Preparation and application of novel chiral 3,4-dihydro-2-alkoxyl-6-benzyl-4-oxopyrimidine (S-DABO) human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitor

A CH3, C6H5 technology, applied in antiviral agents, organic chemistry, etc., can solve problems such as drug-resistant strains

Inactive Publication Date: 2011-07-27
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The common features of this group of compounds are: they can highly inhibit HIV-1, but do not inhibit HIV-2 and other retroviruses; they are not inhibitors of HIV-1 reverse transcriptase substrate competition, but pass the The hydrophobic region of p66 binds and replaces the catalytic aspartic acid residue of the polymerase binding site, thereby achieving the effect of inhibiting HIV-1 replication; it does not inhibit other DNA polymerases, so the toxicity is very s

Method used

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  • Preparation and application of novel chiral 3,4-dihydro-2-alkoxyl-6-benzyl-4-oxopyrimidine (S-DABO) human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitor
  • Preparation and application of novel chiral 3,4-dihydro-2-alkoxyl-6-benzyl-4-oxopyrimidine (S-DABO) human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitor
  • Preparation and application of novel chiral 3,4-dihydro-2-alkoxyl-6-benzyl-4-oxopyrimidine (S-DABO) human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitor

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025]

[0026] Compound 1: Ethyl 3-oxo-4-(1-naphthyl)butanoate

[0027] The activated zinc powder (18g, with 3N hydrochloric acid, H 2 (0, absolute ethanol, anhydrous ether washed three times, then vacuum-dried and dried), suspended in dry THF (125ml) and heated to 85°C for reflux, 20 drops of ethyl bromoacetate was added dropwise, after 45 minutes (the solution became (green) was added 1-naphthaleneacetonitrile (2.004g, 12mmol) in one go, then ethyl bromoacetate (3.3ml, 30mmol) was slowly added dropwise, and the dropwise addition was completed after 1 hour, and then refluxed for 10 minutes. Dilute with THF (3 × 125ml), add potassium carbonate (50%, 54ml) aqueous solution and stir rapidly for 45 minutes, let stand to separate layers, pour out the upper organic solvent, wash the remaining aqueous phase with THF (2 × 100ml), and combine the organic phases Then add hydrochloric acid (10%, 50ml) and stir at room temperature for 45 minutes, 3 When the pH value is adjusted to ...

Embodiment 2

[0191] Embodiment 2 carries out the biological activity evaluation of HIV-1 reverse transcriptase to the synthesized compound

[0192] One experimental principle

[0193] 1. Reverse transcriptase:

[0194] Reverse transcriptase is a DNA polymerase that synthesizes double-stranded DNA using single-stranded RNA as a template. It is a multi-functional enzyme, which has the activities of synthesizing polymerase and ribonuclease H respectively using RNA or DNA as a template.

[0195] 2. Nucleotide microplate covalently cross-linked

[0196] Nucleic acid molecular hybridization can be divided into two types: solid-phase hybridization and liquid-phase hybridization. Solid-phase hybridization is to immobilize one nucleic acid participating in the reaction on a solid support, and the other nucleic acid reaction chain is free in the solution. In this experiment, oligo(dT) will be used as the primer 15 After phosphorylation at the 5' end of NUNC, covalent cross-linking occurs with t...

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Abstract

The invention relates to preparation and an application of a novel chiral 3,4-dihydro-2-alkoxyl-6-benzyl-oxopyrimidine (S-DABO) human immunodeficiency virus (HIV)-1 reverse transcriptase (RT) inhibitor. In the preparation, 3,4-dihydro-2-alkoxyl-6-benzyl-4-oxopyrimidine (DABO) is used as a lead compound combined with a research result of a discussion group, the structure and active relation of the lead compound are linked and merged in a molecule based on a medicament reasonable design basic principle, so that a novel S-DABO compound chiral 3,4-dihydro-2-alkoxyl-6-benzyl-4-oxopyrimidine as shown in a general formula I is designed, wherein in the formula I, definitions of groups are shown in claims. The preparation is focused on the fact that different groups at C2 and C5 positions of a pyrimidine ring are modified, so as to obtain novel compounds which are more favorable of combining with the HIV-1 RT. An HIV-1 RT activity test finds that the novel compounds have high activities, wherein the activity of a compound is 14 times higher than that of clinically used nevirapine. The compounds are likely to become potential novel anti-HIV medicaments.

Description

technical field [0001] This application relates to non-nucleoside HIV-1 (human immunodeficiency virus-1) reverse transcriptase inhibitor 3,4-dihydro-2-alkoxy-6-benzyluracil (DABO) as the lead substance, A series of novel S-DABO compounds were designed and synthesized according to the substrate conformation of HIV-1 reverse transcriptase (HIV-1RT) which interacted with these compounds, and their biological activity was tested. In order to further improve the activity and selectivity of this type of compound, reduce the toxicity and drug resistance of the compound, the inventors based on the methylene-1-naphthylthiouracil derivative at the C6 position, and at the C2 and C5 positions of the pyrimidine ring Structural modifications were carried out on it, and groups with different steric and electrical effects were connected to obtain a series of new S-DABO compounds, which showed good HIV-1 reverse transcriptase inhibitory activity through activity tests. The invention belongs t...

Claims

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Application Information

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IPC IPC(8): C07D239/56A61K31/513A61P31/18
Inventor 刘畅刘俊义
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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