- An improved synthesis of pyrido[2,3-: D] pyrimidin-4(1 H)-ones and their antimicrobial activity
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The screening of a small library of diverse chemical structures resulted in the identification of 2-thioxodihydropyrido[2,3-d]pyrimidine 10a as having broad spectrum antibacterial activity (MIC 0.49-3.9 μg mL-1), and reasonable antifungal activity (MIC 31.25 μg mL-1). An expeditious synthesis of 10a was optimized by varying solvents, catalysts and the use of microwave irradiation with the best conditions using DMF as a solvent, I2 (10 mol%) and a 30 minutes reaction time compared to 15 h for classic conventional heating. The pharmacokinetic properties and calculation of drug likeness of 10a suggested good traditional drug-like properties and led to the synthesis of a small library with seven compounds 10a and 10d-i showing broad antimicrobial activity (MIC = 0.49-7.81 μg mL-1) and selectivity indices of more than 5.6 against the normal colon cell line (CCD-33Co). The antifungal activity of compounds 10d-i was moderate to strong with MIC values of 1.95-15.63 μg mL-1.
- Fares, Mohamed,Abd El Hadi, Soha R.,Eladwy, Radwa A.,Shoun, Aly A.,Abdel-Aziz, Marwa M.,Eldehna, Wagdy M.,Abdel-Aziz, Hatem A.,Keller, Paul A.
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Read Online
- [γ-Fe2O3@HAp-SO3H] an efficient nanocatalyst for the synthesis of highly functionalised 2-thioxopyrido[2,3-d]pyrimidines
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HAp(hydroxyapatite)-encapsulated-γ-Fe2O3 supported sulfonic acid nanoparticles were used for the preparation of two series of 2-thioxopyrido[2,3-d]pyrimidines. In the first series, 2-thioxopyrido[2,3-d]pyrimidines were synthesised fr
- Mamaghani, Manouchehr,Taati, Zahra,Rasoulian, Mona,Yousefizad, Javad,Toraji, Nooshin,Mohsenimehr, Mona,Nia, Roghayeh Hossein
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- Anticancer evaluation and molecular modeling of multi-targeted kinase inhibitors based pyrido[2,3-d]pyrimidine scaffold
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An efficient synthesis of substituted pyrido[2,3-d]pyrimidines was carried out and evaluated for in vitro anticancer activity against five cancer cell lines, namely hepatic cancer (HepG-2), prostate cancer (PC-3), colon cancer (HCT-116), breast cancer (MC
- Elzahabi, Heba S. A.,Nossier, Eman S.,Alasfoury, Rania A.,Khalifa, Nagy M.,El-Manawaty, May A.
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Read Online
- Convenient synthesis and molecular docking of novel pyrido [2,3-d] pyrimidines as potent antimicrobial candidates
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New 3-(3,4-dimethoxyphenyl)-1-(thiophen-2-yl) prop-2-en-1-one has been designed as a starting compound to synthesis a novel series of substituted pyrido[2,3-d]pyrimidine system incorporated to different Schiff's bases and enamine derivatives as potent ant
- Mohamed, Hanaa S.,Nofal, Zeinab M.,Saleh, Abdulrahman M.,Sarhan, Alaadin E.
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p. 399 - 411
(2021/12/17)
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- Preparation method of prodrug intermediate of thymidine phosphorylase inhibitor
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The invention relates to the field of preparation of prodrug intermediates of thymidine phosphorylase inhibitors, and discloses a preparation method of a prodrug intermediate of a thymidine phosphorylase inhibitor. The method comprises the following steps: (1) adding ethyl cyanoacetate into a mixed alcoholic-alkaline solution of thiourea, carrying out reflux reaction for 5-6 hours, performing cooling, crystallizing, filtering, and washing with an ethanol/dioxane mixed solution; (2) mixing pyridine with ammonia water, adding Raney nickel, ZnSO4 and the product obtained in the step (1), heating and reacting at 65-75 DEG C for 7-8 hours, performing filtering while the product is hot, and performing cooling and crystallizing, filtering and washing; and (3) adding the product obtained in the step (2) into a mixed alkali solution, slowly adding 2-bromoacetaldehyde at 45-55 DEG C, reacting for 4-5 hours, and performing cooling, crystallizing, filtering, washing and drying. According to the preparation method disclosed by the invention, the total yield of the prodrug intermediate 4-hydroxypyrrolo[2, 3-d] pyrimidine of the thymidine phosphorylase inhibitor is improved.
