- Discovery of Potent and Selective 2-(Benzylthio)pyrimidine-based DCN1-UBC12 Inhibitors for Anticardiac Fibrotic Effects
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DCN1, a co-E3 ligase, interacts with UBC12 and activates cullin-RING ligases (CRLs) by catalyzing cullin neddylation. Although DCN1 has been recognized as an important therapeutic target for human diseases, its role in the cardiovascular area remains unknown. Here, we first found that DCN1 was upregulated in isolated cardiac fibroblasts (CFs) treated by angiotensin (Ang) II and in mouse hearts after pressure overload. Then, structure-based optimizations for DCN1-UBC12 inhibitors were performed based on our previous work, yielding compound DN-2. DN-2 specifically targeted DCN1 at molecular and cellular levels as shown by molecular modeling studies, HTRF, cellular thermal shift and co-immunoprecipitation assays. Importantly, DN-2 effectively reversed Ang II-induced cardiac fibroblast activation, which was associated with the inhibition of cullin 3 neddylation. Our findings indicate a potentially unrecognized role of DCN1 inhibition for anticardiac fibrotic effects. DN-2 may be used as a lead compound for further development.
- He, Zhang-Xu,An, Qi,Wei, Bo,Zhou, Wen-Juan,Wei, Bing-Fei,Gong, Yun-Peng,Zhang, Xin,Gao, Ge,Dong, Guan-Jun,Huo, Jin-Ling,Zhang, Xin-Hui,Yang, Fei-Fei,Liu, Hong-Min,Ma, Li-Ying,Zhao, Wen
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p. 163 - 190
(2022/01/11)
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- Design, Synthesis and Antibacterial Activity of Novel Pyrimidine-Containing 4H-Chromen-4-One Derivatives**
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A series of pyrimidine-containing 4H-chromen-4-one derivatives were designed and synthesized by combining bioactive substructures. Preliminary biological activity results showed that most of the compounds displayed significant inhibitory activities in vit
- Chen, Mei,He, Ming,Liu, Tingting,Peng, Feng,Su, Shijun,Tang, Xuemei,Xie, Chengwei,Xue, Wei,Zhan, Wenliang,Zhou, Qing
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- Hydrotalcites as catalyst in suitable multicomponent synthesis of uracil derivatives
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Uracil compounds participate in a wide range of biological activities; however, reports on their synthesis using heterogeneous catalysts are scarce. In this work, the multicomponent synthesis of uracil derivatives assisted by layered double hydroxides (LDH) was studied under green chemistry conditions. The incorporation of Ni2+ or Co2+ was successfully performed by co-precipitation method. The yields to uracil derivatives are associated with the presence of weak basic sites and a better interaction of the reagents when the reaction is carried out in solvent-free conditions. The reaction pathway involves the formation of an enone between benzaldehyde and ethyl cyanoacetate, and subsequent reaction with urea, which is assisted by the presence of a basic catalyst. The scope of this synthesis is illustrated with nine examples.
- Nope, Eliana,Sathicq, ángel G.,Martínez, José J.,Rojas, Hugo,Romanelli, Gustavo
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p. 126 - 135
(2021/02/05)
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- Design, synthesis and in vitro evaluation of 4-oxo-6-substituted phenyl-2-thioxo1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives as HIV integrase strand transfer inhibitors
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Aim: To design, synthesis and in vitro evaluation of 4-oxo-6-substituted phenyl-2-thioxo1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives as HIV integrase strand transfer inhibitors. Background: Human immunodeficiency virus-1 (HIV-1), a member of retroviridae family, is the primary causative agent of acquired immunodeficiency syndrome (AIDS). Three enzymes viz: inte-grase (IN), reverse transcriptase (RT) and protease play important role in its replication cycle. HIV-1 integrase is responsible for the incorporation of viral DNA into human chromosomal DNA by cata-lyzing two independent reactions, 3′-processing (3′-P) and strand transfer (ST), which are observed as the “point of no-return” in HIV infection. Objective: To develop inhibitors against HIV integrase strand transfer step. Methods: Our previous results indicated that tetrahydro pyrimidine-5-carboxamide derivatives are potent HIV-1 IN inhibitors (unpublished results from our laboratory). Taking clue from above studies and our own experience, we hypothesized 4-oxo-6-substituted phenyl-2-thioxo1,2,3,4-tetrahydropyrimidine-5-carbonitrile analogues (14a to 14n) as inhibitors of HIV-1 Integrase strand transfer. Prototype compound 14 can be viewed as hybrid structure having characteristics of dihy-dropyrimidine derivatives 10-12 and tyrphostin 13. Results: A total of fourteen derivatives of 4-oxo-6-substituted phenyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile (14a-14n) were synthesized and evaluated using HIV-1 Integrase Assay Kit (Xpressbio Life Science Products, USA). The percentage inhibition of all compounds was investigated at 10 μM concentration and IC50 value of few highly active compounds was studied. The obtained results were validated by in silico molecular docking study using Glide (maestro version 9.3, Schr?dinger suite) in extra precision (XP) mode. Conclusion: Fourteen 4-oxo-6-substituted phenyl-2-thioxo 1,2,3,4-tetrahydropyrimidine-5-carbonitrile analogues were synthesized and evaluated for HIV-1 IN inhibitory activity. Three compounds 14a, 14e, and 14h exhibited significant percentage inhibition of HIV-1 IN. There was good in vitro-in silico correlation. However, none of the derivative was active against HIV-1 and HIV-2 below their cytotoxic concentration. It needs to be seen whether these compounds can be explored further for their anti-HIV or cytotoxic potential.
- Wadhwa, Pankaj,Jain, Priti,Jadhav, Hemant R.
