- Design and synthesis of new thiophene/ thieno[2,3-d]pyrimidines along with their cytotoxic biological evaluation as tyrosine kinase inhibitors in addition to their apoptotic and autophagic induction
-
This work describes the synthesis and anticancer activity against kinase enzymes of newly designed thiophene and thieno[2,3-d]pyrimidine derivatives, along with their potential to activate autophagic and apoptotic cell death in cancer cells. The designed compounds were scanned for their affinity for kinases. The results were promising with affinity ranges from 46.7% to 13.3%. Molecular docking studies were performed, and the compounds were then screened for their antiproliferative effects. Interestingly, compounds 8 and 5 resulted in higher cytotoxic effects than the reference standard against MCF-7 and HepG-2. The compounds were evaluated for their induction of apoptosis and/or necrosis on HT-29 and HepG-2. Three compounds induced significant early apoptosis compared to untreated control HT-29 cells, and four derivatives were more significant compared to untreated HepG-2 cells. We further investigated the effect of four compounds on the autophagy process within HT-29, HepG-2, and MCF-7 cells with flow cytometry. Similar to the apoptosis results, compound 5 showed the highest autophagic induction among all compounds. The potential inhibitory activity of the synthesized compounds on kinases was assessed. Screened compounds showed inhibition activity ranging from 41.4% to 83.5%. Compounds recorded significant inhibition were further investigated for their specific FLT3 kinase inhibitory activity. Noticeably, Compound 5 exhibited the highest inhibitory activity against FLT3.
- Alkahtani, Manal Mubarak,Altwaijry, Najla,Attallah, Nashwah G. M.,Elmongy, Elshaymaa I.,Henidi, Hanan Ali
-
-
- Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents
-
A series of eleven 4-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines were designed and synthesized and their biological activities were evaluated. Synthesis involved the Gewald reaction to synthesize ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate ring, and SNAr reactions. Compound 4 was 1.6-and ~7-fold more potent than the lead compound 1 in cell proliferation and microtubule depolymerization assays, respectively. Compounds 4, 5 and 7 showed the most potent antiproliferative effects (IC50 values 50 values of 53–125 nM). Additionally, compounds 4–8, 10 and 12–13 circumvented Pgp and βIII-tubulin mediated drug resistance, mechanisms that diminish the clinical efficacy of paclitaxel (PTX). In the NCI-60 cell line panel, compound 4 exhibited an average GI50 of ~10 nM in the 40 most sensitive cell lines. Compound 4 demonstrated statistically significant antitumor effects in a murine MDA-MB-435 xenograft model.
- Doshi, Arpit,Gangjee, Aleem,Hamel, Ernest,Islam, Farhana,Mooberry, Susan L.,Quadery, Tasdique M.,Robles, Andrew J.,Zhang, Xin,Zhou, Xilin
-
-
- Discovery of thieno[2,3-d]pyrimidine-based derivatives as potent VEGFR-2 kinase inhibitors and anti-cancer agents
-
Vascular endothelial growth factor-2 (VEGFR-2) is considered one of the most important factors in tumor angiogenesis, and consequently a number of anticancer therapeutics have been developed to inhibit VEGFR-2 signaling. Accordingly, eighteen derivatives of thieno[2,3-d]pyrimidines having structural characteristics similar to VEGFR-2 inhibitors were designed and synthesized. Anticancer activities of the new derivatives were assessed against three human cancer cell lines (HCT-116, HepG2, and MCF-7) using MTT. Sorafenib was used as positive control. Compounds 17c-i, and 20b showed excellent anticancer activities against HCT-116 and HepG2 cell lines, while compounds 17i and 17g was found to be active against MCF-7 cell line. Compound 17f exhibited the highest cytotoxic activities against the examined cell lines, HCT-116 and HepG2, with IC50 values of 2.80 ± 0.16 and 4.10 ± 0.45 μM, respectively. Aiming at exploring the mechanism of action of these compounds, the most active cytotoxic derivatives were in vitro tested for their VEGFR-2 inhibitory activity. Compound 17f showed high activity against VEGFR-2 with an IC50 value of 0.23 ± 0.03 μM, that is equal to that of reference, sorafenib (IC50 = 0.23 ± 0.04 μM). Molecular docking studies also were performed to investigate the possible binding interactions of the target compounds with the active sites of VEGFR-2. The synthesized compounds were analyzed for their ADMET and toxicity properties. Results showed that most of the compounds have low to very low BBB penetration levels and they have non-inhibitory effect against CYP2D6. All compounds were predicted to be non-toxic against developmental toxicity potential model except compounds 17b and 20b.
- El-Metwally, Souad A.,Abou-El-Regal, Mohsen M.,Eissa, Ibrahim H.,Mehany, Ahmed B.M.,Mahdy, Hazem A.,Elkady, Hazem,Elwan, Alaa,Elkaeed, Eslam B.
-
-
- Structure based design, synthesis and evaluation of new thienopyrimidine derivatives as anti-bacterial agents
-
TrmD, tRNA-(N1G37) methyltransferase, a member of SpoU-TrmD (SPOUT) RNA methyltransferase family, is one of the key enzymes responsible for the growth of Staphylococcus aureus, Pseudomonas aeruginosa, Mycobacterium tuberculosis (Mtb) and Mycobacterium abscessus (Mab). A number of TrmD inhibitors including thienopyrimidines and fused thienopyrimidines are reported as potent anti-bacterial and anti-mycobacterial agents. In the current study, a library of ~200 structurally diverse thienopyrimidines were designed and subjected to preliminary in silico studies. 22 of the compounds were selected, synthesized and were evaluated for their inhibitory activities against a panel of pathogens consisting E. coli, S. aureus, K. pneuminiae, A. baumannii and P. aeruginosa and M. tuberculosis (ATCC 27294). Among the tested compounds, 13b, 18a-e were found to inhibit M. tuberculosis (ATCC 27294) with the MIC of 16-32 μg/mL. The compound 18f was found to be selective against S. aureus with the MIC of 4 μg/mL and moderate activity against M. tuberculosis. The selected compounds were further subjected to docking, 3D-QSAR and ADME/T studies to understand the mechanism of action and also their physico chemical profile.
