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Molecules (Basel, Switzerland) Sep 2022To search for Zika virus (ZIKV) antivirals, we have further explored previously reported 7-pyrrolo[2,3-]pyrimidines by examining an alternative substitution pattern of...
To search for Zika virus (ZIKV) antivirals, we have further explored previously reported 7-pyrrolo[2,3-]pyrimidines by examining an alternative substitution pattern of their central scaffold, leading to compound with low micromolar antiviral activity. To circumvent the synthetic difficulties associated with compound , we have exploited a 1-pyrazolo[3,4-]pyrimidine scaffold and performed structure-activity relationship studies on its peripheral rings A and B. While ring B is less sensitive to structural modifications, an electron-withdrawing group at the para position of ring A is preferred for enhanced antiviral activity. Overall, we have not only discovered an alternative substitution pattern centered on a 1-pyrazolo[3,4-]pyrimidine scaffold but also generated anti-ZIKV compounds including and , which possess low micromolar antiviral activity and relatively low cytotoxicity. These compounds represent new chemotypes that will be further optimized in our continued efforts to discover anti-ZIKV agents.
Topics: Amines; Antiviral Agents; Humans; Pyrimidines; Zika Virus; Zika Virus Infection
PubMed: 36144841
DOI: 10.3390/molecules27186109 -
Molecules (Basel, Switzerland) Jun 2011Novel N-methoxymethylated (MOM) pyrimidine (4-13) and pyrimidine-2,4-diones (15-17) nucleoside mimetics in which an isobutyl side-chain is attached at the C-6 position...
Novel N-methoxymethylated (MOM) pyrimidine (4-13) and pyrimidine-2,4-diones (15-17) nucleoside mimetics in which an isobutyl side-chain is attached at the C-6 position of the pyrimidine moiety were synthesized. Synthetic methods via O-persilylated or N-anionic uracil derivatives have been evaluated for the synthesis of N-1- and/or N-3-MOM pyrimidine derivatives with C-6 acyclic side-chains. A synthetic approach using an activated N-anionic pyrimidine derivative afforded the desired N,N-1,3-diMOM and N-1-MOM pyrimidines 4 and 5 in good yield. Introduction of fluorine into the side-chain was performed with DAST as the fluorinating reagent to give a N,N-1,3-diMOM pyrimidine 13 with a 1-fluoro-3-hydroxyisobutyl moiety at C-6. Conformational study of the monotritylated N-1-MOM pyrimidine 12 by the use of the NOE experiments revealed the predominant conformation of the compound to be one where the hydroxymethyl group in the C-6 side-chain is close to the N-1-MOM moiety, while the OMTr is in proximity to the CH(3)-5 group. Contrary to this no NOE enhancements between the N-1-MOM group and hydroxymethyl or fluoromethyl protons in 13 were observed, which suggested a nonrestricted rotation along the C-6 side-chain. Fluorinated N,N-1,3-diMOM pyrimidine 13 emerged as a model compound for development of tracer molecules for non-invasive imaging of gene expression using positron emission tomography (PET).
Topics: Carbon; Nitrogen; Pyrimidines
PubMed: 21694675
DOI: 10.3390/molecules16065113 -
Journal of Bacteriology Nov 1964Baugh, C. L. (Fort Detrick, Frederick, Md.), A. W. Andrews, and M. J. Surgalla. Effects of bicarbonate on growth of Pasteurella pestis. III. Replacement of bicarbonate...
Baugh, C. L. (Fort Detrick, Frederick, Md.), A. W. Andrews, and M. J. Surgalla. Effects of bicarbonate on growth of Pasteurella pestis. III. Replacement of bicarbonate by pyrimidines. J. Bacteriol. 88:1394-1398. 1964.-The effect of carbon dioxide on the growth of virulent Pasteurella pestis cultures at 37 C with aeration was studied by substituting known products of carbon dioxide fixation for bicarbonate in the test system. The growth of the virulent cells in the inoculum is stimulated and the culture remains virulent, if bicarbonate is replaced by orotic acid. The addition of cytosine, uracil, or citrulline also results in the retention of virulence, but the effect on the growth of the virulent cells is not as pronounced as with bicarbonate or orotic acid. It is proposed that an impaired pyrimidine synthesis due to a deficiency in carbomyl phosphate is responsible for the loss of virulence by P. pestis in aerated broth cultures at 37 C. The carbamyl phosphate deficiency may be enhanced by the loss of metabolically produced carbon dioxide at 37 C.
