Abstract
A series of new 5-allyl-6-benzylpyrimidin-4(3H)-ones bearing different substituents at the C-2 position of the pyrimidine core have been synthesized and evaluated for their in vitro activities against human immunodeficiency virus type 1 (HIV-1) in the human T-lymphotropic type (MT-4 cell cultures). The majority of the title compounds showed moderate to good activities against HIV-1. Amongst them, 5-allyl-6-benzyl-2-(3-hydroxypropylthio)pyrimidin-4(3H)-one analogue 11c exhibited the most potent anti-HIV-1 activity (IC50 0.32 µM). The biological testing results clearly indicated that the substitution at C-2 position of the pyrimidine ring could increase the anti-HIV-1 reverse transcriptase (RT) activity.
Highlights
The reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1 RT) is one of the main targets of drugs used in the treatment of AIDS [1,2]
In our continuing efforts to find novel effective and selective anti-HIV-1 agents in 2-alkylsulfanyl-6-benzyl-3,4-dihydropyrimidin4(3H)-ones (S-dihydro alkoxy benzyl oxopyrimdines (DABOs)) type nucleoside reverse transcriptase inhibitors (NNRTIs) [30,31,32,33], we present the synthesis and anti-HIV-1 activities of a series of S-DABO analogs
K2CO3 afforded the desirable target S-DABO analogues 2a-k. 5-Allyl-6-benzyl-2-(methyl acetatethio) pyrimidin-4(3H)-one 3a and 5-Allyl-6-benzyl-2-(ethyl acetatethio)pyrimidin-4(3H)-one 3b were obtained when compound 1 was treated with various halo-esters namely, methyl bromoacetate or ethyl bromoacetae in anhydrous DMF in the presence of K2CO3, respectively
Summary
The reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1 RT) is one of the main targets of drugs used in the treatment of AIDS [1,2]. NNRTIs are a class of antiretroviral drugs which deactivate HIV-1 reverse transcriptase by inducing conformational change of the enzyme via binding to a hydrophobic site close (approximately 10 Å) to its catalytic site [5]. Since these compounds do not need intracellular metabolic activation, have relatively low cytotoxicity, act on a nanomolar scale and are not active against other retroviruses, they are highly specific HIV-1 inhibitors. Among NNRTIs, dihydro alkoxy benzyl oxopyrimdines (DABOs) are an interesting class of compounds active at nanomolar concentration. In our continuing efforts to find novel effective and selective anti-HIV-1 agents in 2-alkylsulfanyl-6-benzyl-3,4-dihydropyrimidin4(3H)-ones (S-DABOs) type NNRTIs [30,31,32,33], we present the synthesis and anti-HIV-1 activities of a series of S-DABO analogs
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