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p. 387 - 395
(2021/06/17)
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- Design and synthesis of pyrimidine-5-carbonitrile hybrids as COX-2 inhibitors: Anti-inflammatory activity, ulcerogenic liability, histopathological and docking studies
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Two new series of 1,3,4-oxadiazole and coumarin derivatives based on pyrimidine-5-carbonitrile scaffold have been synthesized and evaluated for their COX-1/COX-2 inhibitory activity. Compounds 10c, 10e, 10h-j, 14e-f, 14i and 16 were found to be the most potent and selective inhibitors of COX-2 (IC50 0.041–0.081 μM, SI 139.74–321.95). Eight compounds were further investigated for their in vivo anti-inflammatory activity. The most active derivatives 10c, 10j and 14e displayed superior in vivo anti-inflammatory activity (% edema inhibition 39.3–48.3, 1 h; 58.4–60.5, 2 h; 70.8–83.2, 3 h; 78.9–89.5, 4 h) to the reference drug celecoxib (% edema inhibition 38.0, 1 h; 48.8, 2 h; 58.4, 3 h; 65.4, 4 h). These derivatives were also tested for their ulcerogenic liability, compound 10j showed better safety profile with reference to celecoxib while 10c and 14e exhibited mild lesions. Molecular docking studies of 10c, 10j, and 14e in the COX-2 active site revealed similar orientation and binding interactions as selective COX-2 inhibitors with a higher liability to access the selectivity side pocket.
- Alfayomy, Abdallah M.,Abdel-Aziz, Salah A.,Marzouk, Adel A.,Shaykoon, Montaser Sh. A.,Narumi, Atsushi,Konno, Hiroyuki,Abou-Seri, Sahar M.,Ragab, Fatma A.F.
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- Design, synthesis and in silico insights of new 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives with potent anticancer and multi-kinase inhibitory activities
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Aiming to obtain an efficient anti-proliferative activity, structure- and ligand-based drug design approaches were expanded and utilized to design and refine a small compound library. Subsequently, thirty-two 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives were selected for synthesis based on the characteristic pharmacophoric features required for PI3K and B-Raf oncogenes inhibition. All the synthesized compounds were evaluated for their in vitro anticancer activity. Compounds 17 and 22c displayed an acceptable potent activity according to the DTP-NCI and were further evaluated in the NCI five doses assay. To validate our design, compounds with the highest mean growth inhibition percent were screened against the target PI3Kα and B-RafV600E to confirm their multi-kinase activity. The tested compounds showed promising multi-kinase activity. Compounds 17 and 22c anticancer effectiveness and multi-kinase activity against PI3Kα and B-RafV600E were consolidated by the inhibition of B-RafWT, EGFR and VEGFR-2 with IC50 in the sub-micromolar range. Further investigations on the most potent compounds 17 and 22c were carried out by studying their safety on normal cell line, in silico profiling and predicted ADME characteristics.
- Abdel Gawad, Nagwa M.,El Kerdawy, Ahmed M.,George, Riham F.,Georgey, Hanan H.,Mohamed, Abdalla R.
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- Synthesis, antibacterial activities and molecular docking study of thiouracil derivatives containing oxadiazole moiety
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A series of novel thiouracil derivatives 9 containing an oxadiazole moiety have been synthesized by structural modification of a lead SecA inhibitor, 2. These compounds have been evaluated for their antibacterial activities against Bacillus amyloliquefaciens, Staphylococcus aureus and Bacillus subtilis. Among them, compounds 9g and 9n exhibited promising antibacterial activities against the tested strains. Compound 9g was also tested for its inhibitory activities against SecA ATPase, and the IC50 value of compound 9g was 19.9 μg/mL, lower than that of compound 2 (20.8 μg/mL). Molecular docking work indicates that compound 9g likely occupies the pocket formed by SecA IRA2 and NBD domain.
- Cui, Peng-Lei,Zhang, Di,Guo, Xiu-Min,Ji, Shu-Jing,Jiang, Qing-Mei
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supporting information
p. 1754 - 1762
(2021/04/09)
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- Structural insights of three 2,4-disubstituted dihydropyrimidine-5-carbonitriles as potential dihydrofolate reductase inhibitors
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In this report, we describe the structural characterization of three 2,4-disubstituted-dihydropyrimidine-5-carbonitrile derivatives, namely 2-{[(4-nitrophenyl)methyl]sulfanyl}-6-oxo-4-propyl-1,6-dihydropyrimidine-5-carbonitrile 1, 4-(2-methylpropyl)-2-{[(4-nitrophenyl)methyl]sulfanyl}-6-oxo-1,6-dihydropyrimidine-5-carbonitrile 2, and 2-[(2-ethoxyethyl)sulfanyl]-6-oxo-4-phenyl-1,6-dihydropyrimidine-5-carbonitrile monohydrate 3. An X-ray diffraction analysis revealed that these compounds were crystallized in the centrosymmetric space groups and adopt an L-shaped conformation. One of the compounds (3) crystallized with a water molecule. A cyclic motif (R22 (8)) mediated by N–H···O hydrogen bond was formed in compounds 1 and 2, whereas the corresponding motif was not favorable, due to the water molecule, in compound 3. The crystal packing of these compounds was analyzed based on energy frameworks performed at the B3LYP/6-31G(d,p) level of theory. Various inter-contacts were characterized using the Hirshfeld surface and its associated 2D-fingerprint plots. Furthermore, a molecular docking simulation was carried out to assess the inhibitory potential of the title compounds against the human dihydrofolate reductase (DHFR) enzyme.
- Abdelbaky, Mohammed S. M.,Al-Wahaibi, Lamya H.,El-Emam, Ali A.,Elmorsy, Mohammed A.,Garcia-Granda, Santiago,Shaik, Althaf,Thamotharan, Subbiah,Thiruvenkatam, Vijay
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- Synthesis and antibacterial evaluation of thiouracil derivatives containing 1,2,4-triazolo[1,5-a]pyrimidine
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A series of new thiouracil compounds containing 1,2,4-triazolo[1,5-a]pyrimidine were designed and synthesized. The in vitro antibacterial activities of the new compounds against Bacillus am-yloliquefaciens, Staphylococcus aureus and Bacillus subtilis were tested. The results showed that some of the new compounds had strong inhibitory activities against the tested bacteria. At the concentration of 50 μg/mL, the compound 12d had broad and the highest inhibitory activity with the 100% inhibition against the three tested strains, the same as norfloxacin which was used as the control.
