Synthesis and Potent Anti-HIV-1 Activity of Novel 6-Benzyluracil Analogues of 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine

Abstract

Ethyl 2-alkyl-4-aryl-3-oxobutyrates were synthesized from the corresponding arylacetonitriles and 2-bromo esters. Condensation of the butyrates with thiourea followed by treatment with chloroacetic acid afforded the 5-alkyl-6-(arylmethyl)uracils. Condensation of the uracils with acetals using trimethylsilyl triflate (TMS triflate) as a catalyst gave acyclic 5-alkyl-6-(arylmethyl)uracil derivatives. 6-Benzyl-5-ethyluracil was also condensed with methyl 5-O-(tert-butyldiphenylsilyl)-2-deoxy-3-O-(phenoxythiocarbonyl+ ++)-alpha,beta-D-erythro-pentofuranoside, followed by Barton reduction and deprotection, to give the anomers of 6-benzyl-5-ethyl-2',3'-dideoxyuridine. Alkylation of the uracils with alkyl chloromethyl sulfides gave new thio analogues of HEPT. All new N1-substituted uracils were tested for activity against HIV-1, and the thio analogues were found extremely potent.

Non-Nucleoside Reverse Transcriptase Inhibitors: The NNRTI Boom

“…Some have amines, amides and alkene functionalities that are introduced into the N-1 linker between the pyrimidyl moiety and different aromatic rings, for example, phenyl, 2-furyl, 2-thienyl, 2-benzofuranyl and so on (Pontikis et al, 1997). Some 1-substituted (ethylthio)methyl and (methylthio)methyl analogues have shown anti-HIV-1 activity comparable to MKC-442 and although they have higher cytotoxicity, they still have high selectivity indices (6200 to 17000) (Danel et al, 1996). Derivatives with a selenyl in place of sulphur in the (phenylthio) moiety have also been prepared (Kim et al, 1996) and some with activities and selectivities that are comparable to those obtained for MKC-442.…”

Comparative Evaluation of the Inhibitory Activities of a Series of Pyrimidinedione Congeners That Inhibit Human Immunodeficiency Virus Types 1 and 2

“…Compounds with the ethyl linker possessed activity ranging from 0.011 to 2.36 M in the wild-type enzyme assay. Compound 15 exhibited the highest level of activity in the HIV-1 RT inhibition assay (3 nM), while compounds 37,43,17,16,14,20,21, and 49 exhibited activity in the RT inhibition assay at concentrations below 20 nM. As expected based on assays with a single round of replication, no inhibitory activity was detected against purified HIV-2 RT up to the highest concentration tested in the assays for any of the test molecules (data not shown), confirming that inhibition of HIV-2 occurs solely through entry inhibition.…”

Synthesis of Novel MKC-442 Analogues with Potent Activities against HIV-1

“…The uracil derivatives 1 b, c were silylated with N,O-bis-(trimethylsilyl)acetamide (BSA) [21] in acetonitrile and then treated with bis(2-cyclohexen-1-yloxy)methane (2 a) as described by Vorbrüggen [22]. This consisted of using trimethylsilyl trifluoromethanesulfonate (TMS triflate) as a Lewis acid catalyst to give 1-[(2-cyclohexen-1-yl)oxy]methyl-6-(3,6-dimethylbenzyl)-5-ethyluracil (3 a) and 1-[(2-cyclohexen-1-yl)oxy]methyl-6-(3,6-dimethylbenzyl)-5-isopropyluracil (3 b) in 87 % and 84 % yields, respectively.…”