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 an Improved Drug Resistance P

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• 作者：Xiaowei Wang ; Jianfang Zhang ; Yang Huang ; Ruiping Wang ; Liang Zhang ; Kang Qiao ; Li Li ; Chang Liu ; Yabo Ouyang ; Weisi Xu ; Zhili Zhang ; Liangren Zhang ; Yiming Shao ; Shibo Jiang ; Liying Ma ; Junyi Liu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：55
• 期：5
• 页码：2242-2250
• 全文大小：322K
• 年卷期：v.55,no.5(March 8, 2012)
• ISSN：1520-4804

文摘

Because 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. Compound 7b, which had the highest selectivity index (SI = 38鈥?15), is more potent than nevirapine and 18. These results suggest that the introduction of a halogen at the C-5 position may contribute to the effectiveness of these compounds against RTI-resistant variants. In addition, meta 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 an improved antiviral efficacy and drug-resistance profile.