- Cui, Penglei,Zhang, Di,Guo, Xiumin,Ji, Shujing,Jiang, Qingmei
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p. 555 - 560
(2021/07/25)
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- Design, synthesis, molecular docking and antiproliferative activity of some novel benzothiazole derivatives targeting EGFR/HER2 and TS
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Multi-targeted anticancer drugs are in focus as a promising research topic. A new series of benzothiazoles hybridized with pyrimidine moiety was designed and synthesized using the lead compound 4a. Various chemical modifications on the pyrimidine ring of 4a at four different positions were done in a trial to get new multi-targeted anticancer agents. The structures of the newly synthesized compounds were established on their elemental analyses and spectral data. All final synthesized derivatives were submitted to the National Cancer Institute (NCI), USA, to be screened for their in vitro anticancer activity. Further evaluation for the cytotoxic activity of the most active compounds was performed using the MTT assay method. Compounds 4d, 8d, 8h, 8i and 17 were then selected for examining their in vitro enzyme inhibitory activities against EGFR, HER2 and TS enzymes using lapatinib and 5FU as standards. Furthermore, cell cycle analysis and apoptosis induction detection were also evaluated. Finally, molecular docking studies were carried out for compounds 4d, 8d, 8h, 8i and 17 to interpret their observed enzymatic activities based on the ligand–protein interactions.
- Abdellatif, Khaled R. A.,Amin, Noha H.,Belal, Amany,El-Saadi, Mohamed T.,Hemeda, Loah R.,Said, Eman G.
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- Design and synthesis of new 1,6-dihydropyrimidin-2-thio derivatives targeting VEGFR-2: Molecular docking and antiproliferative evaluation
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A series of new 1,6-dihydropyrimidin-2-thiol derivatives (scaffold A) as VEGFR-2 inhibitors has been designed and synthesized. Compounds 3a, 3b, 3e and 4b have been selected for in vitro anticancer screening by the National Cancer Institute. Compound 3e showed remarkable anticancer activity against most of the cell lines tested, where a complete cell death against leukemia, non-small cell lung cancer, colon, CNS, melanoma, and breast cancer cell lines was observed. In vitro five dose tests showed that compound 3e had high activity against most of the tested cell lines with GI50 ranging from 19 to 100 μM and selectivity ratios ranging between 0.75 and 1.71 at the GI50 level. VEGFR-2-kinase was tested against 3a, 3b, 3e, 4b and sorafenib was used as a reference. Compounds 3a and 3e were the most potent analogues with IC50 values of 386.4 nM and 198.7 nM against VEGFR-2, respectively, in comparison to sorafenib (IC50 = 0.17 nM). The results of the docking study showed a good fitting of the new compounds to the active site of VEGFR-2 with binding free energies in the range of ?9.80 to ?11.25 kcal/mol compared to ?12.12 kcal/mol for sorafenib. Compounds 4a-e with the hydroxyimino group had a higher affinity to VEGFR-2 than their parent derivatives 3a-e.
- Abdel-Aziz, Mohamed,Abdel-Aziz, Salah A.,Abdelrahman, Kamal S.,Gouda, Ahmed M.,Marzouk, Adel A.,Wanas, Amira S.,Youssif, Bahaa G. M.
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- Thiouracil-containing 1,2,4-triazolo[1,5-a]pyrimidine compound, and preparation method and application thereof
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The invention discloses a thiouracil-containing 1,2,4-triazolo[1,5-a]pyrimidine compound. A preparation method for the thiouracil-containing 1,2,4-triazolo[1,5-a]pyrimidine compound comprises the following steps: with 3-amino-1,2,4-triazole, aromatic amine and an aromatic aldehyde compound as initial raw materials, dissolving 3-amino-1,2,4-triazole and ethyl 4-chloroacetoacetate in glacial aceticacid for a reflux reaction to obtain an intermediate I; further reacting the intermediate with phosphorus oxychloride and aromatic amine to obtain an intermediate II; subjecting aromatic aldehyde, ethyl cyanoacetate and thiourea to a reaction under the catalysis of piperidine to obtain an intermediate III; and reacting the intermediate II with the intermediate III in an acetonitrile solvent underthe catalysis of potassium carbonate to obtain a target product. The method provided by the invention is simple in process, easy to operate and easy for large-scale production, and experiments prove that the prepared target compound has strong bacteriostatic activity and can be widely applied to bacteriostatic pharmaceutical preparations.
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Paragraph 0012-0013
(2020/08/30)
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- Quantitative analysis of hydrogen and chalcogen bonds in two pyrimidine-5-carbonitrile derivatives, potential DHFR inhibitors: An integrated crystallographic and theoretical study
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Two potential bioactive pyrimidine-5-carbonitrile derivatives have been synthesized and characterized by spectroscopic techniques (1H and 13C-NMR) and the three dimensional structures were elucidated by single crystal X-ray diffraction at low temperature (160 K). In both structures, the molecular conformation is locked by an intramolecular C-H?C interaction involving the cyano and CH of the thiophene and phenyl rings. The intermolecular interactions were analyzed in a qualitative manner based on the Hirshfeld surface and 2D-fingerprint plots. The results suggest that the phenyl and thiophene moieties have an effect on the crystal packing. For instance, the chalcogen bonds are only preferred in the thiophene derivative. However, both structures uses a common N-H?O hydrogen bond motif. Moreover, the structures of 1 and 2 display 1D isostructurality and molecular chains stabilize by intermolecular N-H?O and N-H?N hydrogen bonds. The nature and extent of different non-covalent interactions were further characterized by the topological parameters derived from the quantum theory of atoms-in-molecules approach. This analysis indicates that apart from N-H?O hydrogen bonds, other non-covalent interactions are closed-shell in nature. A strong and linear N-H?O hydrogen bond shows intermediate bonding character between shared and closed-shell interactions. The molecular docking analysis suggests that both compounds display potential inhibitory effect against the dihydrofolate reductase (DHFR) enzyme from humans and Staphylococcus aureus.
