| Title | 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 |
| Authors | Wang, Xiaowei Zhang, Jianfang Huang, Yang Wang, Ruiping Zhang, Liang Qiao, Kang Li, Li Liu, Chang Ouyang, Yabo Xu, Weisi Zhang, Zhili Zhang, Liangren Shao, Yiming Jiang, Shibo Ma, Liying Liu, Junyi |
| Affiliation | Chinese Ctr Dis Control & Prevent, State Key Lab Infect Dis Prevent & Control, Natl Ctr AIDS STD Control & Prevent NCAIDS, Beijing 102206, Peoples R China. Peking Univ, Sch Pharmaceut Sci, Dept Biol Chem, Beijing 100191, Peoples R China. Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China. Capital Med Univ, Coll Pharmaceut Sci, Beijing 100069, Peoples R China. Fudan Univ, MOE MOH Key Lab Med Mol Virol, Shanghai Med Coll, Shanghai 200032, Peoples R China. Fudan Univ, Inst Med Microbiol, Shanghai 200032, Peoples R China. |
| Keywords | IMMUNODEFICIENCY-VIRUS TYPE-1 RT INHIBITORS POSITIONAL ADAPTABILITY CONFORMATIONAL-CHANGES DERIVATIVES ANALOGS COMPLEX BINDING RESOLUTION THERAPY |
| Issue Date | 2012 |
| Publisher | journal of medicinal chemistry |
| Citation | JOURNAL OF MEDICINAL CHEMISTRY.2012,55,(5),2242-2250. |
| 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. |
| URI | http://hdl.handle.net/20.500.11897/323050 |
| ISSN | 0022-2623 |
| DOI | 10.1021/jm201506e |
| Indexed | SCI(E) PubMed |
| Appears in Collections: | 药学院 天然药物与仿生药物国家重点实验室 |