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Paragraph 0041; 0043-0044; 0049-0052; 0057-0060; 0065-0068
(2021/04/14)
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- Production process 4 -chloropyrrolo [2, 3 - d] pyrimidine
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The production process of 4 - chloropyrrolo [2, 3 - d] pyrimidine comprises the following steps: S1, adding the compound I and the compound II to the mixed solvent I, carrying out temperature rise reaction under the catalysis of the base I to obtain the compound III. S2, sodium alkoxide I was added to alcoholic solvent II, compound IV and compound III were added to raise the temperature, and organic solvent III, organic solvent IV and compound V were added to raise the temperature to give 4 - chloropyrrolo [2, 3 - d] pyrimidine crude product. Among them, compound I is. . Compound II was obtained. . Compound III was obtained. . The compound IV is formamidine. Compound V was POCl. 3 To the method, bromoacetaldehyde dimethyl acetal and cyanoethyl acetate are subjected to reflux reaction, and 2 - cyano -4, 4 - methoxybutyric acid ethyl ester and formamidine acetate are subjected to one-pot chlorofluorination reaction, so that the reaction period is greatly shortened.
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Paragraph 0108-0110
(2021/10/27)
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- Discovery and evaluation of new compounds targeting ribosomal protein S1 in antibiotic-resistant Mycobacterium Tuberculosis
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The emergence of antibiotic-resistant Mycobacterium Tuberculosis (Mtb) infections compels new treatment strategies, of which targeting trans-translation is promising. During the trans-translation process, the ribosomal protein S1 (RpsA) plays a key role, and the Ala438 mutant is related to pyrazinamide (PZA) resistance, which shows its effects after being hydrolysed to pyrazinoic acid (POA). In this study, based on the structure of the RpsA C-terminal domain (RpsA-CTD) and POA complex, new compounds were designed. After being synthesized, the compounds were tested in vitro with saturation transfer difference (STD), fluorescence quenching titration (FQT) and chemical shift perturbation (CSP) experiments. Finally, six of the 17 new compounds have high affinity for both RpsA-CTD and its Ala438 deletion mutant. The active compounds provide new choices for targeting trans-translation in Mtb, and the analysis of the structure-activity relationships will be helpful for further structural modifications based on derivatives of 2-((hypoxanthine-2-yl)thio)acetic acid and 2-((5-hydroxylflavone-7-yl)oxy)acetamide.
- Dai, Yazhuang,Guo, Chenyun,Lin, Donghai,Lin, Kejiang,Xu, Yinqiu,Xue, Xiaowen
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- PB-10, a thiazolo[4,5-d] pyrimidine derivative, targets p21-activated kinase 4 in human colorectal cancer cells
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Targeting p21-activated kinase 4 (PAK4) is a potential therapeutic strategy against human colorectal cancer (CRC). In this study, we synthesized a series of novel thiazolo[4,5-d]pyrimidine derivatives (PB-1–12) and identified PB-10 (PAK4 IC50 = 15.12 μM) as a potential and potent PAK4 inhibitor. Our results showed that PB-10 significantly suppressed the proliferation and colony formation of human CRC cells. PB-10 also arrested HCT-116 CRC cells at sub G0/G1 phase while promoting the expression of proapoptotic proteins. In addition, PB-10 inhibited migration, invasion, and adhesion as well as the PAK4 downstream signaling pathway in HCT-116 cells. Molecular docking analysis showed possible binding modes between PB-10 and PAK4. Our study provides a novel compound that may block the PAK4 signaling in CRC cells.