- Al-Mutairi, Aamal A.,Al-Shaalan, Nora H.,Al-Wahaibi, Lamya H.,Blacque, Olivier,Chakraborty, Kushumita,El-Emam, Ali A.,Percino, M. Judith,Syed Majeed, Mohamed Yehya Annavi,Thamotharan, Subbiah
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p. 36806 - 36817
(2020/10/27)
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- Substituted pyrimidine-containing myricetin derivative as well as preparation method and application thereof
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The invention discloses a substituted pyrimidine-containing myricetin derivative as well as a preparation method and application thereof. The general structural formula of the myricetin derivative isshown in the specification, R represents a substituted phenyl group or a substituted aromatic heterocyclic group; n is the number of carbon in a carbon chain and is 2-6; wherein the substituted phenylgroup is on the ortho-, meta-and para- position of a benzene ring and contains C1-6 alkyl groups, C1-6 alkoxyl groups, nitro groups, halogen atoms and hydrogen atoms; the aromatic heterocyclic groupis thienyl, furyl, pyrrolyl or pyridyl; and substituent groups on substituted aromatic heterocycle are ortho-, meta-and para- positions and contain C1-6 alkyl groups, C1-6 alkoxyl groups, nitro groups, halogen atoms and hydrogen atoms. The derivative can well inhibit the activity of pathogenic bacteria of plants.
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Paragraph 0029; 0034-0035
(2020/12/05)
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- Pyrimidone molecule for promoting SOD activity in cosmetics and preparation method and application thereof
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The invention discloses a pyrimidone molecule for prompting the SOD activity in cosmetics and a preparation method and application thereof, and belongs to the technical field of synthesis of proteaseagonists. According to the technical scheme, the molecule is characterized in that the pyrimidone molecule is of the structure shown in the specification, methyl benzoate with the low cost is adoptedas a starting raw material, and the novel pyrimidone molecule of the novel structure can be obtained through condensation substitution, ring formation, chlorination, cyanogroup substitution, aethrization and other poly-step reactions. The molecule is easy and rapid to operate, high in yield and suitable for industrial mass production, can effectively improve the activity of SOD in cosmetics, and has the potential as a domestic auxiliary additive.
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- Design, synthesis, molecular modelling, and biological evaluation of novel substituted pyrimidine derivatives as potential anticancer agents for hepatocellular carcinoma
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New anticancer agents are highly needed to overcome cancer cell resistance. A novel series of pyrimidine pyrazoline-anthracene derivatives (PPADs) (4a-t) were designed and synthesised. The anti-liver cancer activity of all compounds was screened in vitro against two hepatocellular carcinoma (HCC) cell lines (HepG2 and Huh-7) as well as normal fibroblast cells by resazurin assay. The designed compounds 4a-t showed a broad-spectrum anticancer activity against the two cell lines and their activity was more prominent on cancer compared to normal cells. Compound 4e showed high potency against HepG2 and Huh-7 cell lines ((IC50=5.34 and 6.13 μg/mL, respectively) comparable to that of doxorubicin (DOX) activities. A structure activity relationship (SAR) has been investigated and compounds 4e, 4i, 4m, and 4q were the most promising anticancer agents against tested cell lines. These compounds induced apoptosis in HepG2 and Huh-7 cells through significant activation of caspase 3/7 at all tested concentrations. In conclusion, 4e could be a potent anticancer drug.
- Ahmed, Naglaa Mohamed,Youns, Mahmoud,Soltan, Moustafa Khames,Said, Ahmed Mohammed
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p. 1110 - 1120
(2019/06/06)
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- α-Amino-β-carboxymuconate-?-semialdehyde Decarboxylase (ACMSD) Inhibitors as Novel Modulators of de Novo Nicotinamide Adenine Dinucleotide (NAD+) Biosynthesis
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NAD+ has a central function in linking cellular metabolism to major cell-signaling and gene-regulation pathways. Defects in NAD+ homeostasis underpin a wide range of diseases, including cancer, metabolic disorders, and aging. Although the beneficial effects of boosting NAD+ on mitochondrial fitness, metabolism, and lifespan are well established, to date, no therapeutic enhancers of de novo NAD+ biosynthesis have been reported. Herein we report the discovery of 3-[[[5-cyano-1,6-dihydro-6-oxo-4-(2-thienyl)-2-pyrimidinyl]thio]methyl]phenylacetic acid (TES-1025, 22), the first potent and selective inhibitor of human ACMSD (IC50 = 0.013 μM) that increases NAD+ levels in cellular systems. The results of physicochemical-property, ADME, and safety profiling, coupled with in vivo target-engagement studies, support the hypothesis that ACMSD inhibition increases de novo NAD+ biosynthesis and position 22 as a first-class molecule for the evaluation of the therapeutic potential of ACMSD inhibition in treating disorders with perturbed NAD+ supply or homeostasis.
- Pellicciari, Roberto,Liscio, Paride,Giacchè, Nicola,De Franco, Francesca,Carotti, Andrea,Robertson, Janet,Cialabrini, Lucia,Katsyuba, Elena,Raffaelli, Nadia,Auwerx, Johan
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p. 745 - 759
(2018/02/17)
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- Part III: Novel checkpoint kinase 2 (Chk2) inhibitors; design, synthesis and biological evaluation of pyrimidine-benzimidazole conjugates
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Recently a dramatic development of the cancer drug discovery has been shown in the field of targeted cancer therapy. Checkpoint kinase 2 (Chk2) inhibitors offer a promising approach to enhance the effectiveness of cancer chemotherapy. Accordingly, in this study many pyrimidine-benzimidazole conjugates were designed and twelve feasible derivatives were selected to be synthesized to investigate their activity against Chk2 and subjected to study their antitumor activity alone and in combination with the genotoxic anticancer drugs cisplatin and doxorubicin on breast carcinoma, (ER+) cell line (MCF-7). The results indicated that the studied compounds inhibited Chk2 activity with high potency (IC50 = 5.56 nM - 46.20 nM). The studied candidates exhibited remarkable antitumor activity against MCF-7 (IG50 = 6.6 μM - 24.9 μM). Compounds 10a-c, 14 and 15 significantly potentiated the activity of the studied genotoxic drugs, whereas, compounds 9b and 20–23 antagonized their activity. Moreover, the combination of compound 10b with cisplatin revealed the best apoptotic effect as well as combination of compound 10b with doxorubicin led to complete arrest of the cell cycle at S phase where more than 40% of cells are in the S phase with no cells at G2/M. Structure-activity relationship was discussed on the basis of molecular modeling study using Molecular modeling Environment program (MOE).
