56-05-3Relevant articles and documents
A modular approach towards functionalized highly stable self-complementary quadruple hydrogen bonded systems
Rayavarapu, Suresh,Kheria, Sanjeev,Shinde, Dinesh R.,Gonnade, Rajesh G.,Sanjayan, Gangadhar J.
, p. 10087 - 10094 (2017)
Self-complementary quadruple hydrogen bonded systems have shown potential as key building blocks for developing various supramolecular polymers. Opportunities for the introduction of multiple functionalities would further augment, in principle, their application potential. Herein, we report a novel modular approach to simultaneously introduce two closely aligned side chains into AADD-type self-complementary quadruple hydrogen-bonding systems. Dithiane-tethered ureidopyrimidinone has been used as a reactive intermediate to efficiently attach closely aligned side chains by simply reacting with amines to form highly stable molecular duplexes. These duplexes featuring AADD-type arrays of hydrogen bonding codes are highly stable in non-polar solvents (Kdim > 1.9 × 107 M-1 in CDCl3) as well as in polar solvents (Kdim > 105 in 10% DMSO-d6/CDCl3). Another notable feature of these self-assembling systems is their insensitivity to prototropy-related issues owing to their prototropic degeneracy, which will enhance their application potential in supramolecular chemistry.
Preparation method of 2-amino-4,6-dichloro-5-nitropyrimidine
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Paragraph 0024-0025, (2021/08/25)
The invention discloses a preparation method of 2-amino-4,6-dichloro-5-nitropyrimidine, which comprises the following steps: (1) carrying out chlorination reaction on 2-amino-6-hydroxy-4[1H]-pyrimidone to generate 2-amino-4,6-dichloropyrimidine; and (2) enabling the 2-amino-4,6-dichloropyrimidine to react with a nitration reagent in acid or acid anhydride, so as to generate 2-amino-4,6-dichloro-5-nitropyrimidine. The nitration reagent is concentrated nitric acid, the concentrated nitric acid is a nitric acid aqueous solution with the mass fraction of 55%-85%, the acid is concentrated sulfuric acid, the concentrated sulfuric acid is a sulfuric acid aqueous solution with the mass fraction of 70%-98.5%, and the anhydride is trifluoroacetic anhydride and/or acetic anhydride. The method has the advantages of few steps, high yield, good purity, low cost, simple operation process and suitability for industrial application.
Cinnamide derived pyrimidine-benzimidazole hybrids as tubulin inhibitors: Synthesis, in silico and cell growth inhibition studies
Sana, Sravani,Reddy, Velma Ganga,Srinivasa Reddy,Tokala, Ramya,Kumar, Rahul,Bhargava, Suresh K.,Shankaraiah, Nagula
, (2021/03/15)
An approach in modern medicinal chemistry to discover novel bioactive compounds is by mimicking diverse complementary pharmacophores. In extension of this strategy, a new class of piperazine-linked cinnamide derivatives of benzimidazole-pyrimidine hybrids have been designed and synthesized. Their in vitro cytotoxicity profiles were explored on selected human cancer cell lines. Specifically, structural comparison of target hybrids with tubulin-DAMA-colchicine and tubulin-nocodazole complexes has exposed a deep position of benzimidazole ring into the αT5 loop. All the synthesized compounds were demonstrated modest to interesting cytotoxicity against different cancer cell lines. The utmost cytotoxicity has shown with an amine linker of benzimidazole-pyrimidine series, with specificity toward A549 (lung cancer) cell line. The most potent compound in this series was 18i, which inhibited cancer cell growth at micromolar concentrations ranging 2.21–7.29 μM. Flow cytometry studies disclosed that 18i inhibited the cells in G2/M phase of cell cycle. The potent antitumor activity of 18i resulted from enhanced microtubule disruption at a similar level as nocodazole on β-tubulin antibody, explored using immunofluorescence staining. The most active compound 18i also inhibited tubulin polymerization with an IC50 of 5.72 ± 0.51 μM. In vitro biological analysis of 18i presented apoptosis induction on A549 cells with triggering of ROS generation and loss of mitochondrial membrane potential, resulting in DNA injury. In addition, 18i displayed impairment in cellular migration and inhibited the colony formation. Notably, the safety profile of most potent compound 18i was revealed by screening against normal human pulmonary epithelial cells (L132: IC50: 69.25 ± 5.95 μM). The detailed binding interactions of 18i with tubulin was investigated by employing molecular docking, superimposition and free energy analyses. Thus remarks made in this study established that pyrimidine-benzimidazole hybrids as a new class of tubulin polymerization inhibitors with significant anticancer activity.