- Li, Ruijuan,Wang, Hanxun,Wang, Jian,Cheng, Maosheng
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- Pyrimidinone derivative, preparation method thereof and application thereof in resisting mycobacterium tuberculosis infection
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The invention discloses a pyrimidinone derivative, a preparation method thereof and an application thereof in resisting mycobacterium tuberculosis infection. The structure of the pyrimidinone derivative is shown as a formula I, wherein R1, m, X, Y, Z, R2
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Paragraph 0148-0150
(2020/11/25)
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- Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and PDGFR-β related to anticancer drug resistance
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With ongoing resistance problems against the marketed EGFR inhibitors having a quinazoline core scaffold there is a need for the development of novel inhibitors having a modified scaffold and, thus, expected lower EGFR resistance problems. An additional problem concerning EGFR inhibitor resistance is an observed heterodimerization of EGFR with PDGFR-β that neutralises the sole inhibitor activity towards EGFR. We developed novel pyrimido[4,5-b]indoles with varied substitution patterns at the 4-anilino residue to evaluate their EGFR and PDGFR-β inhibiting properties. We identified dual inhibitors of both EGFR and PDGFR-β in the nanomolar range which have been initially screened in cancer cell lines to prove a benefit of both EGFR and PDGFR-β inhibition.
- Fischer, Tim,Najjar, Karim,Totzke, Frank,Sch?chtele, Christoph,Sippl, Wolfgang,Ritter, Christoph,Hilgeroth, Andreas
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- Synthesis, experimental and computational studies of N-(4-amino-6-oxo-1,6-dihydropyrimidin-5-yl)benzamide
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Background: Blockade of kainate receptors is an emerging strategy to treat neurodegenera-tive diseases, including Parkinson’s disease as well as to treat epilepsy. In particular, non-competitive antagonists of kainate receptors are promising due to the expected good safety profile. We present here synthesis, experimental and computational studies of N-(4-amino-6-oxo-1,6-dihydropyrimidin-5-yl)benzamide which is an intermediate in the synthesis of hypoxanthine derivatives which were designed as non-competitive antagonists of kainate GluK1/GluK2 receptors. Method: The title compound was obtained in a five-step synthesis protocol and characterized used X-ray crystallography and experimental and computed spectra. Results: The presented detailed X-ray studies of the title compound confirm the reaction course. The title compound crystallizes in triclinic P-1 space group. The asymmetric unit comprises two independent molecules of the compound (A and B) and a DMF solvent molecule. The interpretation of IR spectra was facilitated by Potential Energy Distribution (PED) analysis. The low value of HOMO-LUMO gap indicates that the studied compound is relatively reactive. Conclusion: The title compound is a well-characterized intermediate which will be subjected to cycli-zation to hypoxanthine derivative designed as non-competitive antagonist of kainate GluK1 and GluK2 receptors.
- Kaczor, Agnieszka A.,Bartyzel, Agata,Pitucha, Monika,Wróbel, Tomasz M.,Wo?niak, Sylwia,Matosiuk, Dariusz
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p. 491 - 502
(2019/05/01)
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- Structural-based design, synthesis, and antitumor activity of novel alloxazine analogues with potential selective kinase inhibition
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Protein kinases are promising therapeutic targets for cancer therapy. Here, we applied multiple approaches to optimize the potency and selectivity of our reported alloxazine scaffold. Flexible moieties at position 2 of the hetero-tricyclic system were inc
- Malki, Waleed H.,Gouda, Ahmed M.,Ali, Hamdy E.A.,Al-Rousan, Rabaa,Samaha, Doaa,Abdalla, Ashraf N.,Bustamante, Juan,Abd Elmageed, Zakaria Y.,Ali, Hamed I.
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- Design, synthesis and biological evaluation of pyrido[2,3-d] pyrimidine derivatives as potential anticancer agents
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Background: CDK2 shows a fundamental role as a controller of cell growing, which makes it as one of the goals of anticancer inhibitors. Methods: The current study participated in design (docking and binding energy), which used to select the promising prop
- Al-Otaibi, Jamelah S.,Ibrahim, Diaa A.,El Gogary, Tarek M.
