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 profile

  • J Med Chem. 2012 Mar 8;55(5):2242-50. doi: 10.1021/jm201506e.
Xiaowei Wang  1 ,  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
Affiliations
  • 1. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
PMID: 22283377 DOI: 10.1021/jm201506e
Abstract

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 = 38 215), 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.

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