Design And Synthesis Of The Pyrazolothiadiazines And Thienothiadiazines As HIV Reverse Transcriptase Inhibitors

Acquired immunodeficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV), which is a retrovirus that replicates in a human host cell. The reverse transcriptase (RT) plays a crucial role for the replication of HIV type-1 (HIV-1) in the virus life cycle, and is responsible for the convertion of the single-stranded RNA viral genome into double-stranded DNA that subsequently integrates into the host DNA.Because of the distinct function of RT in the virus life cycle, it is one of the important targets of antiviral therapy. Two main classes of RT inhibitors have been hitherto discovered: (1) nucleoside reverse transcriptase inhibitors (NRTIs), which compete with natural substrates by mimicking the normal deoxynucleoside triphosphate and function as chain terminators, and (2) the non-nucleoside reverse transcriptase inhibitors (NNRTIs), which inhibit the enzyme by an non-competitively allosteric mechanism involving binding to a site adjacent to the deoxyribonucleoside triphosphate binding site of the enzyme. Both of them have been found to be effective in halting the enzymatic function of RT.Several classes of non-nucleoside compounds have been identified as highly specific reverse transcriptase inhibitors. Substituted thieno[3,4-e][1,2,4]thiadiazine derivatives (TTDs) is one representative of the newly found potent NNRTIs which can inhibit some other NRTI-resistant or NNRTI-resistant mutant HTV-1 strains. Based on the general crystal structures of the HIV-1 RT complexed with NNRTIs, which is like a...