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
experimental part, 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.
