Synthesis of novel uracil non-nucleosides analogues of 3,4-dihydro-2-alkylthio-6-benzyl-4-oxopyrimidines and 6-benzyl-1-ethoxymethyl-5-isopropyluracil (original) (raw)
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Archiv der Pharmazie, 2009
A series of new uracil non-nucleosides analogues of S-DABO's was synthesised by reaction of 5-alkyl-6-(p-chlorobenzyl)-2-thiouracils with chloroethyl dialkylamine hydrochloride, N-(2-chloroethyl)-pyrrolidine hydrochloride, N-(2-chloroethyl)-piperidine hydrochloride or appropriate haloethers. Novel emivirine analogues were synthesised by silylation of 5-alkyl-6-(p-chlorobenzyl)uracils and treatment with bromomethyl methyl ether, chloromethyl ethyl ether or benzyl chloromethyl ether. Compounds 6-(p-chlorobenzyl)-5-ethyl-1-ethyloxymethyluracil (9d) and 1-benzyloxymethyl-6-(4-chlorobenzyl)-5-ethyluracil (9f) showed activity against wild-type HIV-1 strain III B in MT-4 cells.
ChemInform, 2010
Novel emivirine and TNK-651 analogues 5a -d were synthesized by reaction of chloromethyl ethyl ether and / or benzyl chloromethyl ether, respectively, with uracils having 5-ethyl and 6-(4methylbenzyl) or 6-(3,4-dimethoxybenzyl) substituents. A series of new uracil non-nucleosides substituted at N-1 with cyclopropylmethyloxymethyl 9a -d, 2-phenylethyloxymethyl 9e -h, and 3-phenylprop-1-yloxymethyl 9i -l were prepared on treatment of the corresponding uracils with the appropriate acetals 8a -c. Some of the tested compounds showed good activity against HIV-1 wild type. Among them, 1-cyclopropylmethyloxymethyl-5-ethyl-6-(3,5-dimethylbenzyl)uracil 9c and 5-ethyl-6-(3,5-dimethylbenzyl)-1-(2-phenylethyloxymethyl)uracil 9g showed inhibitory potency equally to emivirine against HIV-1 wild type. Furthermore, compounds 9c and 9g showed marginal better activity against NNRTI resistant mutants than emivirine.
Synthesis of new uracil non-nucleoside derivatives as potential inhibitors of HIV-1
Journal of Heterocyclic Chemistry, 2003
6-(2-Phenylethyl) and 6-cyclohexyl 5-cyanouracils (1a,b) were synthesized and reacted with chloromethyl ethyl ether, benzyl chloromethyl ether, chloromethyl methyl sulfide and (2-acetoxyethoxy)methyl bromide. New uracil analogues of (S)-DHPA were synthesized by reaction of compounds (1a,b) with ((S)-2,2-dimethyl-1,3-dioxolane-4-yl) alkyl p-toluenesulfonate.
Journal of Medicinal Chemistry, 2002
This paper reports the synthesis and the antiviral activities of a series of 6-arylmethyl-1-(allyloxymethyl)-5-alkyluracil derivatives, which can be viewed as analogues of the anti-HIV-1 drug emivirine (formerly MKC-442) from which they differ in the replacement of the ethoxymethyl group with variously allyloxymethyl moieties. The most active compounds N-1 allyloxymethyl-and N-1 3-methylbut-2-enyl substituted 5-ethyl-6-(3,5-dimethylbenzyl)uracils (12 and 13) showed activity against HIV-1 wild-type in the picomolar range with selective index of greater than 5 × 10 6 and activity in the submicromolar range against the clinically important Y181C and K103N mutant strains known to be resistant to emivirine. Structureactivity relationship studies established a correlation between the anti-HIV-1 activity and the substitution pattern of the N-1 allyloxymethyl group.
Bioorganic & Medicinal Chemistry, 2006
A series of the novel purine and pyrimidine nucleoside analogues were synthesised in which the sugar moiety was replaced by the 4-amino-2-butenyl (2-6 and 10-18) and oxiranyl (8 and 20) spacer. The Z-(2-6) and E-isomers (10-18) of unsaturated acyclic nucleoside analogues were synthesized by condensation of 2-and 6substituted purine and 5-substituted uracil bases with Z-(1) or E-phthalimide precursors. The oxiranyl nucleoside analogues (8 and 20) were obtained by epoxidation of 1 and 9 with m-chloroperoxybenzoic acid and subsequent coupling with adenine. The new compounds were evaluated for their antiviral and antitumor cell activities. Among the olefinic nucleoside analogues, Z-isomer of adenine containing 4-amino-2-butenyl side chain (6) exhibited the best cytostatic activities, particularly against colon carcinoma (SW 620, IC50 = 26 M). Its E-isomer 15 did not show any antiprolipherative activity against malignant tumor cell lines, except for a slight inhibition of colon carcinoma (SW 620, IC50 = 56.5 M) cells. In general, Z-isomers showed better cytostatic activities than the corresponding E-isomers. (Z)-4-Amino-2-butenyl-adenine nucleoside analogue 6 showed albeit modest but selective activity against HIV-1 (EC50 = 4.83 gmL -1 ).
Antimicrobial Agents and Chemotherapy, 2012
ABSTRACTNonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are important components of current combination therapies for human immunodeficiency virus type 1 (HIV-1) infection. In screening of chemical libraries, we found 6-azido-1-benzyl-3-(3,5-dimethylbenzyl)uracil (AzBBU) and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl)uracil (AmBBU) to be highly active and selective inhibitors of HIV-1 replicationin vitro. To determine the resistance profiles of these compounds, we conducted a long-term culture of HIV-1-infected MT-4 cells with escalating concentrations of each compound. After serial passages of the infected cells, escape viruses were obtained, and they were more than 500-fold resistant to the uracil derivatives compared to the wild type. Sequence analysis was conducted for RT of the escape viruses at passages 12 and 24. The amino acid mutation Y181C in the polymerase domain of RT was detected for all escape viruses. Docking studies using the crystal structure of RT showed t...
Asymmetric synthesis of 1,3-dioxolane-pyrimidine nucleosides and their anti-HIV activity
Journal of Medicinal Chemistry, 1992
In order to study the structureactivity relationships of dioxolane nucleosides as potential anti-HIV agents, various enantiomerically pure dioxolane-pyrimidine nucleosides have been synthesized and evaluated against HIV-1 in human peripheral blood mononuclear cells. The enantiomerically pure key intermediate 8 has been synthesized in nine steps from 1,6-anhydro-~-mannose (l), which was condensed with 5-substituted pyrimidines to obtain various dioxolane-pyrimidine nucleosides. Upon evaluation of these compounds, cytosine derivative 19 was found to exhibit the moat potent anti-HIV agent although it is the most toxic. The order of anti-HN potency was as follows: cytosine (&isomer) > thymine > cytosine (a-isomer) > 5-chlorouracil > 5-bromouracil > 5-fluorouracil derivatives. Uracil, 5-methylcytosine, and 5-iodouracil derivatives were found to be inactive. Interestingly, a-isomer 20 showed good anti-HN activity without cytotoxicity. As expected, other a-isomers did not exhibit any significant antiviral activity. (-)-Dioxolane-T was 5-fold less effective against AZT-resistant virus than AZT-sensitive virus.