- Galal, Shadia A.,Khattab, Muhammad,Shouman, Samia A.,Ramadan, Raghda,Kandil, Omaima M.,Kandil, Omnia M.,Tabll, Ashraf,El Abd, Yasmine S.,El-Shenawy, Reem,Attia, Yasmin M.,El-Rashedy, Ahmed A.,El Diwani, Hoda I.
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p. 687 - 708
(2018/02/10)
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- Synthesis and Cytotoxicity of Some Thieno[2,3-d]pyrimidine Derivatives
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A series of compounds 5-amino-2-ethylmercapto-4-phenyl-6-subistitutedthieno[2,3-d]pyrimidines (8a–d), 4-chloro-7-ethylmercapto-9-phenylpyrimido[5′,4′:4,5]thieno[3,2-d]triazine (9), and 2-ethylmercapto-8-oxo-4-phenyl-7-(4-chlorophenyl)pyrimido [4′,5′:4,5]thieno[2,3-d]pyrimidine (10) were synthesized and their structures were confirmed by 1H NMR, 13C NMR, and MS. All compounds were evaluated for their IC50 values against three cancer cell lines (MCF-7, HUH-7 and BHK) and WISH cells. The IC50 of compound (8d) was calculated for each cell line. Interestingly, the IC50 for the normal human amnion WISH cell line was much higher (723 μg/mL) than those found for the tumor cell lines BHK (17 μg/mL), HUH-7 (5.8 μg/mL), and MCF-7 (8.3 μg/mL). The proliferation inhibition of normal (WISH) and tumor (BHK, HUH-7, and MCF-7) cells by compound (8d) was investigated using MTT assay, and the IC50 was calculated after 48 h of treatment for each cell line.
- Saddik, Abdelreheem A.,Kamal El-Dean, Adel M.,El-Sokary, Gamal H.,Hassan, Khairy M.,Abbady, Mohamed S.,Ismail, Ismail A.,Saber, Saber H.
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- Design, synthesis and antimicrobial activities of thiouracil derivatives containing triazolo-thiadiazole as SecA inhibitors
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A series of novel thiouracil derivatives containing a triazolo-thiadiazole moiety (7a-7l) have been synthesized by structural modifications on a lead SecA inhibitor, 2. All the compounds have been evaluated for their antibacterial activities against Bacillus amyloliquefaciens, Staphylococcus aureus, and Bacillus subtilis. Compounds 7d and 7g were also tested for their inhibitory activities against SecA ATPase due to their promising antimicrobial activities. The inhibitory activity of compound 7d was found to be higher than that of 2. Molecular docking work suggests that compound 7d might bind at a pocket close to the ATPase ATP-binding domain.
- Cui, Penglei,Li, Xiaoliu,Zhu, Mengyuan,Wang, Binghe,Liu, Jing,Chen, Hua
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p. 159 - 165
(2017/01/03)
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- Amino group-containing terminal alkyne structure unit with kind of urea pyrimidine derivatives, preparation method and application
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The invention belongs to the field of medicinal chemistry, and discloses pyrimidine compounds containing semicarbazide and terminal alkyne structural units, and preparation methods and applications of the pyrimidine compounds in preparation of antitumor d
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Paragraph 0060; 0075-0076
(2016/10/07)
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- INHIBITORS OF α-AMINO-β-CARBOXYMUCONIC ACID SEMIALDEHYDE DECARBOXYLASE
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The present disclosure discloses compounds capable of modulating the activity of α-amino-β-carboxymuconic acid semialdehyde decarboxylase (ACMSD), which are useful for the prevention and/or the treatment of diseases and disorders associated with defects in NAD+ biosynthesis, e.g., metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, kidney diseases, and diseases associated with ageing. The present application also discloses pharmaceutical compositions comprising said compounds and the use of such compounds as a medicament.
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Page/Page column 103
(2016/03/22)
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- Synthesis of 4-(thiazol-2-ylamino)-benzenesulfonamides with carbonic anhydrase I, II and IX inhibitory activity and cytotoxic effects against breast cancer cell lines
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A series of 4-(thiazol-2-ylamino)-benzenesulfonamides was synthesized and screened for their carbonic anhydrase (CA, EC 4.2.1.1) inhibitory and cytotoxic activity on human breast cancer cell line MCF-7. Human (h) CA isoforms I, II and IX were included in the study. The new sulfonamides showed excellent inhibition of all three isoforms, with KIs in the range of 0.84-702 nM against hCA I, of 0.41-288 nM against hCA II and of 5.6-29.2 against the tumor-associated hCA IX, a validated anti-tumor target, with a sulfonamide (SLC-0111) in Phase I clinical trials for the treatment of hypoxic, metastatic solid tumors overexpressing CA IX. The new compounds showed micromolar inhibition of growth efficacy against breast cancer MCF-7 cell lines.
- Abdel Gawad, Nagwa M.,Amin, Noha H.,Elsaadi, Mohammed T.,Mohamed, Fatma M.M.,Angeli, Andrea,De Luca, Viviana,Capasso, Clemente,Supuran, Claudiu T.
