- Structure of radicals derived from hydroxypyrimidines in aqueous solution
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EPR spectra of radicals derived from the three isomeric trihydroxypyrimidines and from 2-hydroxypyrimidine were obtained either in reduction or oxidation conditions at various pH values. Additionally, three other pyrimidine derivatives, 2-thiobarbituric a
- Novais, Horacio M.,Telo, Joao P.,Steenken, Steen
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- Cinnamide derived pyrimidine-benzimidazole hybrids as tubulin inhibitors: Synthesis, in silico and cell growth inhibition studies
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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.
- Sana, Sravani,Reddy, Velma Ganga,Srinivasa Reddy,Tokala, Ramya,Kumar, Rahul,Bhargava, Suresh K.,Shankaraiah, Nagula
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- Ultrasound-assisted rapid synthesis of 2-aminopyrimidine and barbituric acid derivatives
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Novel, inexpensive, and relatively expeditious procedure to achieve the synthesis of different 2-aminopyrimidine and barbituric acid derivatives is presented here, starting from readily available compounds such as guanidine hydrochloride, urea, 1,3-dialkylurea, or thiourea. Under ultrasonic irradiation, base-driven (Na2CO3, NaOH, or NaOC2H5) heterocyclization reactions of the aforementioned substrates with diethyl malonate, diethyl-2-alkyl malonate, pentane-2,4-dione, or ethyl-3-oxobutanoate yielded corresponding products. Significant advantages of this sonochemical synthetic protocol with regard to the conventional thermal methods include easy reaction setup and work-up steps, reasonably mild conditions, shorter reaction times (～30 min) and comparably high product yields. The characterization of the synthesized compounds was based on melting points, FT-IR, GC-MS, 1H-NMR techniques, and the obtained data were also checked from the previously published studies.
- Bayramo?lu, Duygu,Kurtay, Gülbin,Güllü, Mustafa
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p. 649 - 658
(2020/02/11)
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- Prebiotic Origin of Pre-RNA Building Blocks in a Urea “Warm Little Pond” Scenario
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Urea appears to be a key intermediate of important prebiotic synthetic pathways. Concentrated pools of urea likely existed on the surface of the early Earth, as urea is synthesized in significant quantities from hydrogen cyanide or cyanamide (widely accepted prebiotic molecules), it has extremely high water solubility, and it can concentrate to form eutectics from aqueous solutions. We propose a model for the origin of a variety of canonical and non-canonical nucleobases, including some known to form supramolecular assemblies that contain Watson-Crick-like base pairs.The dual nucleophilic-electrophilic character of urea makes it an ideal precursor for the formation of nitrogenous heterocycles. We propose a model for the origin of a variety of canonical and noncanonical nucleobases, including some known to form supramolecular assemblies that contain Watson-Crick-like base pairs. These reactions involve urea condensation with other prebiotic molecules (e. g., malonic acid) that could be driven by environmental cycles (e. g., freezing/thawing, drying/wetting). The resulting heterocycle assemblies are compatible with the formation of nucleosides and, possibly, the chemical evolution of molecular precursors to RNA. We show that urea eutectics at moderate temperature represent a robust prebiotic source of nitrogenous heterocycles. The simplicity of these pathways, and their independence from specific or rare geological events, support the idea of urea being of fundamental importance to the prebiotic chemistry that gave rise to life on Earth.
- Menor Salván,Bouza, Marcos,Fialho, David M.,Burcar, Bradley T.,Fernández, Facundo M.,Hud, Nicholas V.
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p. 3504 - 3510
(2020/10/02)
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- Exploration of carbamide derived pyrimidine-thioindole conjugates as potential VEGFR-2 inhibitors with anti-angiogenesis effect
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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.
- Bhandari, Sonal,Bhargava, Suresh K.,Reddy, T. Srinivasa,Reddy, Velma Ganga,Sakla, Akash P.,Sana, Sravani,Shankaraiah, Nagula,Tokala, Ramya
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- Preparation method of famciclovir
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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.
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Paragraph 0022-0024
(2019/03/28)
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- Synthesis method of 2-amino-4, 6-dihydroxypyrimidine
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The invention relates to a synthesis method of 2-amino-4, 6-dihydroxypyrimidine. Guanidine nitrate and diethyl malonate are employed as the raw materials for one-step cyclization reaction. The steps include: employing a new-made sodium ethoxide solution, diethyl malonate and self-made guanidine nitrate to carry out stirring reflux reaction for 0.5-1.5h, distilling off ethanol, then dissolving the obtained white solid in water, then using a 4-6% acetic acid solution to conduct acidification to a pH value of 4-6, and carrying out filtering, washing and drying, thus obtaining a white solid 2-amino-4, 6-dihydroxypyrimidine. The method provided by the invention has the advantages of simple reaction steps, low reaction temperature, safety and environmental protection, is suitable for industrial production, and has wide application prospect.
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Paragraph 0012; 0013; 0014
(2017/03/21)
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- A 2,5-diamino -4,6-dihydroxy-pyridine synthesis method (by machine translation)
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The invention relates to a method for synthesis of compound, a 2,5? Diaminotriphenylamine? 4,6? Dihydroxybenzonic pyridine synthesis method. This method, in order to c diethyl adipic acid and hydrochloric acid guanidine is raw materials, through nitration, ammoniation reduction a series of reaction 2,5? Diaminotriphenylamine? 4,6? Dihydroxybenzonic pyridine, the method the production cost is cheap, mild reaction conditions, high yield. (by machine translation)
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Paragraph 0004; 0007
(2016/11/17)
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- An efficient and simple methodology for the synthesis of 2-amino-4-(N-alkyl/arylamino)-6-chloropyrimidines
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In this study, twenty-nine 2-aminopyrimidine derivatives are synthesized in good to excellent yields by fusing 2-amino-4,6-dichloropyrimidine with different amines in the presence of triethylamine without using any solvent or catalyst. Nucleophilic substitution reactions of 2-amino-4,6-dichloropyrimidine with amines have also been performed in ethanol. Comparisons of the yields and reaction times for both solvent and solvent-free conditions have shown that the newly developed solvent-free protocol is high yielding, more efficient, and simpler compared to conventional methods.
