Design Synthesis and Biological Evaluation of 1-(2-benzyloxyl/alkoxyl) methyl-5-halo-6-aryluracils as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors with Improved Drug Resistance Profile

摘要

Since the emergence of drug-resistant mutants has limited the efficacy of non-nucleoside reverse transcriptase inhibitors (NNRTIs), it is essential to develop new antivirals with better drug-resistance and pharmacokinetic profiles. Here we designed and synthesized a series of 1-[(2-benzyloxyl/alkoxyl)methyl]-5-halo-6-aryluracils, the HEPT analogues, and evaluated their biological activity using Nevirapine and >18 (TNK-651) as reference compounds. Most of these compounds, especially >6b, >7b, >9b, 11b and >7c, exhibited highly potent anti-HIV-1 activity against both wild-type and NNRTI-resistant HIV-1 strains. The compound >7b, that had the highest selectivity index (SI = 38,215), is more potent than Nevirapine and >18. These results suggest that introduction of halogen at the C-5 position may contribute to the effectiveness of these compounds against RTI-resistant variants. In addition, m-substituents on the C-6 aromatic moiety could significantly enhance activity against NNRTI-resistant HIV-1 strains. These compounds can be further developed as next-generation NNRTIs with improved antiviral efficacy and drug-resistance profile.