Arylthiopyrrole (AThP) Derivatives as Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors. Synthesis, Structure-Activity Relationships and Docking Studies. Part 1.

Novel arylthio isopropyl pyridinylmethylpyrrolemethanol (AThP) derivatives 3–5, which are related to capravirine (S-1153), were synthesized and tested for their ability to block the replication cycle of HIV-1 in infected cells. The newly synthesized AThPs are active in the concentration range of 0.008–53 μM. Even if compounds 3–5 are generally less potent than S-1153, their SI values are in some cases similar to that of the reference drug. In fact, the cytotoxicities of AThPs are generally lower than that of S-1153. Compound 4 e was the most active derivative of this series in cell-based assays; its potency is similar to that of S-1153 (EC50=8 and 3 nM, respectively), as is its selectivity index (SI=6250 and 7000, respectively). AThP derivatives were proven to target HIV-1 RT. In fact, compounds 3–5 generally inhibited the viral enzyme at concentrations similar to those observed in cell-based assays. A selected number of AThPs (4 k and 5 a,e) were tested against clinically relevant drug-resistant forms of recombinant reverse transcriptase (rRT) carrying the K103N and Y181I mutations. Carbamate 5 e showed an approximate 240-fold decrease in activity against Y181I, but only a 10-fold loss in potency against the K103N rRT form. Docking calculations were also performed to investigate the binding mode of compounds 2, 4 e, 4 j, 4 k and 5 e into the non-nucleoside binding site of HIV-1 RT and to rationalize some structure–activity relationships and resistance data.