- Khan, Khalid Mohammed,Iqbal, Sarosh,Bashir, Muhammad Arslan,Ambreen, Nida,Perveen, Shahnaz,Voelter, Wolfgang
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supporting information
p. 1179 - 1182
(2015/03/04)
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- Synthesis and biological activities of O, O-dialkyl 1-((4,6- Dichloropyrimidin-2-yl)carbamyloxy) alkylphosphonates
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(Equation present) A series of new 1-((4,6-dichloropyrimidin-2-yl) carbamyloxy) alkylphosphonates were designed and synthesized. The structures of all the title compounds were confirmed by IR, 1H-NMR, 31P-NMR and elemental analysis. The results of the bioassay showed that all of title compounds exhibited weak herbicidal activities against monocotyledons and dicotyledons; however, some of them showed potential plant growth regulatory activities. 2014 Copyright Taylor & Francis Group, LLC.
- Xu, Liang,You, Geyun,Peng, Hao,He, Hongwu
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p. 812 - 818
(2014/07/08)
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- Sulfonylureas have antifungal activity and are potent inhibitors of Candida albicans acetohydroxyacid synthase
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The sulfonylurea herbicides exert their activity by inhibiting plant acetohydroxyacid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthesis pathway. It has previously been shown that if the gene for AHAS is deleted in Candida albicans, attenuation of virulence is achieved, suggesting AHAS as an antifungal drug target. Herein, we have cloned, expressed, and purified C. albicans AHAS and shown that several sulfonylureas are inhibitors of this enzyme and possess antifungal activity. The most potent of these compounds is ethyl 2-(N-((4-iodo-6-methoxypyrimidin-2-yl)carbamoyl) sulfamoyl)benzoate (10c), which has a Ki value of 3.8 nM for C. albicans AHAS and an MIC90 of 0.7 μg/mL for this fungus in cell-based assays. For the sulfonylureas tested there was a strong correlation between inhibitory activity toward C. albicans AHAS and fungicidal activity, supporting the hypothesis that AHAS is the target for their inhibitory activity within the cell.
- Lee, Yu-Ting,Cui, Chang-Jun,Chow, Eve W. L.,Pue, Nason,Lonhienne, Thierry,Wang, Jian-Guo,Fraser, James A.,Guddat, Luke W.
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supporting information
p. 210 - 219
(2013/02/23)
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- Synthesis and antimicrobial evaluation of guanylsulfonamides
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A series of guanylsulfonamides, 2-amino-9-[2-substituted-4-(4-substituted piperidin-1-sulfonyl)phenyl]-1,9-dihydropurin-6-ones, was synthesized by adopting reductive aminoformylation of 2-amino-5-nitro-6-[4-(piperidin-1-sulfonyl)phenylamino]-3H-pyrimidin- 4-one and subsequent intramolecular ring condensation as key steps. All the guanylsulfonamides were assayed for their in vitro antibacterial activities against Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus, and Streptococcus faecalis, and their antifungal activities against Aspergillus flavus, Aspergillus niger, and Candida albicans. Of the guanylsulfonamides, 13e and 13f displayed better antibacterial activities than that of Norfloxacin against the bacterial strains S. aureus and S. faecalis except 13f against S. faecalis, which exhibited the activity similar to that of Norfloxacin. Against the fungal strains A. flavus and A. niger, 13g and 13h showed similar activities to that of Griseoflavin-16 except 13h against A. niger, which displayed a profound drop in the activity compared to that of Griseoflavin-16. The remarkable inhibition of the growth of the bacterial and fungal strains makes these substances promising microbial agents.
- Patel, Pratik R.,Ramalingan, Chennan,Park, Yong-Tae
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p. 6610 - 6614
(2008/09/18)
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- New strategies for the synthesis of A3 adenosine receptor antagonists
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New A3 adenosine receptor antagonists were synthesized and tested at human adenosine receptor subtypes. An advanced synthetic strategy permitted us to obtain a large amount of the key intermediate 5 that was then submitted to alkylation procedures in order to obtain the derivatives 6-8. These compounds were then functionalised into ureas at the 5-position (compounds 9-11, 18 and 19) to evaluate their affinity and selectivity versus hA3 adenosine receptor subtype; in particular, compounds 18 and 19 displayed a value of affinity of 4.9 and 1.3 nM, respectively. Starting from 5, the synthetic methodologies employed permitted us to perform a rapid and a convenient divergent synthesis. A further improvement allowed the regioselective preparation of the N8-substituted compound 7. This method could be used as an helpful general procedure for the design of novel A3 adenosine receptor antagonists without the difficulty of separating the N8-substituted pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines from the corresponding N 7-isomers.
- Baraldi, Pier Giovanni,Bovero, Andrea,Fruttarolo, Francesca,Romagnoli, Romeo,Tabrizi, Mojgan Aghazadeh,Preti, Delia,Varani, Katia,Borea, Pier Andrea,Moorman, Allan R.
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p. 4161 - 4169
(2007/10/03)
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