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p. 1240 - 1251
(2018/11/01)
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- Synthesis of bulky-tailed sulfonamides incorporating pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-1(5H)-yl) moieties and evaluation of their carbonic anhydrases I, II, IV and IX inhibitory effects
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Using celecoxib as lead, two novel series of sulfonamides incorporating the pyridotriazolopyrimidine scaffold have been synthesized and evaluated in vitro as inhibitors against four relevant human (h) carbonic anhydrases (CAs, EC 4.2.1.1), the cytosolic and ubiquitous hCA I and II as well as the transmembrane hCA IV and hCA IX. Most of the reported sulfonamides acted as efficient, low micromolar inhibitors of hCAI, II and IV, whereas they displayed higher efficacy in inhibiting the tumor-associated isoform hCA IX. Many derivates herein reported showed better hCA IX versus hCA II selectivity ratios compared to celecoxib or acetazolamide. Considering isoform IX is a validated target for the diagnosis and treatment of hypoxic tumors, discovery of selective CA IX inhibitors represents a promising step to unveil more effective anticancer therapies.
- Fares, Mohamed,Eladwy, Radwa A.,Nocentini, Alessio,El Hadi, Soha R. Abd,Ghabbour, Hazem A.,Abdel-Megeed, Ashraf,Eldehna, Wagdy M.,Abdel-Aziz, Hatem A.,Supuran, Claudiu T.
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p. 2210 - 2217
(2017/03/23)
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- Synthesis process of 4-chloropyrrolo[2,3-D]pyrimidine
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The invention relates to a synthesis process of 4-chloropyrrolo[2,3-D]pyrimidine. The synthesis process comprises the step of sequentially synthesizing 2-sulfydryl-4-amino-6-hydroxypyrimidine, 4-amino-6-hydroxypyrimidine, 4-hydroxypyrrolo[2,3-D]pyrimidine and 4-chloropyrrolo[2,3-D]pyrimidine through four-step reaction by taking ethyl cyanoacetate, thiourea, sodium ethoxide, 2-chloroacetaldehyde and sodium acetate as raw materials, ethanol, ammonia water, water and phosphorus oxychloride as solvents as well as active nickel and titanium dioxide as catalysts to obtain a target product, namely 4-chloropyrrolo[2,3-D]pyrimidine. According to the synthesis process, the cheap and available titanium dioxide is additionally provided in the second step and is used as the catalyst, so that the yield of 4-amino-6-hydroxypyrimidine serving as an intermediate product in the second step is remarkably increased, furthermore, the total yield of 4-chloropyrrolo[2,3-D]pyrimidine is increased, the cost is effectively reduced, and the synthesis process is suitable for large-scale industrial synthesis application.
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Paragraph 0022
(2016/12/01)
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- Preparation method of Cangrelor intermediate
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The invention discloses a preparation method of a Cangrelor intermediate. The preparation method comprises the following steps of enabling ethyl cyanoacetate and thiourea to perform closed-loop reaction to generate a product under the alkaline condition,
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Paragraph 0065; 0066; 0067; 0068
(2017/05/02)
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- Synthesis of substituted pyrimidin-4(1H)-one (uracil) derivatives and some of their reactions
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In this paper I described two practical routes for the synthesis of substituted Uracilderivatives and achieved some of their reactions. In the first synthesis which is based on the condensation reaction of ethyl 2- cyanoacetate and thiourea, the cyclized compound 6-amino-2- mercaptopyrimidin-4(3H)-one (I) achieved in the presence of sodium ethanoate. Thecompund (I) react with 2-(chloromethyl)oxirane in the given medium (II) was produced, then treated in medium of ethanol in peresence of KOH which new recyclized product 8-amino-3,4-dihydro-3- hydroxypyrimido[2,1-b][1,3]thiazin-6(2H)-one (III) was obtained.The other ring closing cyclization proceeded 6-methyl-2,3-dihydro-2- thioxopyrimidin-4(1H)-one (IV) by ethyl acetoacetate and thiourea in ethyl alcohol and potassium hydroxide medium. In the next reaction, firstly Sodium Salt of (V) was gained, then it was reacted with 2-(chloromethyl)oxirane. At the end, substitued derivative (VI) was resulted.All synthesized products were confirmed by IR, 1H NMR, 13C NMR, and elemental analysis. All the experimental data is described extensively in this report.