Developing novel classes of protein kinase CK1δ inhibitors by fusing [1,2,4]triazole with different bicyclic heteroaromatic systems
Grieco, Ilenia,Bissaro, Maicol,Tiz, Davide Benedetto,Perez, Daniel I.,Perez, Conception,Martinez, Ana,Redenti, Sara,Mariotto, Elena,Bortolozzi, Roberta,Viola, Giampietro,Cozza, Giorgio,Spalluto, Giampiero,Moro, Stefano,Federico, Stephanie
, (2021/03/16)
Protein kinase CK1δ expression and activity is involved in different pathological situations that include neuroinflammatory and neurodegenerative diseases. For this reason, protein kinase CK1δ has become a possible therapeutic target for these conditions. 5,6-fused bicyclic heteroaromatic systems that resemble adenine of ATP represent optimal scaffolds for the development of a new class of ATP competitive CK1δ inhibitors. In particular, a new series of [1,2,4]triazolo[1,5-c]pyrimidines and [1,2,4]triazolo[1,5-a][1,3,5]triazines was developed. Some crucial interactors have been identified, such as the presence of a free amino group able to interact with the residues of the hinge region at the 5- and 7- positions of the [1,2,4]triazolo[1,5-c]pyrimidine and [1,2,4]triazolo[1,5-a][1,3,5]triazine scaffolds, respectively; or the presence of a 3-hydroxyphenyl or 3,5-dihydroxyphenyl moiety at the 2- position of both nuclei. Molecular modeling studies identified the key interactions involved in the inhibitor-protein recognition process that appropriately fit with the outlined structure-activity relationship. Considering the fact that the CK1 protein kinase is involved in various pathologies in particular of the central nervous system, the interest in the development of new inhibitors permeable to the blood-brain barrier represents today an important goal in the pharmaceutical field. The best potent compound of the series is the 5-(7-amino-5-(benzylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)benzen-1,3-diol (compound 51, IC50 = 0.18 μM) that was predicted to have an intermediate ability to cross the membrane in our in vitro assay and represents an optimal starting point to both studies the therapeutic value of protein kinase CK1δ inhibition and to develop new more potent derivatives.
Exploration of carbamide derived pyrimidine-thioindole conjugates as potential VEGFR-2 inhibitors with anti-angiogenesis effect
Bhandari, Sonal,Bhargava, Suresh K.,Reddy, T. Srinivasa,Reddy, Velma Ganga,Sakla, Akash P.,Sana, Sravani,Shankaraiah, Nagula,Tokala, Ramya
, (2020/05/18)
The development of new small molecules from known structural motifs through molecular hybridization is one of the trends in drug discovery. In this connection, we have combined the two pharmacophoric units (pyrimidine and thioindole) in a single entity via molecular hybridization strategy along with introduction of urea functionality at C2 position of pyrimidine to increase the efficiency of H-bonding interactions. Among the synthesized conjugates 12a-aa, compound 12k was found to exhibit significant IC50 values 5.85, 7.87, 6.41 and 10.43 μM against MDA-MB-231 (breast), HepG2 (liver), A549 (lung) and PC-3 (prostate) cancer cell lines, respectively. All these compounds were further evaluated for their inhibitory activities against VEGFR-2 protein. The results specified that among the tested compounds, 12d, 12e, 12k, 12l, 12p, 12q, 12t and 12u prominently suppressed VEGFR-2, with IC50 values of 310–920 nM in association to the positive control (210 nM). Angiogenesis inhibition was evident by tube formation assay in HUVECs and cell-invasion by transwell assay. The mechanism of cellular toxicity on MDA-MB-231 was found through depolarisation of mitochondrial membrane potential, increased ROS production and subsequent DNA damage resulting in apoptosis induction. Moreover, clonogenic and wound healing assays designated the inhibition of colony formation and cell migration by 12k in a dose-dependent manner. Molecular docking studies also shown that compound 12k capably intermingled with catalytically active residues GLU-885, ASP-1046 of the VEGFR-2 through hydrogen-bonding interactions.