Topics: Arginine; Bicarbonates; Carbamates; Carbon Dioxide; Citrulline; Culture Media; Cytosine; Metabolism; Orotic Acid; Pharmacology; Phosphates; Pyrimidines; Research; Uracil; Yersinia pestis
PubMed: 14234798
DOI: 10.1128/jb.88.5.1394-1398.1964 -
Bioorganic & Medicinal Chemistry Jan 2017Janus kinases inhibitor is considered to have therapeutic potential for the treatment of oncology and immune-inflammatory diseases. Two series of...
Janus kinases inhibitor is considered to have therapeutic potential for the treatment of oncology and immune-inflammatory diseases. Two series of 4-(2-benzofuranyl)pyrimidin-2-amine and 4-(4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl)pyrimidin-2-amine derivatives have been designed and synthesized. Primary SAR studies resulted in the discovery of a novel class of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine based JAK2 inhibitors with higher potency (IC of 0.7nM) and selectivity (>30 fold) to JAK3 kinase than tofacitinib.
Topics: Amines; Cell Line; Humans; Janus Kinase 2; Janus Kinase 3; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles
PubMed: 27771180
DOI: 10.1016/j.bmc.2016.10.011 -
The Journal of Chemical Physics Oct 2008The C 1s and N 1s Auger spectra of pyrimidine, 2-chloropyrimidine, and 5-bromopyrimidine have been measured in an electron impact experiment at 1000 eV. In the case of...
The C 1s and N 1s Auger spectra of pyrimidine, 2-chloropyrimidine, and 5-bromopyrimidine have been measured in an electron impact experiment at 1000 eV. In the case of the halogen-substituted pyrimidines, also the Cl 2p and Br 3d Auger spectra have been recorded. We have thoroughly analyzed and interpreted all the Auger spectra recorded here with the aid of accurate Green's function calculations with a large basis set. The spectra are extremely complex with thousands of states contributing and almost no single-state feature even near the double ionization threshold. Besides reproducing and explaining with great detail nearly all the main spectral features observed, the calculations have successfully unraveled the interplay among the different C 1s core hole chemical shifts in each molecule and how this affects some fingerprinting details in the composite C 1s Auger spectra.
Topics: Carbon; Halogenation; Nitrogen; Pyrimidines; Spectrum Analysis
PubMed: 19045195
DOI: 10.1063/1.2993317 -
Plant Science : An International... Aug 2018Thiamin is essential for plant growth but is short-lived in vivo and energetically very costly to produce - a combination that makes thiamin biosynthesis a prime target...
Thiamin is essential for plant growth but is short-lived in vivo and energetically very costly to produce - a combination that makes thiamin biosynthesis a prime target for improvement by redesign. Thiamin consists of thiazole and pyrimidine moieties. Its high biosynthetic cost stems from use of the suicide enzyme THI4 to form the thiazole and the near-suicide enzyme THIC to form the pyrimidine. These energetic costs lower biomass yield potential and are likely compounded by environmental stresses that destroy thiamin and hence increase the rate at which it must be made. The energy costs could be slashed by refactoring the thiamin biosynthesis pathway to eliminate the suicidal THI4 and THIC reactions. To substantiate this design concept, we first document the energetic costs of the THI4 and THIC steps in the pathway and explain how cutting these costs could substantially increase crop biomass and grain yields. We then show that a refactored pathway must produce thiamin itself rather than a stripped-down analog because the thiamin molecule cannot be simplified without losing biological activity. Lastly, we consider possible energy-efficient alternatives to the inefficient natural THI4- and THIC-mediated steps.
Topics: Metabolic Engineering; Metabolic Networks and Pathways; Oxygen; Plants; Pyrimidines; Synthetic Biology; Thiamine; Thiazoles
PubMed: 29907313
DOI: 10.1016/j.plantsci.2018.01.019 -
Current Topics in Medicinal Chemistry 2023Pyrazolo[1,5-a]pyrimidines are fused heterocycles that have spawned many biologically active antitumor drugs and are important privileged structures for drug...
