-1,3-Thiazolidin-4-One Derivatives As HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

The human immunodeficiency virus type 1(HIV-1) is the main cause of the acquired immunodeficiency syndrome(AIDS),which was first identified in the western world in 1981.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 spread of many drug-resistant forms of HIV-1 means there is a danger that progress already made will be reversed.HIV reverse transcriptase(RT) is one of the main targets for the action of anti-AIDS drugs. non-nucleoside reverse transcriptase inhibitors(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.Several thiazolidin-4-one leads were identified as novel NNRTIs.Substituted 2,3-diaryl-1,3-thiazolidin-4-one derivatives represented a new class of specific HIV-1 NNRTIs.Based on the general crystal structure of the HIV-1 RT complexed with NNRTIs,which is like a "butterfly" type,and furthermore, 2,3-diaryl-1,3-thiazolidin-4-one are served as templates,and according to the general principle of bioisosteric replacement in medicinal chemistry,we designed and synthesized a series of novel 2,3-diaryl-1,3-thiazolidin-4-one derivatives.The newly designed and synthesized thiazolidin-4-one derivatives have the following structural characters:(â…°) substituents methylnaphthalene linked to the C-1 positions,(â…±) alter diaryl at N-1 positions to substituted benzyl,(â…²) substituents thiazolidin-4-one to 1-methylpiperidin-2-one,to possess potent anti-HIV-1 activity of the NNRTIs.For the preparation of the newly designed thiazolidones,we chose amidobenzene,mercapto-acetic acid and aromatic alcohol as the starting material respectively,through ring-closure and sulfurization.Totally,30 novel compounds have been synthesized.All of their structures were identified by IR,MS and ¹H-NMR, ¹³C-NMR spectral analysis respectively.All the compounds are screened for anti-HIV activity in vitro.The results showed that some compunds exhibited inhibition against HIV-1 replication with the EC₅₀ value 1.49μM,Structure-activity relationship analysis reveald that the different substitute aromatic ring played an important role in affecting the anti-HIV activities, and the position substitute in aromatic ring is essential for preserving the activity.Superior substituent groups were introduced to the novel scaffolds based on the docking results of virtual screening.New selected compounds were synthesized.In the last,compound e2 has been identified as a anti-HIV agent,through computer-aided drug design and biological evaluation,which is worth future investigation and development.Structure-activity relation was discussed and some useful information was obtained in the design and development of new HIV-1 NNRTI.