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.
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.
authors.affiliation: Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wang
authors.forename: Jianfang
authors.initials: J
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Huang
authors.forename: Ruiping
authors.initials: R
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Kang
authors.initials: K
authors.lastname: Qiao
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.forename: Yabo
authors.initials: Y
authors.lastname: Ouyang
authors.forename: Weisi
authors.initials: W
authors.lastname: Xu
authors.forename: Zhili
authors.initials: Z
authors.lastname: Zhang
authors.forename: Liangren
authors.initials: L
authors.lastname: Zhang
authors.forename: Yiming
authors.initials: Y
authors.lastname: Shao
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Liying
authors.initials: L
authors.lastname: Ma
authors.forename: Junyi
authors.initials: J
authors.lastname: Liu
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D014498:Uracil; D054303:HIV Reverse Transcriptase