- Malasala, Satyaveni,Polomoni, Anusha,Ahmad, Md. Naiyaz,Shukla, Manjulika,Kaul, Grace,Dasgupta, Arunav,Chopra, Sidharth,Nanduri, Srinivas
-
-
- Design, molecular docking and biological evaluation of fused thienopyrimidines and quinazoline
-
The anticancer activity of the condensed pyrimidine and quinazoline moieties are pronounced with a different pathway. Thienopyrimidine is considered as ring equivalent bioisosteres of quinazolines and present in other heterocyclic compounds including thienopyrimidine. The present investigation focused on the synthesis of thienopyrimidine and quinazoline derivatives for their anticancer activity against the human oral squamous carcinoma-3 (HSC-3) cell line. The synthesized compound confirmed for their structural characteristics from spectral analysis and tested for anti-proliferative activity from MTT assay. The electron-withdrawing group in 4-chloro thienopyrimidines and amino ester derivate/facilitate the inhibition of cancer cells. Further probing by docking studies revealed that the compounds exhibit possible interactions with VEGF, FGFR and c-Met proteins, which are known to have a role in the pathogenesis of oral squamous cell carcinoma. Among the derivatives a moderate activity demonstrated by substituted 4-chloro-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidine (4a) and ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (1a) derivatives. Lack of chirality and the presence of bulky substituents in few of the compounds were found to be the cause for lower potency.
- Kaliraj,Jeyalakshmi,Kathiravan,Madhavan,Devi, Arikketh
-
p. 537 - 544
(2021/02/27)
-
- Synthesis of New Thieno[2,3-d]pyrimidines Containing a 1,2,3-Triazole Ring and Their Therapeutic Response in NCI-60 Cell Line Panel
-
Abstract: A series of new tetrahydro[1]benzothieno[2,3-d]pyrimidines containing a 1,2,3-triazole fragment linkedthrough an oxymethylene spacer have been synthesized by click reaction of4-(prop-2-yn-1-yloxy)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidines with various aryl and alkyl azides inthe presence of copper sulfate and sodium ascorbate as a catalyst. Thestructures of the synthesized compounds were characterized by variousspectroscopic techniques (1H and13C NMR, FT-IR, and mass spectrometry), and theirin vitro anticancer activity against NCI-60 human tumor cell lines wasevaluated. Among the compounds tested, N-(pyridine-3-yl)-acetamide derivative exhibited significantactivity against several cancer cell lines, including SF-539 (CNS cancer),HCT-116 (colon cancer), OVCAR-8 (ovarian cancer), PC-3 (prostate cancer), andCCRF-CEM (leukemia).
- Baluja, S. H.,Bhensdadia, K. A.,Lalavani, N. H.
-
p. 1668 - 1677
(2021/12/13)
-
- Discovery of novel akt1 inhibitor induces autophagy associated death in hepatocellular carcinoma cells
-
In this study, a series of thieno [2,3-d]pyrimidine derivatives were designed, synthesized and evaluated as novel AKT1 inhibitors. In vitro antitumor assay results showed that compounds 9d-g and 9i potently suppressed the enzymatic activities of AKT1 and
- Yu, Meng,Zeng, Minghui,Pan, Zhaoping,Wu, Fengbo,Guo, Li,He, Gu
-
-
- Discovery of new apoptosis-inducing agents for breast cancer based on ethyl 2-amino-4,5,6,7-tetra hydrobenzo[b]thiophene-3-carboxylate: Synthesis, in vitro, and in vivo activity evaluation
-
A multicomponent synthesis was empolyed for the synthesis of ethyl 2-amino-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate 1. An interesting cyclization was obtained when the amino-ester 1 reacted with ethyl isothiocyanate to give the benzo[4,5]thieno[
- Barakat, Assem,Boraei, Ahmed T. A.,Eltamany, Elsayed H.,Gad, Emad M.,Hammad, Magdy S. A. G.,Nafie, Mohamed S.
-
-
- Design, synthesis and anticancer evaluation of thieno[2,3-d]pyrimidine derivatives as dual EGFR/HER2 inhibitors and apoptosis inducers
-
Deregulation of many kinases is directly linked to cancer development and the tyrosine kinase family is one of the most important targets in current cancer therapy regimens. In this study, we have designed and synthesized a series of thieno[2,3-d]pyrimidine derivatives as an EGFR and HER2 tyrosine kinase inhibitors. All the synthesized compounds were evaluated in vitro for their inhibitory activities against EGFRWT; and the most active compounds that showed promising IC50 values against EGFRWT were tested in vitro for their inhibitory activities against mutant EGFRT790M and HER2 kinases. Moreover, the antitumor activities of these compounds were tested against four cancer cell lines (HepG2, HCT-116, MCF-7 and A431). Compounds 13g, 13h and 13k exhibited the highest activities against the examined cell lines with IC50 values ranging from 7.592 ± 0.32 to 16.006 ± 0.58 μM comparable to that of erlotinib (IC50 ranging from 4.99 ± 0.09 to 13.914 ± 0.36 μM). Furthermore, the most potent antitumor agent (13k) was selected for further studies to determine its effect on the cell cycle progression and apoptosis in MCF-7 cell line. The results indicated that this compound arrests G2/M phase of the cell cycle and it is a good apoptotic agent. Finally, molecular docking studies showed a good binding pattern of the synthesized compounds with the prospective target, EGFRWT and EGFRT790M.