Microwave-assisted synthesis and docking studies of phenylureas as candidates for the drug design against the biological warfare agent Yersinia pestis
Bastos, Leonardo da Costa,Bendahan, David,Chacón-Huete, Franklin,Cuya, Teobaldo,Forgione, Pat,Fran?a, Tanos Celmar Costa,Sirouspour, Mehdi
, p. 631 - 637 (2020/04/17)
Background: Bubonic plague is amongst the diseases with the highest potential for being used in biological warfare attacks today. Introduction: This disease, caused by the bacterium Yersina pestis, is highly infectious and can achieve 100% of fatal victims when in its most dangerous form. Besides, there is no effective vac-cine, and the chemotherapy available today against plague is ineffective if not administered at the beginning of the infection. Willing to contribute for changing this reality we propose here new phe-nylureas as candidates for the drug design against plague meant to target the enzyme dihydrofolate reductase from Y. pestis (YpDHFR). Methods: Seven phenylureas, four of them new, were synthesized, following synthetic routes adapted from procedures available in the literature, and using microwave irradiation. After, they were submitted to docking studies inside YpDHFR and human DHFR (HssDHFR) in order to check their potential as selective inhibitors. Results & Conclusion: Our results revealed four new phenylureas and a new synthetic route for this kind of molecule using microwave irradiation. Also, our docking studies pointed to two of the phe-nylureas as selective inhibitors of YpDHFR and, therefore, candidates for the design of new drugs against plague.
Preparation method of famciclovir
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Paragraph 0025-0027, (2019/03/28)
The invention relates to a preparation method of famciclovir. The preparation method comprises the following steps of: adopting guanidine nitrate and diethyl malonate as raw materials, carrying out ring-closing reaction under an alkaline condition to obtain 2-amino-4,6-pyrimidinediol, then obtaining 2-amino-4,6-dichloropyrimidine by hydroxyl chlorination, reacting with 2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl-1-amine to generate 6-chloro-N(i)4(/i)-(2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl)pyrimidine-2,4-diamine, then reacting with sodium nitrite under the acidic condition to obtain 2-(2-((2-amino-6-chloro-5-nitrosopyrimidin-4-yl)amino)ethyl)propane-1,3-diol, and finally carrying out reduction/dechloridation, ring-closing and esterification reaction to obtain the famciclovir. The preparation method has the beneficial effects that the problems of poor N-alkylation reaction selectivity and need of additional purification of reaction intermediates and the like in the current process are solved.
In the stripping column in the application of the dichloro pyrimidine purification (by machine translation)
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Paragraph 0046-0047; 0050, (2018/09/08)
The present invention provides a pure aliphatic chloro pyrimidine of stripping method, comprises the following steps: A) dihydroxy pyrimidine carried out after the chlorination reaction, to obtain dichloro pyrimidine reaction mixed solution; B) reaction mixed solution adding water hydrolysis, or by adding ice water to ice solution, then the organic solvent extraction, including two chlorine pyrimidine crude product obtained organic phase; C) containing dichloro pyrimidine crude organic phase is the top or upper part enters the stripping column, or the lower part of the water vapor from the bottom of the stripping column, containing two chloro pyrimidine crude organic phase flushes steams, including two chlorine pyrimidine pure product obtained organic phase; D) organic phase containing dichloro pyrimidine pure product, reduced pressure or normal pressure distillation concentrated, the temperature crystallization, centrifugation or filtration to obtain two chloro pyrimidine pure product. This invention adopts the reverse steam stripping column, two chloro pyrimidine crude to drip or spray mode, the state of the droplet, direct contact with water vapor, so that the purification efficiency, refining yield is greatly improved, and is suitable for industrial production and application. (by machine translation)
Method for preparing 4,6-dichloro-2-aminopyrimidine
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Paragraph 0023-0032, (2019/01/13)
The invention discloses a method for preparing 4,6-dichloro-2-aminopyrimidine. The method mainly includes the following steps that 1, 4,6-dyhydroxy-2-aminopyrimidine is used as a raw material, in a reaction solvent, a chlorinating agent is added, and reaction is carried out at a certain temperature to obtain a mixed solution; 2, the mixed solution obtained in the step 1 is subjected to pH adjustment, standing is conducted for layering, and spinning is conducted to obtain the target product 4,6-dichloro-2-aminopyrimidine. In the preparation method, the reaction is full, the reaction conditionsare mild, the reaction yield is significantly improved, and by-products are greatly reduced; in a reaction process, no acid-binding agent is needed, so that the production cost is reduced; in the reaction process, no three-waste are generated, so that the preparation method is beneficial for environmental protection.
PYRIMIDINE COMPOUNDS CONTAINING ACIDIC GROUPS
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Paragraph 1106; 1107, (2018/06/15)
The present disclosure relates to a class of pyrimidine derivatives having immunomodulating properties that act via TLR7 which are useful in the treatment of viral infections and cancers.
