scholarly journals Synthesis of 1-benzyl-3-(3,5-dimethylbenzyl)Uracil Derivatives with Potential Anti-HIV Activity

2011 ◽  
Vol 22 (2) ◽  
pp. 57-65 ◽  
Author(s):  
Yohei Isono ◽  
Norikazu Sakakibara ◽  
Paula Ordonez ◽  
Takayuki Hamasaki ◽  
Masanori Baba ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Structural Modifications ◽  
Half Maximal Effective Concentration ◽  
Reverse Transcriptase Inhibitor ◽  
Anti Hiv Agents ◽  
Substituted 1 ◽  
Anti Hiv ◽  
Hiv 1

Background: Nine novel uracil analogues were synthesized and evaluated as inhibitors of HIV-1. Methods: Key structural modifications included replacement of the 6-chloro group of 1-benzyl-6-chloro-3-(3,5-dimethylbenzyl)uracil by other functional groups or N1-alkylation of 3-(3,5-dimethylbenzyl)-5-fluorouracil. Results: These compounds showed only micromolar potency against HIV-1 in MT-4, though two of them; 6-azido-1-benzyl-3-(3,5-dimethylbenzyl) uracil and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil were highly potent (half maximal effective concentration =0.067 and 0.069 μM) and selective (selectivity index =685 and 661), respectively. Structure–activity relationships among the newly synthesized uracil analogues suggest the importance of the H-bond formed between 6-amino group of 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil and amide group of HIV-1 reverse transcriptase. Conclusions: We discovered two 6-substituted 1-benzyl-3-(3,5-dimethylbenzyl) uracils, (6-azido-1-benzyl-3-(3,5-dimethylbenzyl) uracil and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil) as novel anti-HIV agents. These compounds should be further pursued for their toxicity and pharmacokinetics in vivo as well as antiviral activity against non-nucleoside reverse transcriptase inhibitor-resistant strains.

Effect of N'-Benzyl Substituted Uracil and the Analogues on HIV-1 Inhibition

2021 ◽  
pp. 2723-2728
Author(s):  
Olga Nesterova ◽  
Dmitrii Babaskin ◽  
Yuliya Tikhonova ◽  
Natalia Molodozhnikova ◽  
Sergey Kondrashev
Keyword(s):  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Uracil Derivatives ◽  
Half Maximal Effective Concentration ◽  
Infected Cells ◽  
New Generation ◽  
Anti Hiv ◽  
Hiv 1

The aim of the research is to study the effect of the synthesis of uracil derivatives on the HIV-1 activity. To achieve the goal, the following tasks were determined: to study the specificity of possible compounds for HIV-1 treatment; to synthesize uracil derivatives; to study the effect of the compounds on HIV-1 replication in vitro and select the most optimal concentrations, considering the cytotoxic effect; to determine the most effective anti-HIV-1 compounds for further research. Thus, nine new uracil analogues have been synthesized and proved to be inhibitors of HIV-1. Key structural modifications included replacement of the 6-chloro group of 1-benzyl-6-chloro-3-(3,5-dimethylbenzyl) uracil by other functional groups or N (1)-alkylation of 3-(3,5-dimethylbenzyl)-5-fluorouracil. These compounds showed only micromolar potency against HIV-1 in MT-4, though two of them; 6-azido-1-benzyl-3-(3,5-dimethylbenzyl) uracil and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil were highly potent (half maximal effective concentration =0.081 and 0.069μM) and selective (selectivity index =679 and 658), respectively. Structure-activity relationships among the newly synthesized uracil analogues suggest the importance of the H-bond formed between 6-amino group of 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil and amide group of HIV-1 reverse transcriptase. Two 6-substituted 1-benzyl-3-(3,5-dimethylbenzyl) uracils, (6-azido-1-benzyl-3-(3,5-dimethylbenzyl) uracil and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil) were discovered as novel anti-HIV agents. Compound’s activity against HIV-1 was determined based on inhibition of virus-induced cytopathogenicity in MT-4 cells. The compounds were tested for efficacy in infected cells and cytotoxicity. These compounds should be further pursued for their toxicity and pharmacokinetics in vivo as well as antiviral activity against non-nucleoside reverse transcriptase inhibitor-resistant strains. Thus, it will contribute to the development of a new generation of compounds effective against different viruses, considering their quickly mutation and increased resistance.

Synthesis and anti-HIV-1 Activity of [1-[2′,5′-Bis-O-(Tert-Butyldimethylsilyl)-β-L-Ribofuranosyl]Thymine]-3′-Spiro-5″-(4″-Amino-1″,2″-Oxathiole-2″,2″-Dioxide) (L-TSAO-T), the L-enantiomer of the Highly Specific HIV-1 Reverse Transcriptase Inhibitor TSAO-T

1995 ◽  
Vol 6 (6) ◽  
pp. 365-370 ◽  
Author(s):  
S. T. Ingate ◽  
M.-J. Camarasa ◽  
E. De Clercq ◽  
J. Balzarini
Keyword(s):  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Reverse Transcriptase Inhibitor ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Antiretroviral Activity

The L-isomer of the potent HIV-1-RT inhibitor TSAO-T has been stereospecifically synthesized and tested for its ‘ in vitro’ antiretroviral activity against HIV-1. Unlike the D-isomer, the L-isomer did not show appreciable inhibition of HIV-1 replication. The cytotoxicity was comparable with the cytotoxicity of the D-enantiomer.

Structure and conformational analysis of the anti-HIV reverse transcriptase inhibitor AZT using MP2 and DFT methods. Differences with the natural nucleoside thymidine. Simulation of the 1st phosphorylation step with ATP

2014 ◽  
Vol 16 (45) ◽  
pp. 24763-24783 ◽  
Author(s):  
M. Alcolea Palafox
Keyword(s):  
Proton Transfer ◽  
Conformational Analysis ◽  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Transfer Mechanism ◽  
Hiv Reverse Transcriptase ◽  
Dft Methods ◽  
Reverse Transcriptase Inhibitor ◽  
Anti Hiv ◽  
Hiv 1

A proton-transfer mechanism is proposed for the first phosphorylation step of the nucleoside HIV-1 reverse transcriptase inhibitor AZT (3′-azido-3′ deoxythymidine) by interacting with ATP.

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