Pyrazolo[1,5-a]pyrimidines are fused heterocycles that have spawned many biologically active antitumor drugs and are important privileged structures for drug development. Pyrazolo[1,5- a]pyrimidine derivatives have played an important role in the development of antitumor agents due to their structural diversity and good kinase inhibitory activity. In addition to their applications in traditional drug targets such as B-Raf, KDR, Lck, and Src kinase, some small molecule drugs with excellent activity against other kinases (Aurora, Trk, PI3K-γ, FLT-3, C-Met kinases, STING, TRPC) have emerged in recent years. Therefore, based on these antitumor drug targets, small molecule inhibitors containing pyrazolo[1,5-a]pyrimidine scaffold and their structure-activity relationships are summarized and discussed to provide more reference value for the application of this particular structure in antitumor drugs.
Topics: Antineoplastic Agents; Structure-Activity Relationship; Pyrimidines; Molecular Structure; Protein Kinase Inhibitors; Drug Screening Assays, Antitumor
PubMed: 36852801
DOI: 10.2174/1568026623666230228111629 -
Bioorganic & Medicinal Chemistry Letters Nov 2021In order to find efficient new antitumor drugs, a series of novel trifluoromethyl-substituted pyrimidine derivatives were designed and synthesized, and the bioactivity...
In order to find efficient new antitumor drugs, a series of novel trifluoromethyl-substituted pyrimidine derivatives were designed and synthesized, and the bioactivity against four human tumor cells (PC-3, MGC-803, MCF-7 and H1975) was evaluated by MTT assay. Compound 17v displayed potent anti-proliferative activity on H1975 (IC = 2.27 μΜ), which was better than the positive control 5-FU (IC = 9.37 μΜ). Further biological evaluation studies showed that compound 17v induced apoptosis of H1975 cells and arrested the cell cycle at G2/M phase. Furthermore, compound 17v induced H1975 cells apoptosis through increasing the expression of pro-apoptotic proteins Bax and p53 and down-regulating the anti-apoptotic protein Bcl-2. In addition, compound 17v was able to be tightly embedded in the active pocket of EGFR. In summary, these results demonstrated that compound 17v has a potential as a lead compound for further investigation.
Topics: Antineoplastic Agents; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Molecular Structure; Pyrimidines; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 34302974
DOI: 10.1016/j.bmcl.2021.128268 -
Journal of Combinatorial Chemistry Nov 2010
Topics: Combinatorial Chemistry Techniques; Molecular Structure; Pyrazoles; Pyrimidines; Small Molecule Libraries
PubMed: 20804211
DOI: 10.1021/cc1001204 -
Bioorganic & Medicinal Chemistry Feb 2011Syntheses of a series of novel 3-sulfonyl-pyrazolo[1,5-a]pyrimidines and their 5-HT(6) receptor antagonistic structure-activity relationship are disclosed. The nature...
Syntheses of a series of novel 3-sulfonyl-pyrazolo[1,5-a]pyrimidines and their 5-HT(6) receptor antagonistic structure-activity relationship are disclosed. The nature and position of substituents, which affect their receptor antagonistic activity, are analyzed. Among all synthesized derivatives, {3-(3-chlorophenylsulfonyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl}-methyl-amine 33 (K(i)=190 pM), (3-phenylsulfonyl-7-methyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 44 (K(i)=240 pM), (3-phenylsulfonyl-5-metoxymethyl-7-methyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 50 (K(i)=270 pM), and (3-phenylsulfonyl-5-methyl-7-metoxymethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 52 (K(i)=280 pM) are the most potent antagonists of the 5-HT(6) receptors.
Topics: Cell Line; Heterocyclic Compounds, 3-Ring; Humans; Models, Molecular; Molecular Structure; Pyrazoles; Pyrimidines; Receptors, Serotonin; Serotonin Antagonists; Structure-Activity Relationship; Sulfur Compounds
PubMed: 21277782
DOI: 10.1016/j.bmc.2010.12.055