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p. 3043 - 3051
(2016/06/13)
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- Synthesis, molecular modeling, and biological evaluation of novel benzimidazole derivatives as inhibitors of hepatitis C virus RNA replication
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In this study, synthesis and docking studies of a series of new benzimidazole derivatives linked to substituted pyrimidines either through the methylenethio linkage or its bioisosteric methylene amino bridge were carried out. All the synthesized compounds were evaluated for their hepatitis C virus (HCV) RNA replication-inhibitory activity. Compounds 4d, 4f, and 4h were found to be more potent than VX-950 (IC50/90of 4d=0.123/0.321, 4f=0.145/0.345, 4h=0.129/0.432, VX-950=0.20/0.45μM, respectively) and 6d (IC50/90=0.116/0.452μM) displayed activity very similar to that of the standard. Compounds 4d, 4f, 4h, and 6d were potent HCV RNA replication inhibitors and are good drug candidates for further investigations.
- El Diwani, Hoda Ibrahim,Abdel-Mohsen, Heba Tawfik,Salama, Ismail,Ragab, Fatma Abdel-Fattah,Ramla, Mostafa Mahmoud,Galal, Shadia Ahmed,Abdalla, Mohamed Mostafa,Abdel-Wahab, Abeer,El Demellawy, Maha Adel
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p. 856 - 866
(2015/02/19)
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- Synthesis and evaluation of thiouracil derivatives as dipeptidyl peptidase iv inhibitors
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A series of thiouracil derivatives were designed, synthesized and screened for in vitro inhibition of dipeptidyl peptidase IV. The SAR study indicated the influence of substituted chemical modifications on thiouracil scaffold. Compounds 8 (IC50
- Sharma, Mani,Singh, Divya,Gupta, Monica
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p. 257 - 264
(2013/03/14)
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- Laccase-catalyzed domino reaction between catechols and 6-substituted 1,2,3,4-tetrahydro-4-oxo-2-thioxo-5-pyrimidinecarbonitriles for the synthesis of pyrimidobenzothiazole derivatives
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The laccase-catalyzed domino reaction between catechols and 6-substituted 1,2,3,4-tetrahydro-4-oxo-2-thioxo-5-pyrimidinecarbonitriles using aerial O 2 as the oxidant delivers new pyrimidobenzothiazole derivatives. The complete structure elucida
- Abdel-Mohsen, Heba T.,Conrad, Juergen,Beifuss, Uwe
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p. 7986 - 8003
(2013/09/12)
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- Synthesis, biological evaluation and molecular docking studies of some pyrimidine derivatives
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Some novel pyrimidine-5-carbonitrile derivatives bearing various substituent have been synthesized. The structures of target compounds were confirmed by elemental analysis and spectral data. Some selected members of the newly synthesized compounds were investigated for their cytotoxic potency against certain human tumor cell lines. Five representative active anticancer compounds 6a, 6c, 6d, 17a and 18a were subjected to docking using MOE program on the 3D structure of two enzymes, namely; thymidylate synthase and dihydrofolate reductase. The antimicrobial activities of the synthesized compounds were tested against Staphylococcus aureus, Pseudomonas aeruginosa, Shigella flexneri and Candida albicans. Compounds 2c, 7a and 9c showed broad spectrum antimicrobial activity.
- Fargualy, Ahmed M.,Habib, Nargues S.,Ismail, Khadiga A.,Hassan, Ahmed M. M.,Sarg, Marwa T. M.
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p. 276 - 295
(2013/10/01)
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- Synthesis of a 2,4,6-trisubstituted 5-cyano-pyrimidine library and evaluation of its immunosuppressive activity in a Mixed Lymphocyte Reaction assay
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A series of novel pyrimidine analogues were synthesized and evaluated for immunosuppressive activity in the Mixed Lymphocyte Reaction assay, which is well-known as the in vitro model for in vivo rejection after organ transplantation. Systematic variation of the substituents at positions 2, 4 and 6 of the pyrimidine scaffold led to the discovery of 2-benzylthio-5-cyano-6-(4- methoxyphenyl)-4-morpholinopyrimidine with an IC50 value of 1.6 μM in the MLR assay.
- Stella, Alessandro,Van Belle, Kristien,De Jonghe, Steven,Louat, Thierry,Herman, Jean,Rozenski, Jef,Waer, Mark,Herdewijn, Piet
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p. 1209 - 1218
(2013/03/28)
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- Microwave-assisted synthesis, molecular docking and antitubercular activity of 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives
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Based on bioisosteric similarities with isoniazid, a series of 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives has been designed. The target compounds have been synthesized by multicomponent reaction which involves one-pot organic reactions using ethylcyanoacetate, urea/thiourea and arylaldehydes in presence of ethanolic K2CO3. Two methodologies, conventional and microwave-assisted, have been adopted for the synthesis. The later strategy gave high yields in less than 10 min as compared to long hours using the former approach. Molecular docking of the target compounds into the enzyme Mycobacterium tuberculosis enoyl reductase (InhA) revealed important structural information on the plausible binding interactions. Major binding interactions were found to be of dispersion type (residues Tyr158, Ile215, Met103 and Met199) and a hydrogen bond with Tyr158. Binding poses of the all the compounds were energetically favorable and showed good interactions with the active site residues. Few selected compounds were also evaluated for antitubercular activity in vitro against drug-sensitive M. tuberculosis H37Rv strain and clinically isolated S, H, R and E resistant M. tuberculosis by luciferase reporter phage (LRP) assay method. Some compounds displayed promising antimycobacterial activity comparable or less than the standard drugs isoniazid and rifampicin.
- Mohan, Sahoo Biswa,Ravi Kumar,Dinda,Naik,Prabu Seenivasan,Kumar, Vanaja,Rana, Dharmarajsinh N.,Brahmkshatriya, Pathik S.