- Elmetwally, Souad A.,Saied, Khaled F.,Eissa, Ibrahim H.,Elkaeed, Eslam B.
-
-
- Design, synthesis, biological evaluation and molecular modeling study of new thieno[2,3-d]pyrimidines with anti-proliferative activity on pancreatic cancer cell lines
-
Pancreatic cancer is one of the most challenging diseases with seven months only as median survival time due to its poor prognosis. Several enzymes are blamed for the progress of pancreatic cancer especially, platelet-derived growth factor receptors (PDGFRs), this in turn makes them promising targets for its treatment. In this study, twenty eight new compounds based on thieno[2,3-d]pyrimidine scaffold were synthesized as anti-pancreatic cancer agents mimicking the benzofuro[3,2-d]pyrimidine derivative, amuvatinib. Various linkers including amides, esters, ketones, urea and thiourea derivatives were utilized to study their effect on the anti-proliferative activity of these compounds. Most of the tested compounds revealed good cytotoxic activities against pancreatic carcinoma cell line PANC-1. Compound 9d showed the highest cytotoxicity with an IC50 value of 5.4 μM. Furthermore, 9d showed excellent platelet derived growth factor receptor (PDGFR-α) inhibitory activity, with IC50 value 0.155 μM. Docking study was carried out into PDGFR-α active site which showed comparable binding mode to that of FDA approved PDGFR-α inhibitor, imatinib. 3D-Quantitative structure activity relationship (QSAR) model was built up with five-featured pharmacophore which could be implemented for emerging effective lead structures. These compounds could serve as a new chemotype for discovering new agents for pancreatic cancer therapy.
- Salem, Mohamed S.H.,Abdel Aziz, Yasmine M.,Elgawish, Mohamed S.,Said, Mohamed M.,Abouzid, Khaled A.M.
-
-
- Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D2 receptor
-
We recently described a structurally novel series of negative allosteric modulators (NAMs) of the dopamine D2 receptor (D2R) based on thieno[2,3-d]pyrimidine 1, showing it can be structurally simplified to reveal low molecular weight, fragment-like NAMs that retain robust negative cooperativity, such as 3. Herein, we report the synthesis and functional profiling of analogues of 3, placing specific emphasis on examining secondary and tertiary amino substituents at the 4-position, combined with a range of substituents at the 5/6-positions (e.g. aromatic/aliphatic carbocycles). We identify analogues with diverse pharmacology at the D2R including NAMs with sub-μM affinity (9h) and, surprisingly, low efficacy partial agonists (9d and 9i).
- Fyfe, Tim J.,Kellam, Barrie,Mistry, Shailesh N.,Scammells, Peter J.,Lane, J. Robert,Capuano, Ben
-
p. 474 - 490
(2019/03/07)
-
- Design, synthesis and biological evaluation of 4-aniline-thieno[2,3-d]pyrimidine derivatives as MNK1 inhibitors against renal cell carcinoma and nasopharyngeal carcinoma
-
MAP Kinase Interacting Serine/Threonine Kinase 1 (MNK1)play important roles in the signaling transduction of MAPK pathways. It is significantly overexpressed in renal clear cell carcinoma and head-neck squamous cell carcinoma tissues in both mRNA and prot
- Zhang, Min,Jiang, Li,Tao, Jia,Pan, Zhaoping,He, Mingyao,Su, Dongyuan,He, Gu,Jiang, Qinglin
-
p. 2268 - 2279
(2019/04/25)
-
- Identification of 4-methoxythieno[2,3-d]pyrimidines as FGFR1 inhibitors
-
Aim. To identify novel FGFR1 inhibitors using virtual screening approach. Methods. We used methods of organic synthesis, molecular docking via the Autodock 4.2.6 program package and in vitro biochemical tests with γ-32P. Results. In vitro experiments showed that 9 of 23 tested compounds possess inhibitory activity against FGFR1 with IC50 values in the range from 0.9 to 5.6 μM. Conclusions. Nine FGFR1 inhibitors were developed. The mode of compounds binding with the ATP-acceptor site was determined using molecular docking methods and the dependence of the compounds’ activity on the substituents R1, R4 and R5 was evaluated.
- Balanda, A. O.,Bdzhola, V. G.,Kotey, I. M.,Pletnova, L. V.,Protopopov, M. V.,Prykhod’ko, A. O.,Starosyla, S. A.,Yarmoluk, S. M.
-
p. 152 - 162
(2020/06/02)
-
- Design, Synthesis, and Biological Evaluation of 6-Substituted Thieno[3,2- d]pyrimidine Analogues as Dual Epidermal Growth Factor Receptor Kinase and Microtubule Inhibitors
-
The clinical evidence for the success of tyrosine kinase inhibitors in combination with microtubule-targeting agents prompted us to design and develop single agents that possess both epidermal growth factor receptor (EGFR) kinase and tubulin polymerization inhibitory properties. A series of 6-aryl/heteroaryl-4-(3′,4′,5′-trimethoxyanilino)thieno[3,2-d]pyrimidine derivatives were discovered as novel dual tubulin polymerization and EGFR kinase inhibitors. The 4-(3′,4′,5′-trimethoxyanilino)-6-(p-tolyl)thieno[3,2-d]pyrimidine derivative 6g was the most potent compound of the series as an antiproliferative agent, with half-maximal inhibitory concentration (IC50) values in the single- or double-digit nanomolar range. Compound 6g bound to tubulin in the colchicine site and inhibited tubulin assembly with an IC50 value of 0.71 μM, and 6g inhibited EGFR activity with an IC50 value of 30 nM. Our data suggested that the excellent in vitro and in vivo profile of 6g may be derived from its dual inhibition of tubulin polymerization and EGFR kinase.
