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

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...

AI Technical Summary

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 small and the toxicity is very high The antiviral selection index, the shortcoming is that the use in vivo and in vitro can quickly produce drug-resistant strains

There are currently three anti-human immunodeficiency syndrome drugs belonging to NNRTIs, namely nevirapine (Nevirapine), delavirdine (Delavirdine) and efavirenz (Efavirenz), which have a strong inhibitory effect on HIV-1, but are not effective against HIV -2 and Simian HIV (SIV) have no inhibitory activity

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