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

摘要

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.