- Romagnoli, Romeo,Prencipe, Filippo,Oliva, Paola,Baraldi, Stefania,Baraldi, Pier Giovanni,Schiaffino Ortega, Santiago,Chayah, Mariem,Kimatrai Salvador, Maria,Lopez-Cara, Luisa Carlota,Brancale, Andrea,Ferla, Salvatore,Hamel, Ernest,Ronca, Roberto,Bortolozzi, Roberta,Mariotto, Elena,Mattiuzzo, Elena,Viola, Giampietro
-
p. 1274 - 1290
(2019/01/30)
-
- Synthesis of some new pyrimidine selanyl derivatives
-
The targeted synthesis of 2-(methylsulfanyl)-6-(furan-2-yl)-4(3H)-selenoxo -pyrimidine-5-carbonitrile failed due to the formation 1-methyl-2-methylsulfanyl-6-oxo -4-(furan-2-yl)-1,6-dihydropyrimidine-5-carbonitrile. A new series of 5,6,7,8-tetrahydro-1-benzo thieno[2,3-d]pyrimidine-4-yl substituted selanyl derivatives were prepared by the reaction of sodium diselenide with 4-chloro-5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidine followed by the reaction with chloroacetic acid derivatives such as ethyl chloroacetate, chloroacetamide or chloroacetonitrile. Hydrazinolysis of ethyl (5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidine- 4-ylselanyl)acetate with hydrazine hydrate gave the corresponding hydrazino derivative. The latter reacted with ethyl acetoacetate, acetylacetone, diethyl malonate, ethoxymethylenemalononitrile or ethyl 2-cyano-3-ethoxyacetate to afford 5-methyl-2-[2-(5,6,7,8-tetrahydro-1-benzothieno [2,3-d]pyrimidine-4-ylselanyl)acetyl]-2,4-dihydropyrazol-3-one, 1-(3,5-dimethylpyrazol-1-yl)-2- (5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidin-4-ylselanyl)ethanone, 1-[2-(5,6,7,8-tetrahydro -1-benzothieno[2,3-d]pyrimidine-4-ylselanyl)acetyl]-2,4-dihydropyrazolidine-3,5-dione and 5-Amino-1-[2-(5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidin-4-ylselanyl)acetyl]-1H-pyrazol -4-yl substituted carbonitrile or ethyl carboxylate, respectively. The structure of the novel compounds was confirmed by spectroscopic tools (IR, 1H NMR 13C NMR and mass spectra) and elemental analysis.
- Alshahrani, Refaah A.,Gobouri, Adil A.,Alshanbari, Naif A.,Ahmed, Saleh A.,Abdel-Hafez, Shams H.
-
p. 345 - 349
(2018/02/06)
-
- Containing amide four tetrahydrobenz [4, 5] thieno [2, 3 - d] pyrimidine compound and use thereof
-
The invention belongs to the technical field of medicine, and relates to a tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidines compound containing amide, an application of the compound as an epidermal growth factor receptor tyrosine kinase inhibitor and a pr
- -
-
-
- 4-Substituted thieno[2,3-d]pyrimidines as potent antibacterial agents: Rational design, microwave-assisted synthesis, biological evaluation and molecular docking studies
-
In an attempt to discover a new class of antibacterial agents with improved efficacy and to overcome the drug-resistant problems, some novel 4-substituted thieno[2,3-d]pyrimidines have been synthesized via microwave-assisted methodology and evaluated for their in vitro antibacterial activity against various pathogenic bacterial strains. Compounds 12b and 13c showed the promising inhibitory potencies against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and Escherichia coli with MICs ranging from 2 to 10?μg/ml. Compound 13c was also found to be highly potent against methicillin-resistant S. aureus (MRSA) with MIC value of 4?μg/ml. Docking simulation studies have been performed to unravel the mode of action and association study indicate the binding of potent compounds with DHPS enzyme. In silico ADME studies suggest the drug-like characteristics of the potent compounds.
- Gill, Rupinder K.,Singh, Harpreet,Raj, Tilak,Sharma, Anuradha,Singh, Gagandeep,Bariwal, Jitender
-
p. 1115 - 1121
(2017/10/06)
-
- A Thieno[2,3- d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D2 Receptor
-
Recently, a novel negative allosteric modulator (NAM) of the D2-like dopamine receptors 1 was identified through virtual ligand screening. This ligand comprises a thieno[2,3-d]pyrimidine scaffold that does not feature in known dopaminergic ligands. Herein, we provide pharmacological validation of an allosteric mode of action for 1, revealing that it is a NAM of dopamine efficacy and identify the structural determinants of this allostery. We find that key structural moieties are important for functional affinity and negative cooperativity, while functionalization of the thienopyrimidine at the 5- and 6-positions results in analogues with divergent cooperativity profiles. Successive compound iterations have yielded analogues exhibiting a 10-fold improvement in functional affinity, as well as enhanced negative cooperativity with dopamine affinity and efficacy. Furthermore, our study reveals a fragment-like core that maintains low μM affinity and robust negative cooperativity with markedly improved ligand efficiency.
