Chiral Indolylarylsulfone Non-Nucleoside Reverse Transcriptase Inhibitors as New Potent and Broad Spectrum Anti-HIV-1 Agents

Abstract

We designed and synthesized a series of chiral indolyarylsulfones (IASs) as new HIV-1 NNRTIs. The new IASs 8-37 showed potent inhibition of the HIV-1 WT NL4-3 strain and of the mutant K103N, Y181C, Y188L, and K103N-Y181C HIV-1 strains. Six racemic mixtures, 8, 23-25, 31, and 33, were separated at semipreparative level into their pure enantiomers. The (R)-8 enantiomer bearing the chiral (α-methylbenzyl) was superior to the (S)-counterpart. IAS derivatives bearing the (S) alanine unit, (S)-23, (S,R)-25, (S)-31, and (S)-33, were remarkably more potent than the corresponding (R)-enantiomers. Compound 23 protected hippocampal neuronal cells from the excitotoxic insult, while efavirenz (EFV) did not contrast the neurotoxic effect of glutamate. The present results highlight the chiral IASs as new NNRTIs with improved resistance profile against the mutant HIV-1 strains and reduced neurotoxic effects.

Recent Advances in the Design and Development of Non‐nucleoside Reverse Transcriptase Inhibitor Scaffolds

“…[59] Most recently,F amiglini et al designed, synthesized,a nd evaluated the inhibitory activity of new derivatives of IASs against HIV-1 with the goal of investigating the SAR of chiral groups at the indole-2-carboxamide nitrogen. [60] Moreover,t he neuron-damaging side effects of the prepared compounds was evaluated. Almost all the synthesized compounds exhibited anti-WTH IV-1 activity in MT-4 cells at sub-nanomolar EC 50 values.…”

Indolylarylsulfones, a fascinating story of highly potent human immunodeficiency virus type 1 non-nucleoside reverse transcriptase inhibitors

“…A new series of chiral IASs showed potent inhibition of the HIV-1 WT NL4-3 strain and of the HIV-1 K103N, Y181C, Y188L and K103N-Y181C HIV-1 mutant strains. 70 Six racemic mixtures were separated at the semipreparative level by enantioselective HPLC into their pure enantiomers. The (R) -enantiomers of IAS derivatives bearing the chiral α-methylbenzyl were superior to the (S) -counterparts.…”

What do docking and QSAR tell us about the design of HIV-1 reverse transcriptase nonnucleoside inhibitors?

“…The currently licensed antiviral medications include drugs falling into five main classes targeting different steps in the HIV life cycle: reverse transcription (nucleoside/nucleotide and non-nucleoside reverse transcriptase inhibitors), assembly, budding, and maturation (protease inhibitors), viral entry (fusion inhibitors and co-receptor antagonists), and integration (integrase inhibitors). Standard first-line antiretroviral therapy (ART) for adults consists of three reverse transcriptase inhibitors (two nucleosides plus nonnucleoside) or two nucleoside reverse transcriptase inhibitors in combination with an integrase inhibitor [ 3 , 4 ]. Although ART has its limitations, it has proved largely effective, particularly in the early stages of the disease, reducing the mortality from AIDS and turning the disease from lethal to chronic [ 5 ].…”