- 6-Benzoyl-3-hydroxypyrimidine-2,4-diones as dual inhibitors of HIV reverse transcriptase and integrase
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N-3-Hydroxylation of pyrimidine-2,4-diones was recently found to yield inhibitors of both HIV-1 reverse transcriptase (RT) and integrase (IN). An extended series of analogues featuring a benzoyl group at the C-6 position of the pyrimidine ring was synthesized. Through biochemical studies it was found that these new analogues are dually active against both RT and IN in low micromolar range. Antiviral assays confirmed that these new inhibitors are active against HIV-1 in cell culture at nanomolar to low micromolar range, further validating 3-hydroxypyrimidine-2,4-diones as a viable scaffold for antiviral development.
- Tang, Jing,Maddali, Kasthuraiah,Dreis, Christine D.,Sham, Yuk Y.,Vince, Robert,Pommier, Yves,Wang, Zhengqiang
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p. 2400 - 2402
(2011/05/15)
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- Synthesis and antimicrobial activity of some novel 5-alkyl-6-substituted uracils and related derivatives
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6-Chloro-5-ethyl-, n-propyl- and isopropyluracils 5a-c were efficiently prepared from the corresponding 5-alkybarbituric acids 3a-c via treatment with phosphorus oxychloride and N,N-dimethylaniline to yield the corresponding 5-alkyl-2,4,6-trichloropyrimidines 4a-c, which were selectively hydrolyzed by heating in 10% aqueous sodium hydroxide for 30 minutes. The reaction of compounds 5a-c with 1-substituted piperazines yielded the corresponding 5-alkyl-6-(4-substituted-1-piperazinyl)uracils 6a-j. The target 8-alkyltetrazolo[1,5-f]pyrimidine-5,7(3H,6H)-diones 7a-c were prepared via the reaction of 5a-c with sodium azide. Compounds 6a-j and 7a-c were tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Compound 6h displayed potent broad-spectrum antibacterial activity, while compound 6b showed moderate activity against the Gram-positive bacteria. All the tested compounds were practically inactive against Candida albicans.
- Al-Turkistani, Abdulghafoor A.,Al-Deeb, Omar A.,El-Brollosy, Nasser R.,El-Emam, Ali A.
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p. 4764 - 4774
(2011/09/12)
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- N1-Alkyl pyrimidinediones as non-nucleoside inhibitors of HIV-1 reverse transcriptase
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A series of N1-alkyl pyrimidinediones were designed, synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Our efforts identified compound 10b, which represents the lead compound in this series with pharmacokinetics
- Mitchell, Michael L.,Son, Jong Chan,Guo, Hongyan,Im, Yun-A,Cho, Eun Jung,Wang, Jianhong,Hayes, Jaclyn,Wang, Michael,Paul, Amber,Lansdon, Eric B.,Chen, James M.,Graupe, Doris,Rhodes, Gerry,He, Gong-Xin,Geleziunas, Romas,Xu, Lianhong,Kim, Choung U.
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scheme or table
p. 1589 - 1592
(2010/06/19)
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- Non-nucleoside HIV-1 reverse transcriptase inhibitors, part 7. Synthesis, antiviral activity, and 3D-QSAR investigations of novel 6-(1-naphthoyl) HEPT analogues
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A series of novel 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogues bearing a 6-(1-naphthoyl) group of non-nucleoside human immunodeficiency virus (HIV) reverse transcriptase inhibitors were synthesized and evaluated for their activity against HIV-1 and HIV-2. It was found that most of these compounds showed good activity against HIV-1. Among them, compound 5-isopropyl-6-(1-naphthoyl)-1-[(2E)-3-phenylallyl]-2,4-pyrimidinedione (23) displayed the greatest inhibitory potency (IC50=0.14 μM), which is about 35-fold more active than HEPT and DDI. To rationalize the relationships between structure and activity of these novel compounds, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was also generated. The results provided a tool for guiding the further design of more potent antiviral agents and for predicting the affinity of related compounds.
- Ji, Lei,Chen, Fen-Er,Feng, Xiao-Qing,De Clercq, Erik,Balzarini, Jan,Pannecouque, Christophe
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p. 1248 - 1253
(2008/09/20)
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- Synthesis of certain 6-(arylthio)uracils as potential antiviral agents
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A series of 6-(Arylthio)uracils have been prepared via condensation of 6-chlorouracil or 5-ethyl-6-chlorouracil with the corresponding thiopnenol derivatives in pyridine or ethanolic potassium hydroxide. The synthesized compounds were tested for their antiviral activity. Some of the 5-ethyl-6-(arylthio)uracil derivatives 10a-g showed moderate activities against hepatitis B Virus (HBV) and HIV-1 virus.
- El-Emam, Ali A.,Nasr, Magda N. A.,Pedersen, Erik B.,Fouad, Tarek,Nielsen, Claus
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- 5,6-Dihydropyrrolo[1,2-c]pyrimidine-1,3(2H,5H)-diones as annulated analogues of the anti-HIV compound MKC-442 (6-benzyl-1-(ethoxymethyl)-5-isopropyluracil)
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Annulated analogues of the anti-HIV compound MKC-442 were synthesized from 6-benzoyl-5-ethyl-2,4-dimethoxypyrimidine (4) by reaction with Zn/NH4Cl and 3-bromopropene. The intermediate homoallylic alcohol is subjected to a ring closure reaction by treatment with bromine either directly or after O-benzylation to give 5,6-dihydropyrrolo[1,2-c]pyrimidinones. No activity against HIV was observed, neither for the annulated analogues nor the derivatives synthesized from 4. Only compound 4 showed activity against HIV-1.
- Danel, Krzysztof,Pedersen, Erik B.,Nielsen, Claus
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p. 1021 - 1026
(2007/10/03)
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