56741-94-7Relevant articles and documents
An efficient microwave assisted synthesis of N′-aryl/(alkyl)-substituted N-(4-hydroxy-6-phenylpyrimidin-2-yl)guanidines: Scope and limitations
Machicao, Paulo A.,Burt, Scott R.,Christensen, Ryan K.,Lohner, Nathan B.,Singleton,Peterson, Matt A.
, p. 2318 - 2321 (2017)
Treatment of N-[(4-hydroxy-6-phenyl)pyrimidin-2-yl]cyanamide with 1° alkyl or arylamines in isopropyl alcohol for only 10?min at 110–120?°C under microwave conditions gave the corresponding N′-alkyl(aryl)guanidine derivatives in excellent yields (65–84%). Isolated yields were greatest when >1.0?equiv. of amines were employed, but excellent results were also obtained when aryl and alkylamines were reacted with a more atom-economical loading (1.0?equiv.; 70% and 72% ave. yields, respectively). Arylamines with either highly electron withdrawing substituents (e.g. CO2H) or pi-deficient heterocycles (e.g. variously substituted aminopyridines) did not work well under these conditions, and reaction with ureas and/or amino acids did not give detectable products. Work-up was exceedingly simple, and involved simple collection and washing of product on a sintered glass funnel. Products were obtained in analytically pure form and required approximately 1?h to prepare, start to finish.
High-Performance Liquid Chromatographic Determination of 5-Halopyrimidinone Interferon Inducers
Wynalda, M. A.,Fitzpatrick, F. A.
, p. 1931 - 1934 (1980)
High-performance liquid chromatography with microparticulate, bonded, reversed-phase columns separates closely related 5-halopyrimidinones that are interferon inducers.A method was developed to a quantitate serum levels of 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone, an important analogue of this new series.The method is, with minor modifications, suitable to measure other 5-halophenylpyrimidinone analoques.Results show that the quantitation of serum levels as low as 2 μg mL-1 is possible with ultraviolet detection at 235 nm.Protein precipitation and extraction prior to chromatography improve the daily sample throughput by removing interfering peaks with capacity factors greater than 45.Preliminary results indicate a species-dependent variation in the half-lives of elimination of the free compound after its administration, orally, to experimental animals.Rats clear the drug with a half-life of 4.5 h; cats clear the drug with half-lives ranging from 10 to 18 h depending on the dose administered.The differences in metabolic clearance may be relevant to observed toxicity differences between these species.
Screening of focused compound library targeting liver X receptors in pancreatic cancer identified ligands with inverse agonist and degrader activity
Karaboga, Husna,Huang, Wentao,Srivastava, Shivangi,Widmann, Scott,Addanki, Sridevi,Gamage, Kasuni Thawalama,Mazhar, Zahra,Ebalunode, Jerry O.,Briggs, James M.,Gustafsson, Jan-?ke,Filgueira, Carly S.,Gilbertson, Scott R.,Lin, Chin-Yo
, p. 2916 - 2928 (2020/11/18)
Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer. PDACs harbor oncogenic mutations in the KRAS gene, and ongoing efforts to directly target its mutant protein product to inhibit tumor growth are a priority not only in pancreatic cancer but in other malignancies such as lung and colorectal cancers where KRAS is also commonly mutated. An alternative strategy to directly targeting KRAS is to identify and target druggable receptors involved in dysregulated cancer hallmarks downstream of KRAS dysregulation. Liver X receptors (LXRs) are members of the nuclear receptor family of ligand-modulated transcription factors and are involved in the regulation of genes which function in key cancer-related processes, including cholesterol transport, lipid and glucose metabolism, and inflammatory and immune responses. Modulation of LXRs via small molecule ligands has emerged as a promising approach for directly targeting tumor cells or the stromal and immune cells within the tumor microenvironment. We have previously shown that only one of the two LXR subtypes (LXRβ) is expressed in pancreatic cancer cells, and targeting LXR with available synthetic ligands blocked the proliferation of PDAC cells and tumor formation. In a screen of a focused library of drug-like small molecules predicted to dock in the ligand-binding pocket of LXRβ, we identified two novel LXR ligands with more potent antitumor activity than current LXR agonists used in our published studies. Characterization of the two lead compounds (GAC0001E5 and GAC0003A4) indicates that they function as LXR inverse agonists which inhibit their transcriptional activity. Prolonged treatments with novel ligands further revealed their function as LXR “degraders” which significantly reduced LXR protein levels in all three PDAC cell lines tested. These findings support the utility of these novel inhibitors in basic research on ligand design, allosteric mechanisms, and LXR functions and their potential application as treatments for advanced pancreatic cancer and other recalcitrant malignancies.