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supporting information
p. 7539 - 7542
(2013/02/21)
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- Synthesis and bioactivity evaluation of new 6-aryl-5-cyano thiouracils as potential antimicrobial and anticancer agents
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Several novel 6-aryl-5-cyano thiouracil derivatives were synthesized and explored for their activities as antibacterial, antifungal and anticancer agents. The antimicrobial evaluation revealed that compounds 7b and 7c possessed superior antibacterial activity against the Gram positive bacteria S. aureus and B. subtilis compared to the reference drug amoxicillin. Moreover, compound 4i was found to be a broad spectrum antimicrobial agent and it also exhibited the highest antifungal activity against C. albicans, even higher than the reference drug amphotericin B (MIC = 2.34, 3.00 μg/mL respectively). Selected compounds were tested for in vitro cytotoxicity at a single 10-5 M concentration in accordance to the NCI (USA) protocol. The preliminary screening results showed that most of the compounds had limited cytotoxic activity against renal cancer UO-31 and/or A498 cell lines. Nevertheless, compounds 6d and 6i displayed potent growth inhibitory effect toward non-small cell lung cancer HOP-92 and leukemia MOLT-4 cell lines, respectively.
- Taher, Azza Taher,Abou-Seri, Sahar Mahmoud
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p. 9868 - 9886
(2012/11/13)
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- Part I: Synthesis, cancer chemopreventive activity and molecular docking study of novel quinoxaline derivatives
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The reaction of o-phenylene diamine and ethyl oxamate is reinvestigated and led to 3-aminoquinoxalin-2(1H)-one rather than benzimidazole-2-carboxamide as was previously reported. The structure of the obtained quinoxaline has been confirmed by X-ray. The anti-tumor activity of synthesized quinoxalines 1-21 has been evaluated by studying their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13- acetate (TPA). Among the studied compounds 1-21, compounds 12, 8, 13, 18, 17 and 19, respectively, demonstrated strong inhibitory effects on the EBV-EA activation without showing any cytotoxicity and their effects being stronger than that of a representative control, oleanolic acid. Furthermore, compound 12 exhibited a remarkable inhibitory effect on skin tumor promotion in an in vivo two-stage mouse skin carcinogenesis test using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter. The result of the present investigation indicated that compound 12 might be valuable as a potent cancer chemopreventive agent. Moreover, the molecular docking into PTK (PDB: 1t46) has been done for lead optimization of the aforementioned compounds as potential PTK inhibitors.
- Galal, Shadia A.,Abdelsamie, Ahmed S.,Tokuda, Harukuni,Suzuki, Nobutaka,Lida, Akira,Elhefnawi, Mahmoud M.,Ramadan, Raghda A.,Atta, Mona H.E.,El Diwani, Hoda I.
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scheme or table
p. 327 - 340
(2011/02/25)
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- Synthesis and antiviral activity of new substituted pyrimidine glycosides
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A number of N-substituted pyrimidine glycosides were synthesized by coupling reaction of the pyrimidine base with acetobromosugars followed by deprotection. The synthesized compounds were tested for their antiviral activity against Hepatitis B Virus (HBV). Plaque reduction infectivity assay was used to determine virus count reduction as a result of treatment with tested compounds which showed moderate to high anti viral activities.
- Ramiz, Mahmoud M. M.,El-Sayed, Wael A.,Hagag, Ezzat,Abdel-Rahman, Adel A.-H.
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experimental part
p. 1028 - 1038
(2011/11/29)
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- Synthesis of novel 6-phenyl-2,4-disubstituted pyrimidine-5-carbonitriles as potential antimicrobial agents
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New series of 6-phenyl-2,4-disubstituted pyrimidine-5-carbonitriles namely, 2-substitued thio-6-phenyl-3,4-dihydro-4-oxopyrimidine-5-carbonitriles (5a-d, 6, 7a-d, 8), 2-(4-chlorobenzylthio)-4-chloro-6-phenylpyrimidine-5-carbonitrile (9), 2-(4-chlorobenzylthio)-4-arylthio-6-phenylpyrimidine-5-carbonitriles (10a-d) and 2-(4-chlorobenzylthio)-4-arylamino-6-phenylpyrimidine-5- carbonitriles (11a-d) was synthesized and tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Compounds 5b, 5c, 6, 7a, 7b, 7c, 9 and 11a displayed marked antibacterial activity particularly against the tested Gram-positive bacteria, while compounds 6, 7c, 7d and 9 were moderately or weakly active against C. albicans.
- Al-Abdullah, Ebtehal S.,Al-Obaid, Abdul-Rahman M.,Al-Deeb, Omar A.,Habib, Elsayed E.,El-Emam, Ali A.
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scheme or table
p. 4642 - 4647
(2011/11/04)
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- Synthesis and screening of substituted eugenol and paracetamol linked pyrimidines
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Several 6-(substituted)-5-cyano-2-methylthio-3-N-methyl-3,4- dihydropyrimidin-4-ones 1a-e were treated with N-[4-(2-hydrazinyl-2-oxoethoxy) phenyl] acetamide and 2-[3-methoxy-4-(prop-2-en-1-yl) phenoxy] aceto hydrazide, to get 2a-e and 3a-e respectively. All the synthesized compounds were screened for their antimicrobial activity and were characterized by elemental analyses, IR, 1H NMR and mass spectral data.
- Basavaraja,Padmashali, Basavaraj,Bhat, K. Ishwar,Hussain, Mumtaz M.,Vijaykumar
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p. 241 - 244
(2013/09/24)
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- Novel benzimidazole-pyrimidine conjugates as potent antitumor agents
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As a continuation to our previous work in synthesizing antitumor benzimidazoles, a series of 2-((1H-benzo[d]imidazol-2-yl)methylthio)-4-(substituted)-6-phenylpyrimidine-5-carbonitriles was synthesized. Evaluation of the synthesized compounds for their in vitro cytotoxic activity against twelve cell lines namely, Cervical carcinoma (KB), Ovarial carcinoma (SK OV-3), CNS cancer (SF-268), Non small lung cancer (NCI H460), Colonadenocarcinoma (RKOP27), Leukaemia (HL60, U937, K562), Melanoma (G361, SK-MEL-28) and Neuroblastoma (GOTO, NB-1) revealed their marked potency when compared with known anticancer drugs.
