- N-Hydroxyimides and hydroxypyrimidinones as inhibitors of the DNA repair complex ERCC1-XPF
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A high throughput screen allowed the identification of N-hydroxyimide inhibitors of ERCC1-XPF endonuclease activity with micromolar potency, but they showed undesirable selectivity profiles against FEN-1. A scaffold hop to a hydroxypyrimidinone template g
- Chapman, Timothy M.,Wallace, Claire,Gillen, Kevin J.,Bakrania, Preeti,Khurana, Puneet,Coombs, Peter J.,Fox, Simon,Bureau, Emilie A.,Brownlees, Janet,Melton, David W.,Saxty, Barbara
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Read Online
- Antitubercular 2-Pyrazolylpyrimidinones: Structure-Activity Relationship and Mode-of-Action Studies
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Phenotypic screening of a Medicines for Malaria Venture compound library against Mycobacterium tuberculosis (Mtb) identified a cluster of pan-active 2-pyrazolylpyrimidinones. The biology triage of these actives using various tool strains of Mtb suggested a novel mechanism of action. The compounds were bactericidal against replicating Mtb and retained potency against clinical isolates of Mtb. Although selected MmpL3 mutant strains of Mtb showed resistance to these compounds, there was no shift in the minimum inhibitory concentration (MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible resistance mechanism for the compounds but not necessarily as the target. RNA transcriptional profiling and the checkerboard board 2D-MIC assay in the presence of varying concentrations of ferrous salt indicated perturbation of the Fe-homeostasis by the compounds. Structure-activity relationship studies identified potent compounds with good physicochemical properties and in vitro microsomal metabolic stability with moderate selectivity over cytotoxicity against mammalian cell lines.
- Soares De Melo, Candice,Singh, Vinayak,Myrick, Alissa,Simelane, Sandile B.,Taylor, Dale,Brunschwig, Christel,Lawrence, Nina,Schnappinger, Dirk,Engelhart, Curtis A.,Kumar, Anuradha,Parish, Tanya,Su, Qin,Myers, Timothy G.,Boshoff, Helena I. M.,Barry, Clifton E.,Sirgel, Frederick A.,Van Helden, Paul D.,Buchanan, Kirsteen I.,Bayliss, Tracy,Green, Simon R.,Ray, Peter C.,Wyatt, Paul G.,Basarab, Gregory S.,Eyermann, Charles J.,Chibale, Kelly,Ghorpade, Sandeep R.
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supporting information
p. 719 - 740
(2021/02/03)
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- Synthesis of modified uracil and cytosine nucleobases using a microwave-assisted method
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Modified nucleobases and nucleic acids have found many biological and pharmaceutical applications. Here we report a microwave-directed synthesis of a variety of modified uracil and cytosine nucleobases with high yields under solvent-free conditions. The reaction yields were further improved by addition of Lewis acid. The crystal structures of 5-isopropyl-6-methyluracil and 6-phenyluracil were also determined.
- Burgula, Laxmi Narayana,Radhakrishnan,Kundu, Lal Mohan
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supporting information; experimental part
p. 2639 - 2642
(2012/06/30)
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- Regioselective direct C-H arylations of protected uracils. Synthesis of 5- and 6-aryluracil bases
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A new regioselective synthesis of 5- and 6-aryluracil bases based on direct C-H arylations of diverse 1,3-protected uracils has been developed. Benzyl-protected uracils were selected as the most practical in terms of stability during the arylation and fac
- Cernova, Miroslava,Cerna, Igor,Pohl, Radek,Hocek, Michal
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experimental part
p. 5309 - 5319
(2011/08/05)
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- Microwave assisted one-pot synthesis of nitrogen and oxygen containing heterocycles from acyl Meldrum's acid
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One-pot syntheses of biologically active nitrogen and oxygen containing heterocyclic compounds such as uracils and thiouracils and 1,4-benzothiazines, 4-methylcoumarins and 4H-1,4- dihydropyridines, using acyl Meldrum's acids are reported.
- More,Mahulikar
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experimental part
p. 745 - 747
(2011/06/27)
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- NOVEL SEH INHIBITORS AND THEIR USE
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The invention is directed to novel sEH inhibitors and their use in the treatment of diseases mediated by the sEH enzyme. Specifically, the invention is directed to compounds according to Formula (I): wherein R1, R2, R3, R5a, R6a, A, B, K, L, M, Y, Z, x, a
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Page/Page column 34
(2009/09/05)
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- NOVEL PYRIMIDINE COMPOUNDS, PROCESS FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM
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The present invention provides new heterocyclic compounds, particularly substituted pyrimidines, methods and compositions for making and using these heterocyclic compounds, and methods for treating a variety of diseases and disease states, including atherosclerosis, arthritis, restenosis, diabetic nephropathy, or dyslipidemia, or disease states mediated by the low expression of Perlecan.
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Page/Page column 219
(2008/06/13)
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- Aryl and heterocyclyl substituted pyrimidine derivatives as anti-coagulants
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This invention is directed to aryl and heterocyclyl substituted pyrimidine derivatives selected from the following formulae: wherein Z1, Z2, R1, R2, R3, R4, R5and R6are defined herein. These compounds are useful as anti-coagulants.
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- Microwave promoted efficient synthesis of substituted uracils and thiouracils under solvent-free conditions
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Several substituted uracils and thiouracils were synthesized in good yields by one-pot condensation reaction of methyl or ethyl β-ketoesters and urea (or thiourea) in solvent-free conditions under microwave irradiation and in short time.
- Mojtahedi, Mohammad M.,Saidi, Mohammad R.,Shirzi, Jafar S.,Bolourtchian, Mohammad
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p. 851 - 855
(2007/10/03)
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- New procedures for the synthesis of heterocyclic substituted and 2,4-difunctionalized pyrimidines
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N-Tosyl-2-and -3-acetylpyrrols 1 or N-tosyl-2-pyrrolidone 5 were condensed with cyano compounds in the presence of triflic anhydride (Tf2O) to yield heteroarylpyrimidines. 2,4-Difunctionalized pyrimidines were obtained by reaction of the corresponding 2,4-bis(methylsulfonyl)pyrimidines with nucleophiles.
- Garcia Martinez, Antonio,Herrera Fernandez, Antonio,Moreno Jimenez, Florencio,Munoz Martinez, Pablo J.,Alonso Martin, Cristina,Subramanian, Laksminarayanapuran R.
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p. 7973 - 7982
(2007/10/03)
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