- Barmaki, Mohammad
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experimental part
p. 893 - 899
(2012/03/08)
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- Identification of novel, exosite-binding matrix metalloproteinase-13 inhibitor scaffolds
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Matrix metalloproteinase-13 (MMP-13) has been implicated as the protease responsible for collagen degradation in cartilage during osteoarthritis (OA). Compounds that inhibit the metalloproteinase at the Zn binding site typically lack specificity among MMP family members. Analogs of the low-micromolar lead MMP-13 inhibitor 4, discovered through high-throughput screening, were synthesized to investigate structure-activity relationships in this inhibitor series. Systematic modifications of 4 led to the discovery of MMP-13 inhibitors 20 and 24 which are more selective than 4 against other MMPs. Compound 20 is also approximately fivefold more potent as an MMP-13 inhibitor than the original HTS-derived lead compound 4.
- Roth, Joshua,Minond, Dmitriy,Darout, Etzer,Liu, Qin,Lauer, Janelle,Hodder, Peter,Fields, Gregg B.,Roush, William R.
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scheme or table
p. 7180 - 7184
(2012/01/15)
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- N-Alkylation of 2,6-dichloropurine hydrochloride with a variety of alcohols over alumina catalyst
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2,6-Dichloropurine hydrochloride reacts with various types of alcohols using different alumina catalysts and converts into its N-9-alkyl-2-chloro-6- hydroxy-9H-purine products to an extent of 49-74%. The product selectivity depends on the stability of carbocation generated from the alcohol. More stable carbocation formulates both N-7 and N-9-alkyl-2,6-dichloropurine products, whereas the less stable carbocation results in exclusively N-9-alkyl-2-chloro-6- hydroxy-9H-purine. The catalytic activity of alumina prepared using the sol-gel method has larger Brunauer, Emmett, and Teller (BET) surface area and hence shows significantly greater catalytic activity than the commercially available alumina samples. Copyright
- Tumma, Harikrishna,Nagaraju,Reddy, K. Vijayakumar
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scheme or table
p. 1856 - 1866
(2010/07/02)
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- Coordination trends of 6-amino-4-hydroxy-2-mercaptopyrimidine towards Co (II), Ni (II) and Cu (II) ions
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Co(II), Ni(II), and Cu(II) complexes of 6-amino-4-hydroxy-2- mercaptopyrimidine have been prepared and characterized by several physiochemical tools: in terms, CHNS elemental analyses, infrared, electronic, mass, and proton nuclear magnetic resonance spectroscopy and molar conductivity measurements The CHNS elemental analysis data showed the formation of 1:1 [M:L] ratio The infrared spectral data exhibited the complexation behavior of the ligand towards to metal ions which is through -NH2. -SH and -CN groups. The electronic spectra displayed the existence of π → π* and n→π* transitions. The mass spectral data revealed the possible fragmentations of the ligand The proton nuclear magnetic resonance data of the ligand showed the position of the groups which enter in coordination. The molar conductivity measurements showed that all complexes are non-electrolyte.