- Abdel-Mohsen, Heba T.,Ragab, Fatma A.F.,Ramla, Mostafa M.,El Diwani, Hoda I.
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scheme or table
p. 2336 - 2344
(2010/06/15)
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- The first low μM SecA inhibitors
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SecA ATPase is a critical member of the Sec family, which is important in the translocation of membrane and secreted polypeptides/proteins in bacteria. Small molecule inhibitors can be very useful research tools as well as leads for future antimicrobial agent development. Based on previous virtual screening work, we optimized the structures of two hit compounds and obtained SecA ATPase inhibitors with IC50 in the single digit micromolar range. These represent the first low micromolar synthetic inhibitors of bacterial SecA and will be very useful for mechanistic studies.
- Chen, Weixuan,Huang, Ying-ju,Gundala, Sushma Reddy,Yang, Hsiuchin,Li, Minyong,Tai, Phang C.,Wang, Binghe
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experimental part
p. 1617 - 1625
(2010/05/17)
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- Synthesis of some new pyrimidine and pyrimido[4,5-d]pyrimidine derivatives
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A convenient synthesis of a series of pyrimidine carbonitrile, thiopyrimidine, and pyrimidopyrimidine derivatives, via the reactions of the versatile, readily accessible 6-aryl-4-oxo-2-thioxo-hexahydro-pyrimidine-5- carbonitrile with the appropriate reagents, is described. Copyright Taylor & Francis Group, LLC.
- Fadda, Ahmed A.,El-Latif, Ehab Abd,Bondock, Samir,Samir, Ahmed
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body text
p. 4352 - 4368
(2009/04/11)
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- The Mannich reaction in the synthesis of N,S-containing heterocycles : 55*5. Synthesis and structures of new pyrimido[2,1-b][1,3,5] thiadiazine derivatives
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Reactions of 6-aryl-5-cyano-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidines with formaldehyde and primary amines gave earlier unknown 3,4-dihydro-2H,6H- pyrimido[2,1-b]-[1,3,5]thiadiazine derivatives in 58-94% yields. In boiling AcOH, these pyrimidothiadiazines underwent the retro-Mannich reaction leading to the starting pyrimidine-2-thiones. The structure of 3-(4-ethoxyphenyl)-6-oxo-8- phenyl-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3,5]thiadiazine-7-carbonitrile was studied by X-ray diffraction analysis.
- Dotsenko,Krivokolysko,Rusanov,Litvinov
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p. 1437 - 1440
(2008/09/17)
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- An effecient one-pot synthesis of 6-aryl-5-cyano-2-thiopyrimidinone derivatives and their tetra-butyl ammonium ionic forms
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Three-component condensation of benzaldehyde derivatives, methylcyanoacetate and thiourea in the presence of tetra-butyl ammonium hydroxide in reflux condition to afford the corresponding tetra-butyl ammonium 6-aryl-5-cyano-2-thiopyrimidonate ionic forms.
- Mohammadnejad, Mahdieh,Bararjanian, Morteza,Balalaie, Saeed
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p. 467 - 472
(2008/02/12)
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- An efficient one-pot synthesis of 6-aryl-5-cyano-2-thiopyrimidinone derivatives and their piperidinium ionic forms, x-ray crystal structures
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Three-component condensation of benzaldehyde derivatives, alkyl cyanoacetates and thiourea in the presence of piperidine in reflux condition provides a direct route to piperidinium 6-aryl-5-cyano 2-thiopyrimidonate salts in good yields. These reactions were also carried out under microwave irradiation. The yields of products under the microwave condition were better as compared to the reflux media. The acidification of these ionic forms resulted in the formation of 6-aryl-5-cyano-2-thiopyrimidone derivatives. The X-ray structures of the ionic forms (4, 5, and 7) show that there are anionic thiopyrimidinone skeletons hydrogen bridged with piperidinium cations.
- Balalaie, Saeed,Bararjanian, Morteza,Rominger, Frank
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p. 821 - 826
(2007/10/03)
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- Synthesis and anti-microbial activity of some pyrimidine derivatives
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4-Aryl-5-carboethoxy-6-methyl-1,2,3,4-tetrahydropyrimidin-2-ones have been synthesized from easily available starting materials. The carboethoxy group at the C5-position of the pyrimidine ring is converted to corresponding hydrazide which in turn is condensed with cyclising agents such as aromatic aldehydes, CS2 etc. to give fused heterocycles. The fused heterocycles are then subjected to phenacylation to give N3-phenacylpyrimido-heterocycles in excellent yield. In a slightly modified way, uracil derivatives are condensed with ethyl bromoacetate to give N3-β-ethoxycarbonyl derivatives. The hydrazide derivatives of these N3-β-ethoxycarbonyl derivatives subsequently react with 1,2-diketones to give corresponding pyrimido pyridazine derivatives.
- Padhy,Bardhan,Panda
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p. 910 - 915
(2007/10/03)
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- Glycosylation of 2-thiouracil derivatives. A synthetic approach to 3- glycosyl-2,4-dioxypyrimidines
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Reaction of 6-aryl-5-cyano-2-thiouracils 2a-d with glycosyl halides 4a,b under alkaline conditions gave the respective bisglycosylated derivatives 5a- h. However, their deacetylation with ammonia in methanol caused a cleavage of the S-glycosyl residue and gave the N-3 glycosylated analogues 6a-h.
- Khodair,Ibrahim,El Ashry
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p. 433 - 444
(2007/10/03)
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- Synthesis of 7-nitro- qnd 7,9-dinitro-4-aryl-3-cyanopyrimidobenzothiazol-2-ones
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6-Aryl-5-cyano-2-thiouracils (1) on reaction with 2,4-dinitrochlorobenzene (2A) and picryl chloride (2B) separately gives pyrimidobenzothiazol-2-ones 5A and 5B, respectively.
- Ram, Vishnu J.,Roy, Raja,Vlietinck, A. J.
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p. 876 - 878
(2007/10/02)
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