Controlling Keto-Enol Tautomerism of Ureidopyrimidinone to Generate a Single-Quadruple AADD-DDAA Dimeric Array
Ding, Qinwen,Dong, Zeyuan,Fan, Zengming,Mao, Shizhong,Qi, Shuaiwei,Zhang, Chenyang,Zhang, Jing
supporting information, p. 7305 - 7309 (2020/10/05)
Units of ureidopyrimidinone (UPy) which dimerize via strong quadruple hydrogen bonding are widely used for the construction of supramolecular systems. This self-complementary system exists in the tautomerism equilibrium of 4[1H]-pyrimidinone dimer and pyrimidin-4-ol dimer, making generated supramolecular assembly systems essentially complicated. In this contribution, a rational but simple design concept is described for preorganizing the self-complementary quadruple hydrogen bonding of UPy via supramolecular strategy into a single-quadruple DDAA-AADD dimeric array. With this concept, the designed UPy derivatives form only 4[1H]-pyrimidinone dimer with a ketone configuration via intermolecular hydrogen-bonding interactions, both in the solid state as well as in solution, as is evident from single-crystal X-ray diffraction and 1H NMR spectroscopy. The single DDAA-AADD dimeric array provides defined noncovalent driving forces that can be used to generate constitutionally clear supramolecular structures that are vitally important in the fields of supramolecular chemistry and materials.
Synthesis and Investigation of Phthalazinones as Antitubercular Agents
Santoso, Kristiana T.,Cheung, Chen-Yi,Hards, Kiel,Cook, Gregory M.,Stocker, Bridget L.,Timmer, Mattie S. M.
supporting information, p. 1278 - 1285 (2019/02/24)
A series of 2- and 7-substituted phthalazinones was synthesised and their potential as anti-tubercular drugs assessed via Mycobacterium tuberculosis (mc26230) growth inhibition assays. All phthalazinones tested showed growth inhibitory activity (MIC 100 μm), and those compounds containing lipophilic and electron-withdrawing groups generally exhibited better anti-tubercular activity. Several lead compounds were identified, including 7-((2-amino-6-(4-fluorophenyl)pyrimidin-4-yl)amino)-2-heptylphthalazin-1(2H)-one (MIC=1.6 μm), 4-tertbutylphthalazin-2(1H)-one (MIC=3 μm), and 7-nitro-phthalazin-1(2H)-one (MIC=3 μm). Mode of action studies indicated that selected pyrimidinyl-phthalazinones may interfere with NADH oxidation, however, the mode of action of the lead compound is independent of this enzyme. MIC=minimum inhibitory concentration.
Synthesis of 6-arylisocytosines and their potential for hydrogen bonding interactions
Patel, Alpa,Lewis, William,Searle, Mark S.,Stevens, Malcolm F.G.,Moody, Christopher J.
supporting information, p. 7339 - 7343 (2015/08/24)
Abstract The synthesis of a number of 6-arylisocytosines, including linked bis-isocytosines, from the reaction of guanidine with β-ketoesters is described. The compounds were investigated for their ability to form hydrogen-bonded structural networks, and for their potential interactions with the telomeric quadruplex forming sequence AGGG(TTAGGG)3.
HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase
Even?s, Johan,Edfeldt, Fredrik,Lepist?, Matti,Svitacheva, Naila,Synnergren, Anna,Lundquist, Britta,Gr?nse, Mia,R?nnholm, Anna,Varga, Mikael,Wright, John,Wei, Min,Yue, Sherrie,Wang, Junfeng,Li, Chong,Li, Xuan,Chen, Gang,Liao, Yong,Lv, Gang,Tj?rnebo, Ann,Narjes, Frank
, p. 1315 - 1321 (2014/03/21)
The identification of novel, non-purine based inhibitors of xanthine oxidase is described. After a high-throughput screening campaign, an NMR based counterscreen was used to distinguish actives, which interact with XO in a reversible manner, from assay artefacts. This approach identified pyrimidone 1 as a reversible and competitive inhibitor with good lead-like properties. A hit to lead campaign gave compound 41, a nanomolar inhibitor of hXO with efficacy in the hyperuricemic rat model after oral dosing.
Direct synthesis of 5- and 6-substituted 2-aminopyrimidines as potential non-natural nucleobase analogues
Radhakrishnan,Sharma, Namita,Kundu, Lal Mohan
, p. 15087 - 15090 (2014/04/17)
A series of 2-aminopyrimidine derivatives, substituted at 5- and 6-positions, were synthesized. The reaction was carried out in a single step by treatment of the corresponding β-ketoester or β-aldehydoester with guanidine hydrochloride in the presence of K2CO3, in a microwave-assisted method without the requirement of solvent. A unique 1:1 co-crystal structure was obtained which shows that a 6-phenyl-2- aminopyrimidinone forms a strong nucleobase-pair with cytosine, involving three hydrogen bonds. The base-pair was found to be as strong as that of natural guanine:cytosine (G:C), signifying the potential application of the synthesized derivatives. Additionally, we also report a second co-crystal involving 5-isopropyl-6-methyl-2-aminopyrimidinone and cytosine in a 1:1 ratio, which also shows strong base-pairing properties. the Partner Organisations 2014.
Quinolinyl pyrimidines: Potent inhibitors of NDH-2 as a novel class of anti-TB agents
Shirude, Pravin S.,Paul, Beena,Roy Choudhury, Nilanjana,Kedari, Chaitanya,Bandodkar, Balachandra,Ugarkar, Bheemarao G.
supporting information, p. 736 - 740 (2012/10/29)
NDH-2 is an essential respiratory enzyme in Mycobacterium tuberculosis (Mtb), which plays an important role in the physiology of Mtb. Herein, we present a target-based effort to identify a new structural class of inhibitors for NDH-2. High-throughput screening of the AstraZeneca corporate collection resulted in the identification of quinolinyl pyrimidines as the most promising class of NDH-2 inhibitors. Structure-activity relationship studies showed improved enzyme inhibition (IC50) against the NDH-2 target, which in turn translated into cellular activity against Mtb. Thus, the compounds in this class show a good correlation between enzyme inhibition and cellular potency. Furthermore, early ADME profiling of the best compounds showed promising results and highlighted the quinolinyl pyrimidine class as a potential lead for further development.
Identification of an anti-MRSA dihydrofolate reductase inhibitor from a diversity-oriented synthesis
Wyatt, Emma E.,Galloway, Warren R. J. D.,Thomas, Gemma L.,Welch, Martin,Loiseleur, Olivier,Plowright, Alleyn T.,Spring, David R.
supporting information; experimental part, p. 4962 - 4964 (2009/06/06)
The screening of a diversity-oriented synthesis library followed by structure-activity relationship investigations have led to the discovery of an anti-MRSA agent which operates as an inhibitor of Staphylococcus aureus dihydrofolate reductase. The Royal Society of Chemistry.
