Molecular Design,Synthesis And Biological Activity Research Of 6-Naphthylthio Substituted HEPT Analogs As Nonnucleoside HIV-1 Reverse Transcriptase Inhibitors

In the 20 years research on HIV reverse-transcriptase (RT) inhibitors has achieved great success. Among all 22 FDA-approved anti-HIV drugs, 14 come from HIV RT inhibitors, they are divided into two classes: nucleoside reverse-transcriptase inhibitors (NRTIs) and nonnucleoside reverse-transcriptase inhibitors (NNRTIs). l-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogues are an attractive type of NNRTIs, 6-benzyl-l-(ethoxymethyl)-5-isopropyl-uracil (MKC-442), as a representative of HEPT analogue, shows high activity against HTV-1 and even entered into phase III clinical trials, but it was unfortunately discontinued because it can activate a liver enzyme in the P450 family which metabolizes protease inhibitors. It is still the good prospect and high anti-HIV potency in HEPT analogues that attracted us to stick to their further structural modification on this lead compound.Our 3D-QSAR and Dock study on previous HEPT analogues showed that our designed 6-naphthylthio HEPT derivatives were well superimposed on the backbone of HEPT and matched the binding pocket of RT in terms of geometry shape, thus our target compounds would be promising. The 3D-QASR study also suggested that the modifications at N-1 and C-5 positions of HEPT are important.The target compounds FDOl-29 were synthesized by four steps, Condensation of diethyl 2-alkylmalonate with urea afford barbituric acid derivatives which were subjected to chlorization by POCl₃ and N-1 alkylation with alkoxy chloromethyl ether, then sulfenylation with naphthalenethiol to afford FDOl-29. In addition, nitrozation of 5-ethyl-6β-naphthylthio uracil followed by N-1 alkylation with different alkoxy chloromethyl ether provide 6β-(l-nitronaphthylthio) HEPT derivatives FD31-33, which was reduced in the presence of Na₂S₂O₃ and further acetylated with acetyl chloride to afford FD34-37.11 kind of alkoxymethyl N-1 side chain and 5 kind of alkyl C-5 side chain had been used in this structural modification, and 38 target compounds were prepared in the present work. Due to steric hindrance, the introduction of r-butyl group to the C-5 position of HEPT analogues was unfortunately failed.The bioactivity results disclosed that the α-series of 6-naphthylthio HEPT derivatives showed higher anti-HIV activity than the corresponding β-series, and the...