- Fyfe, Tim J.,Zarzycka, Barbara,Lim, Herman D.,Kellam, Barrie,Mistry, Shailesh N.,Katrich, Vsevolod,Scammells, Peter J.,Lane, J. Robert,Capuano, Ben
-
p. 174 - 206
(2018/05/14)
-
- Design and synthesis of novel protein kinase CK2 inhibitors on the base of 4-aminothieno[2,3-d]pyrimidines
-
An extension of our previous research work has resulted in a number of new ATP-competitive CK2 inhibitors that have been identified among 4-aminothieno[2,3-d]pyrimidine derivatives. The most active compounds obtained in the course of the research are 3-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-ylamino)-benzoic acid, 5e (NHTP23, IC50 = 0.01 μM), 3-(5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-benzoic acid, 5g (NHTP25, IC50 = 0.065 μM) and 3-(6-methyl-5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-benzoic acid, 5n (NHTP33, IC50 = 0.008 μM). Structure-activity relationships of the tested 4-aminothieno[2,3-d]pyrimidine derivatives have been studied and their binding mode with ATP-acceptor site of CK2 has been proposed. A negative effect of intramolecular hydrogen bonding in the compounds' structure is discussed.
- Ostrynska, Olga V.,Balanda, Anatoliy O.,Bdzhola, Volodymyr G.,Golub, Andriy G.,Kotey, Igor M.,Kukharenko, Olexander P.,Gryshchenko, Andrii A.,Briukhovetska, Nadiia V.,Yarmoluk, Sergiy M.
-
p. 148 - 160
(2016/04/05)
-
- Computer-aided identification, synthesis and evaluation of substituted thienopyrimidines as novel inhibitors of HCV replication
-
A structure-based virtual screening technique was applied to the study of the HCV NS3 helicase, with the aim to find novel inhibitors of the HCV replication. A library of ~450000 commercially available compounds was analysed in silico and 21 structures were selected for biological evaluation in the HCV replicon assay. One hit characterized by a substituted thieno-pyrimidine scaffold was found to inhibit the viral replication with an EC50value in the sub-micromolar range and a good selectivity index. Different series of novel thieno-pyrimidine derivatives were designed and synthesised; several new structures showed antiviral activity in the low or sub-micromolar range.
- Bassetto, Marcella,Leyssen, Pieter,Neyts, Johan,Yerukhimovich, Mark M.,Frick, David N.,Brancale, Andrea
-
-
- Synthesis and anticancer activities of novel (tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine-4-yl)-pyrolidine-2-carboxylic acid derivatives
-
Cancer chemotherapy has been one of the major medical advances in the last few decades. The medications involved in treatment have a narrow therapeutic index, and often the responses produced are only just palliative as well as unpredictable. In contrast,
- Pavase, Laxmikant S.,Mane, Dhananjay V.
-
p. 2380 - 2391
(2016/10/25)
-
- Design and Synthesis of 4-Anilinothieno[2,3-d]pyrimidine-Based Compounds as Dual EGFR/HER-2 Inhibitors
-
Dual inhibition of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER-2) is an attractive cancer therapeutic approach. In this study, new series of 4-anilinothieno[2,3-d]pyrimidines were designed, synthesized, and tested as dual EGFR/HER-2 kinase inhibitors. Five compounds (8a, 8b, 8e–g) demonstrated low to submicromolar inhibition of both kinases with IC50 values of 1.2, 0.6, 0.3, 0.2, 0.4 μM and 8.2, 3.4, 1.3, 0.5, 2.7 μM for the EGFR and HER-2, respectively. Introduction of a 5,6-tetramethylene moiety into the thienopyrimidine core bearing a 4-(3-fluorobenzyloxy)-3-chloroaniline tail resulted in a favorable increase in both the EGFR and HER-2 inhibitory activities. Compound 8f (IC50 EGFR/HER-2: 0.2/0.5 μM) also exhibited significant cell growth inhibition on some specific NCI cell lines, especially ovarian, breast, non-small-cell lung cancer, and renal cancer cell lines.
- Abd El Hadi, Soha R.,Lasheen, Deena S.,Hassan, Mahmoud A.,Abouzid, Khaled A. M.
-
p. 827 - 847
(2016/11/09)
-
- Thienopyrimidine sulphonamide hybrids: Design, synthesis, antiprotozoal activity and molecular docking studies
-
A series of hybrid compounds containing the thienopyrimidine scaffold as a DHFR inhibitor fused with a bioactive sulphonamide piperazine skeleton were synthesized and evaluated against the chloroquine and pyrimethamine resistant K1 strain of Plasmodium falciparum and the HM1:1MSS strain of Entamoeba histolytica, respectively. A few of the compounds showed better results than the standard drugs. The toxicity of the hybrids was measured on the Chinese hamster cell line. The majority of the compounds had low toxicity. The binding modes of the most potent antimalarial compounds (5, 6 and 8) were also investigated against PfDHFR using molecular docking and enzyme binding studies, whereby 5 and 6 were found to the most promising against PfDHFR. The present studies suggest that these hybrids might be possible antiprotozoal lead compounds worth further investigation.
- Leeza Zaidi, Saadia,Agarwal, Subhash M.,Chavalitshewinkoon-Petmitr, Porntip,Suksangpleng, Thidarat,Ahmad, Kamal,Avecilla, Fernando,Azam, Amir
-
p. 90371 - 90383
(2016/10/07)
-
- Stimulation of cortical bone formation with thienopyrimidine based inhibitors of Notum Pectinacetylesterase
-
A group of small molecule thienopyrimidine inhibitors of Notum Pectinacetylesterase are described. We explored both 2-((5,6-thieno[2,3-d]pyrimidin-4-yl)thio)acetic acids and 2-((6,7-thieno[3,2-d]pyrimidin-4-yl)thio)acetic acids. In both series, highly potent, orally active Notum Pectinacetylesterase inhibitors were identified.