- Khalifa, Khalifa Mosbeh,Maihub, Abdsullam Ali,El-Ajaily, Marei Miloud,Mobain, Soad Ali
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experimental part
p. 650 - 653
(2012/07/27)
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- Synthesis of certain pyrimidine derivatives as antimicrobial agents and anti-inflammatory agents
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A variety of novel bicyclic and tricyclic pyrimidine derivatives was obtained via reaction of 6-amino-2-thioxo-1H-pyrimidine-4-one (1) with a different reagents. The antimicrobial and anti-inflammatory activities of some of the synthesized compounds were
- Mohamed, Mosaad S.,Awad, Samir M.,Sayed, Amira Ibrahim
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scheme or table
p. 1882 - 1890
(2010/05/18)
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- 6-Amino-2-mercapto-3H-pyrimidin-4-one derivatives as new candidates for the antagonism at the P2Y12 receptors
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P2Y12 plays an important role in platelet aggregation, which makes it an interesting target for antithrombotic agents. Compounds that antagonize P2Y12 include the active metabolites of thienopyridines and molecules that are structurally related to ATP, which is an antagonist of P2Y12. During the last few years, our group has been working on the development of P2Y12 receptors antagonists that are based on an extremely simple chemical structure, the 6-amino-2-mercapto-3H-pyrimidin-4-one, variously substituted at the sulfur and oxygen functions. This nucleus represents the simplified combination of two known P2Y12 antagonists: the active metabolite of the thienopyridines and ATP derivatives. The effects of the synthesized compounds were tested on ADP-induced human platelet aggregation, using light transmission aggregometry. None of the tested compounds induced platelet aggregation, while some of them, at concentration of 10-4 M, partially inhibited platelet aggregation induced by ADP 10-6 M. The most potent compound, 6b, antagonized the inhibitory effect of 2-methylthio-ADP on the forskolin-induced accumulation of cyclic-AMP in CHO FlpIN cells expressing recombinant human P2Y12-receptors. In addition, none of the tested compounds, including 6b, interfered with ligand binding to P1 receptors. Our results suggest that some of the synthesized compounds are specific antagonists of P2 receptors, and in particular of P2Y12 and suggest that further development of this structurally new series of compounds as P2Y12 receptors antagonists is recommended.
- Crepaldi, Pamela,Cacciari, Barbara,Bonache, Maria-Cruz,Spalluto, Giampiero,Varani, Katia,Borea, Pier Andrea,Kuegelgen, Ivar von,Hoffmann, Kristina,Pugliano, Mariateresa,Razzari, Cristina,Cattaneo, Marco
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experimental part
p. 4612 - 4621
(2009/10/23)
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- Antitumor studies. Part 3: Design, synthesis, antitumor activity, and molecular docking study of novel 2-methylthio-, 2-amino-, and 2-(N-substituted amino)-10-alkyl-2-deoxo-5-deazaflavins
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Various novel 10-alkyl-2-deoxo-2-methylthio-5-deazaflavins have been synthesized by reaction of 6-(N-alkylanilino)-2-methylthiopyrimidin-4(3H)-ones with Vilsmeier reagent. The similar 2-(N-substituted amino) derivatives were prepared by nucleophilic replacement reaction of the 2-methylthio moiety by appropriate amines. The 2-oxo derivatives (i.e., 5-deazaflavins) were obtained by acidic hydrolysis of the 2-methylthio derivatives. The antitumor activities against CCRF-HSB-2 and KB cells and the antiviral activities against HSV-1 and HSV-2 have been investigated in vitro, and many compounds showed promising antitumor activities. Furthermore, AutoDock molecular docking into PTK has been done for lead optimization of these compounds as potential PTK inhibitors. Whereas, the designed 2-deoxo-5-deazaflavins connected with amino acids at the 2-position exhibited the good binding affinities into PTK with more hydrogen bonds.
- Ali, Hamed I.,Ashida, Noriyuki,Nagamatsu, Tomohisa
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p. 6336 - 6352
(2008/03/18)
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- Microwave-expedited one-pot, two-component, solvent-free synthesis of functionalized pyrimidines
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The synthesis of a series of diversely substituted pyrimidines under solvent-free conditions in good yields is described. Under microwave irradiation, a variety of nucleophilic substrates containing the N?C?N unit with ?-dicarbonyl compounds, ethyl cyanoacetate, malononitrile, and chalcones was cyclized to give pyrimidines. A combinatorial type approach for a one-step synthesis has been developed where a ring-closing condensation is followed by spontaneous aromatization to afford 28 functionalized and aryl/alkyl substituted pyrimidines. CSIRO 2007.
