Synthesis of new 2′-deoxy-2′-fluoro-4′-azido nucleoside analogues as potent anti-HIV agents

We prepared 1-(4′-azido-2′-deoxy-2′-fluoro-β-d-arabinofuranosyl)cytosine (10) and its hydrochloride salt (11) as potential antiviral agents based on the favorable antiviral profiles of 4′-substituted nucleosides. Compounds 10 and 11 were synthesized from 1,3,5-O-tribenzoyl-2-deoxy-2-fluoro-d-arabinofuranoside in multiple steps, and their structures were unequivocally established by IR, 1H NMR, 13C NMR, and 19F NMR spectroscopy, HRMS, and X-ray crystallography. Compounds 10 and 11 exhibited potent anti-HIV-1 activity (EC50: 0.3 and 0.13 nM, respectively) without significant cytotoxicity in concentrations up to 100 μM. Compound 11 exhibited extremely potent anti-HIV activity against NL4-3 (wild-type), NL4-3 (K101E), and RTMDR viral strains, with EC50 values of 0.086, 0.15, and 0.11 nM, respectively. Due to the high potency of 11, it was also screened against an NIH Reagent Program NRTI-resistant virus panel containing eleven mutated viral strains and for cytotoxicity against six different human cell lines. The results of this screening indicated that 11 is a novel NRTI that could be developed as an anti-AIDS clinical trial candidate to overcome drug-resistance issues.

1-(4′-Azido-2′-deoxy-2′-fluoro-β-d-arabinofuranosyl)cytosine (10) and its hydrochloride salt (11) were synthesized, and both showed potent anti-HIV-1 activity (EC50: 0.3 and 0.13 nM, respectively). The hydrochloride salt 11 also exhibited extremely potent anti-HIV activity against NRTI-resistant virus.Figure optionsDownload as PowerPoint slideHighlights
► 1-(4′-Azido-2′-deoxy-2′-fluoro-β-d-arabinofuranosyl)cytosine (10) was synthesized.
► The hydrochloride salt (11) of 10 was also prepared.
► Compounds 10 and 11 exhibited potent anti-HIV-1 activity (EC50: 0.3 and 0.13 nM).
► Compound 11 exhibited extremely potent activity against drug-resistant HIV virus.
► Compound 11 is a novel NRTI and potential anti-AIDS clinical trial candidate.