- Tarver, James E.,Pabba, Praveen K.,Barbosa, Joseph,Han, Qiang,Gardyan, Michael W.,Brommage, Robert,Thompson, Andrea Y.,Schmidt, James M.,Wilson, Alan G.E.,He, Wei,Lombardo, Victoria K.,Carson, Kenneth G.
-
p. 1525 - 1528
(2016/07/27)
-
- Molecular dynamics-based discovery of novel phosphodiesterase-9A inhibitors with non-pyrazolopyrimidinone scaffolds
-
Phosphodiesterase-9A (PDE9A) is a promising therapeutic target for the treatment of diabetes and Alzheimer's disease (AD). The Pfizer PDE9A inhibitor PF-04447943 has completed Phase II clinical trials in subjects with mild to moderate AD in 2013. However, most of the reported PDE9A inhibitors share the same scaffold as pyrazolopyrimidinone, which lacks structural diversity and is unfavorable for the development of novel PDE9A inhibitors. In the present study, a combinatorial method including pharmacophores, molecular docking, molecular dynamics simulations, binding free energy calculations, and bioassay was used to discover novel PDE9A inhibitors with new scaffolds rather than pyrazolopyrimidinones from the SPECS database containing about 200000 compounds. As a result, 15 hits out of 29 molecules (a hit rate of 52%) with five novel scaffolds were identified to be PDE9A inhibitors with inhibitory affinities no more than 50 μM to enrich the structural diversity, different from the pyrazolopyrimidinone-derived family. The high hit ratio of 52% for this virtual screening method indicated that the combinatorial method is a good compromise between computational cost and accuracy. Binding pattern analyses indicate that those hits with non-pyrazolopyrimidinone scaffolds can bind the same active site pocket of PDE9A as classical PDE9A inhibitors. In addition, structural modification of compound AG-690/40135604 (IC50 = 8.0 μM) led to a new one, 16, with an improved inhibitory affinity of 2.1 μM as expected. The five novel scaffolds discovered in the present study can be used for the rational design of PDE9A inhibitors with higher affinities. This journal is
- Li, Zhe,Lu, Xiao,Feng, Ling-Jun,Gu, Ying,Li, Xingshu,Wu, Yinuo,Luo, Hai-Bin
-
p. 115 - 125
(2015/02/05)
-
- Synthesis and electronic aspects of tetrahydrobenzothienopyrimidine derivatives
-
(Chemical Equation Presented) The chemistry of thiophenes, pyrimidines, triazolopyrimidines and benzothiophenes has drawn much attention because of their biological activities. Their interesting properties are connected with their complex π-electron deloc
- Gajda, Katarzyna,Astakhina, Valeriia,Ejsmont, Krzysztof,Kolomeitsev, Dmytro,Kovalenko, Sergiy,Zarychta, Bartosz
-
p. 137 - 143
(2015/02/05)
-
- A facile microwave-assisted synthesis of some fused pyrimidine derivatives
-
The highly accelerated synthesis of thienopyrimidinones, theino- pyrimidines, thioxotheinopyrimidinones and a thienotriazolopyrimidinone derivatives under microwave irradiation is reported. Compared to conventional conditions, microwaves method offered se
- Al-Issa
-
p. 469 - 477
(2014/12/12)
-
- Design, synthesis & evaluation of condensed 2H-4-arylaminopyrimidines as novel antifungal agents
-
A small, focussed library of condensed 2H-4-arylaminopyrimidines, with 3-diversity points, based on an initial design by molecular docking study of this scaffold at the active site of the fungal enzyme of cytochrome P 450 family, lanosterol 14α
- Jain, Kishor S.,Khedkar, Vijay M.,Arya, Nikhilesh,Rane, Prasad V.,Chaskar, Pratip K.,Coutinho, Evans C.
-
p. 166 - 175
(2014/04/03)
-
- Novel dual use of formamide-POCl3 mixture for the efficient, one-pot synthesis of condensed 2 H-pyrimidin-4-amine libraries under microwave irradiation
-
The novel dual use of formamide-POCl3 mixture for the incorporation of a C-N fragment to form the pyrimidine nucleus and its subsequent chlorination in an efficient, one-pot synthesis of potentially bioactive condensed 2H-pyrimidin-4-amine libraries under
- Jain, Kishore S.,Kathiravan, Muthu K.,Bariwal, Jitender B.,Chaskar, Pratip K.,Tompe, Santosh S.,Arya, Nikhilesh
-
p. 719 - 727
(2013/01/15)
-
- IRAK INHIBITORS AND USES THEREOF
-
The present invention relates to compounds and methods useful for inhibiting one or more interleukin-l receptor-associated kinases ("IRAK"). In some embodiments, a provided compound inhibits IRAK-1 and IRAK-4. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.
- -
-
-
- Convenient and efficient synthesis of some novel fused thieno pyrimidines using gewald's reaction
-
Several functionalized thienopyrimidines were synthesized by a facile synthetic method, which includes Gewald's reaction, and were characterized by spectral and analytical data. These functionalized thienopyrimidines were converted to various new chemical
- Nirogi, Ramakrishna V.S.,Kambhampati, Sastri Rama,Kothmirkar, Prabhakar,Arepalli, Sobhanadri,Pamuleti, Narasimha Reddy G.,Shinde, Anil K.,Dubey
-
p. 2835 - 2851
(2011/09/12)
-
- COMPOUNDS, THEIR SYNTHESES, AND THEIR USES
-
Embodiments of the present invention provide compounds (such as Formula (I) compounds, Formula (II) compounds, and various embodiments thereof). Compositions comprising those compounds are also provided. Methods for their preparation are included. Also, uses of the compounds are included, such as administering and treating diseases (e.g., cancer and infections).