- Goswami, Shyamaprosad,Jana, Subrata,Dey, Swapan,Kumar Adak, Avijit
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p. 120 - 123
(2008/02/11)
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- Synthesis of [1′,2′,5′,2-13C4]-2′ -deoxy-D-adenosine by a chemoenzymatic strategy to enable labelling of any of the 215 carbon-13 and nitrogen-15 isotopomers
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Enzymatic trans-N-glycosylation has been selected as the method of choice by which to couple [13C1]-adenine to [13C3]-2-deoxy-D-ribose. The enzymatic pentosylation of the labelled adenine base was achieved in a two-step/one-pot reaction, starting from thymidine labelled in the sugar ring, but not at the thymine base. The efficiency of this thymidine phosphorylase catalysed (TP-catalysed) and purine nucleoside phosphorylase catalysed (PNP-catalysed) transamination reaction was demonstrated by a high yield (91%) and stereochemical purity of the obtained [1′,2′,5′,2-13C4]-2′ -deoxy-D-adenosine. To verify that all carbon and nitrogen positions and combination of positions in both the adenine and the sugar could be substituted by 13C and 15N at a minimum of cost, each of the steps was optimised to convert the commercially available and isotopically highly enriched (99%) synthons (acetaldehyde, acetic acid, ammonia, benzylamine, formic acid, methylamine, potassium cyanide, potassium thiocyanate and sodium nitrite) as quantitatively as possible. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.
- Ouwerkerk, Niels,Van Boom, Jacques,Lugtenburg, Johan,Raap, Jan
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p. 2356 - 2362
(2007/10/03)
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- Structure-based design, synthesis, and in vitro evaluation of bisubstrate inhibitors for catechol O-methyltransferase (COMT)
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The enzyme catechol O-methyltransferase (COMT) catalyzes the Me group transfer from the cofactor S-adenosylmethionine (SAM) to the hydroxy group of catechol substrates. Potential bisubstrate inhibitors of COMT were developed by structure-based design and synthesized. The compounds were tested for in vitro inhibitory activity against COMT obtained from rat liver, and the inhibition kinetics were examined with regard to the binding sites of cofactor and substrate. One of the designed molecules was found to be a bisubstrate inhibitor of COMT with an IC50 = 2 μM. It exhibits competitive kinetics for the SAM and noncompetitive kinetics for the catechol binding site. Useful structure-activity relationships were established which provide important guidelines for the design of future generations of bisubstrate inhibitors of COMT.
- Masjost, Birgit,Ballmer, Patrick,Borroni, Edilio,Zuercher, Gerhard,Winkler, Fritz K.,Jakob-Roetne, Roland,Diederich, Francois
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p. 971 - 982
(2007/10/03)
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- Precious metal composition
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Gold thiolates of formula AuSR'' or a salt thereof, in which R'' is such that HSR'' represents: 4,6-dihydroxy-2-mercaptopyrimidine; N-(2-mercaptoacetyl)glycine; N-(3-mercaptopropionyl)glycine; and N-(2-mercaptopropionyl)glycine. The invention provides also processes for preparing novel gold thiolates.
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- Synthesis of the caffeine metabolites 5-acetylamino-6-formylamino-3-methyluracil (AFMU) and 5-acetylamino-6-amino-3-methyluracil (AAMU) on a preparative scale
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5-Acetylamino-6-amino-3-methyluracil (AAMU) and 5-acetylamino-6-formylamino-3-methyluracil (AFMU) have been prepared by simple chemical transformations starting from thiourea and ethyl cyanoacetate. These compounds AAMU and AFMU are required as standard m
- Roehrkasten,Raatz,Kreher,Blaszkewicz
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p. 1526 - 1532
(2007/10/03)
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- Reactions of nitriles under acidic conditions : Part IX - Synthesis of 6-amino-1-aryluracils, 6-amino-1-aryl-2-thiouracils and 6-amino-1,3-diaryl-2-thiouracils under acidic conditions
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6-Amino-1-aryluracils (11a-g), 6-amino-1-aryl-2-thiouracils (12a-g), and 6-amino-1,3-diaryl-2-thiouracils (6a,b) have been synthesised through the dry hydrogen chloride gas-catalysed condensation of ethyl cyanoacetate (7) with appropriate arylureas and thioureas. 1-Aryl (12a-g) and 1,3-diaryl-2-thiouracils (6c-g) have been converted to the corresponding 1-aryl (15a-g) and novel hitherto unre-ported, 1,3-diaryluracils (5a-e) through their oxidative desulphurisation.
- Shishoo,Jain,Jain,Shah,Ravikumar
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p. 662 - 668
(2007/10/03)
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