16290-64-5Relevant academic research and scientific papers
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
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
, p. 2242 - 2250 (2012/05/20)
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.
Three routes for the synthesis of 6-benzyl-1-ethoxymethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde
Petersen,Pedersen,Nielsen
, p. 559 - 564 (2007/10/03)
6-Benzyl-1-ethoxymethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (1) is an analog of MKC-442, a very potent inhibitor of HIV-1 reverse transcriptase. Compound 1 was synthesized by three different routes. 6-Benzyl-1-ethoxymethyl-5-vinyl-1H-pyrimidine-2,4-dione (7) was synthesized in five steps from 6-benzyl-1H-pyrimidine-2,4-dione (2) by iodination; N-1 alkylation, N-3 protection, Pd(0) catalyzed coupling with tetravinyltin and then N-3 deprotection. Compound 7 was then cleaved with ozone to give compound 1. In another route compound 2 was hydroxymethylated, oxidized and N-1 alkylated to give compound 1. Finally, compound 1 was synthesized from 6-benzyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (10) by reduction with Raney Nickel followed by N-1 alkylation. An attempt was made to use compound 7 as a precursor for 6-benzyl-1-ethoxymethyl-5-oxiranyl-1H-pyrimidine-2,4-dione (11) by reacting 7 with MCPBA, but compound 11 was too reactive and was ring-opened by the m-chlorobenzoate present in the solution. Two intermediates were N-1 alkylated to give new MKC-442 analogs containing a hydroxymethyl group (13) or a cyano group (14) in the C-5 position. None of the compounds showed activity against the mutated HIV-1 virus (Tyr181Cys) but good activities were observed against wild-type HIV-1 for the intermediates 4 and 7 containing iodine or a vinyl group in the C-5 position, respectively.