- -
-
-
- Trypanoside, anti-tuberculosis, leishmanicidal, and cytotoxic activities of tetrahydrobenzothienopyrimidines
-
The synthesis of 2-(5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl)hydrazone-derivatives (BTPs) and their in vitro evaluation against Trypanosoma cruzi trypomastigotes, Mycobacterium tuberculosis, Leishmania amazonensis axenic amastigotes, and six human cancer cell lines is described. The in vivo activity of the most active and least toxic compounds against T. cruzi and L. amazonensis was also studied. BTPs constitute a new family of drug leads with potential activity against infectious diseases. Due to their drug-like properties, this series of compounds can potentially serve as templates for future drug-optimization and drug-development efforts for use as therapeutic agents in developing countries.
- Aponte, José C.,Vaisberg, Abraham J.,Castillo, Denis,Gonzalez, German,Estevez, Yannick,Arevalo, Jorge,Quiliano, Miguel,Zimic, Mirko,Verástegui, Manuela,Málaga, Edith,Gilman, Robert H.,Bustamante, Juan M.,Tarleton, Rick L.,Wang, Yuehong,Franzblau, Scott G.,Pauli, Guido F.,Sauvain, Michel,Hammond, Gerald B.
-
experimental part
p. 2880 - 2886
(2010/07/02)
-
- Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: The role of side chain chirality and michael acceptor group for maximal potency
-
HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19. Both 11 and 19 showed over 3 orders of magnitude enhanced HCC827 a
- Wu, Chia-Hsien,Coumar, Mohane Selvaraj,Chu, Chang-Ying,Lin, Wen-Hsing,Chen, Yi-Rong,Chen, Chiung-Tong,Shiao, Hui-Yi,Rafi, Shaik,Wang, Sing-Yi,Hsu, Hui,Chen, Chun-Hwa,Chang, Chun-Yu,Chang, Teng-Yuan,Lien, Tzu-Wen,Fang, Ming-Yu,Yeh, Kai-Chia,Chen, Ching-Ping,Yeh, Teng-Kuang,Hsieh, Su-Huei,Hsu, John T.-A.,Liao, Chun-Chen,Chao, Yu-Sheng,Hsieh, Hsing-Pang
-
experimental part
p. 7316 - 7326
(2011/02/23)
-
- Fused Bicyclic and Tricyclic Pyrimidine Compounds as Tyrosine Kinase Inhibitors
-
Fused bicyclic or tricyclic compounds of formula (I): wherein A, B, C, X, Y, m, and n are defined herein. Also disclosed are a method for inhibiting EGFR kinase activity and a method for treating cancer with these compounds.
- -
-
Page/Page column 42-43
(2010/06/11)
-
- Synthesis and study of antiproliferative activity of novel thienopyrimidines on glioblastoma cells
-
The receptor tyrosine kinases (for example EGFR, PDGFR, VEGFR) are a transmembrane protein family which plays a crucial role in tumor growth, survival, metastasis dissemination and angiogenesis. During the past 10 years, many tyrosine kinase inhibitors (T
- Pédeboscq, Stéphane,Gravier, Denis,Casadebaig, Fran?oise,Hou, Geneviève,Gissot, Arnaud,De Giorgi, Francesca,Ichas, Fran?ois,Cambar, Jean,Pometan, Jean-Paul
-
scheme or table
p. 2473 - 2479
(2010/07/08)
-
- AlCl3-induced (hetero)arylation of thienopyrimidine ring: a new synthesis of 4-substituted thieno[2,3-d]pyrimidines
-
AlCl3 facilitated C-C bond forming reaction between 4-chloro-thieno[2,3-d]pyrimidines and (hetero)arenes affording a direct and single-step method for the synthesis of 4-(hetero)aryl substituted thieno[2,3-d]pyrimidines. A number of novel thien
- Kumar, K. Shiva,Chamakuri, Srinivas,Vishweshwar, Peddy,Iqbal, Javed,Pal, Manojit
-
supporting information; experimental part
p. 3269 - 3273
(2010/07/18)
-
- Unexpected C - O bond formation in Suzuki coupling of 4-chlorothieno[2,3-d] pyrimidines
-
(Chemical Equation Presented) Palladium-catalyzed Suzuki reactions were performed on 4-chlorothieno[2,3-d]pyrimidines under classical heating conditions and under microwave irradiation. Some unexpected results were obtained during this study as two kinds of compounds were isolated depending on the conditions used. A careful investigation of experimental details has shown that the expected CAC bond formation occurred when degassed solvents were used (both in classical and microwave heating) whereas an unexpected CAO bond formation happened when solvents were not degassed with argon-bubbling before use.
- Perspicace, Enrico,Hesse, Stephanie,Kirsch, Gilbert,Yemloul, Mehdi,Lecomte, Claude
-
scheme or table
p. 459 - 464
(2009/09/28)
-
- FUSED BICYCLIC PYRIMIDINE COMPOUNDS AS AURORA KINASE INHIBITORS
-
Fused bicyclic pyrimidine compounds of formula (I): wherein R1, R3, R4, X1, X2, Y, Z, A, B, C, D, n, and the two bonds are defined herein. Also disclosed are a method for inhibiting Aurora kinase activity and a method for treating cancer with these compounds.
- -
-
Page/Page column 39
(2009/12/02)
-
- Discovery of novel thieno[2,3-d]pyrimidin-4-yl hydrazone-based inhibitors of Cyclin D1-CDK4: Synthesis, biological evaluation, and structure-activity relationships
-
The synthesis and evaluation of new analogues of thieno[2,3-d]pyrimidin-4-yl hydrazones are described. 2-Pyrdinecarboxaldehyde [6-(tert-butyl)thieno[2,3-d]pyrimidine-4-yl]hydrazone derivatives have been identified as cyclin-dependent kinase 4 (CDK4) inhibitors. The potency, selectivity profile, and structure-activity relationship of this series of compounds are discussed.
- Horiuchi, Takao,Chiba, Jun,Uoto, Kouichi,Soga, Tsunehiko
-
scheme or table
p. 305 - 308
(2011/02/28)
-
- Microwave-based synthesis of novel thienopyrimidine bioisosteres of gefitinib
-
A series of novel 2-unsubstituted 4-(substituted)anilinothieno[2,3-d]pyrimidines is synthesized through the chlorination of the corresponding 2-unsubstituted-thieno[2,3-d]-pyrimidin-4-ones, followed by the nucleophilic displacement of the 4-Cl group of 9, with a variety of anilines. All four steps of this synthesis involve microwave irradiation (MWI) and the entire synthesis requires only 2 h.
- Phoujdar, Manisha S.,Kathiravan, Muthu K.,Bariwal, Jitender B.,Shah, Anamik K.,Jain, Kishor S.
-
p. 1269 - 1273
(2008/09/18)
-
- Thieno[2,3-d]pyrimidines as antagonists of the glutamate receptors
-
Although the function of the kainate receptors in the brain is still not clear, they are increasingly defined as targets in the development of new classes of anti-epileptics. The thienopyrimidines described in this report were tested for their antagonisti
- Briel,Rybak,Kronbach,Unverferth
-
experimental part
p. 823 - 826
(2009/04/10)
-
- Synthesis of some thienopyrimidine derivatives
-
Thioxothienopyrimidinones, alkylthio- and arylalkylthiothienopyrimidinones, thienopyrimidinones, thienopyrimidines a thienopyrimidinedione and a thienotriazolopyrimidinone were prepared from 2-amino-3-carboethoxy-4,5- disubstituted thiophenes and 2-amino-
- El-Baih, Fatma E. M.,Al-Blowy, Hanan A. S.,Al-Hazimi, Hassan M.
-
p. 498 - 513
(2007/10/03)
-
- New piperidinylamino-thieno[2,3-D] pyrimidine compounds
-
The invention relates to 5-HT receptor antagonists. Novel piperidinylamino-thieno [2,3-d]pyrimidine compounds represented by Formula I, and synthesis and uses thereof for treating diseases mediated directly or indirectly by 5-HT receptors, are disclosed.
- -
-
-
- Piperidinylamino-thieno[2,3-D] pyrimidine compounds
-
The invention relates to 5-HT receptor modulators, particularly 5-HT2B antagonists. Novel piperidinylamino-thieno [2,3-d] pyrimidine compounds represented by Formula I, II and III, and uses thereof for treating conditions including pulmonary ar
- -
-
-
- Synthesis of fused pyrimidinones by reaction of aminoarene-carboxamide with esters; Preparation of pyrrolo[2,3-d]-, thieno[2,3-d]-, isoxazolo[5,4-d]- and 1,2,3-triazolo[4,5-d]pyrimidinones, and quinazolones
-
Several fused pyrimidinones were synthesized by reaction of aminoarenecarboxamide with esters in moderate to good yields. In the presence of sodium ethoxide, treatments of 2-amino-l-phenyl-3-pyrrolecarboxamide(4, 5, and 6), 2-amino-3-thiophenecarboxamide (14), 3-amino-4-isoxazolecarboxamide (10 and 11), 4-amino-1,2,3-triazole-5-carboxamide (16), and o-aminobenzamide (18) with esters (3) such as ethyl formate (3a) and ethyl acetate (3b) led to the corresponding pyrrolo[2,3-d]- (7, 8, and 9), and thieno[2,3-d]pyrimidin-4(3H)-ones (15), isoxazolo[5,4-d]pyrimidin-4(5H)-ones (12 and 13), 1,2,3-triazolo[4,5-d]pyrimidin-7(6H)-ones (17), and 4(3H)-quinazolones (19), respectively.
- Miyashita, Akira,Fujimoto, Katsuhiro,Okada, Tomomi,Higashino, Takeo
-
p. 691 - 699
(2007/10/03)
-
- Various synthetic routes to imidazothienopyrimidines and pyrimidothienopyrimidines in some cases annelated
-
The tricyclic or tetracyclic imidazothienopyrimidines and pyrimidothienopyrimidines were synthesized by three routes: Route A: Thieno1,3-thiazin-4-thiones E undergo the ring transformation with α,ω-diamino-alkanes to giv
- Leistner, S.,Guetschow, M.,Vieweg, H.,Wagner, G.,Strohscheidt, Th.,Grupe, Renate
-
p. 756 - 760
(2007/10/02)
-
- 3,4-Dihydrothienopyrimidines. II. Synthesis and Sodium Borohydride Reduction of 2-Substituted 4-Chloro- and 4-Unsubstituted-thienopyrimidines
-
The synthesis and sodium borohydride reduction of 4-chloro- (1) and 4-unsubstituted- (3) 5,6,7,8-tetrahydrobenzothienopyrimidines, substituted with various groups, such as chloro, hydrogen, methyl, phenyl, amino, ethoxy, methylthio, methylsulfin
- Yamaguchi, Hitoshi,Ishikawa, Fumiyoshi
-
p. 326 - 332
(2007/10/02)
-