- Computer-aided identification, synthesis and evaluation of substituted thienopyrimidines as novel inhibitors of HCV replication
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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
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- Synthetic strategy for increasing solubility of potential FLT3 inhibitor thieno[2,3-d]pyrimidine derivatives through structural modifications at the C2and C6positions
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Acute myeloid leukemia (AML) is a clonal disorder of hematopoietic progenitor cell. In AML, a mutation in FLT3 is commonly occurs and is associated with poor prognosis. We have previously reported that thieno[2,3-d]pyrimidine derivative compound 1 exhibited better antiproliferative activity against MV4-11 cells which harbor mutant FLT3 than AC220, which is a well-known FLT3 inhibitor, and has good microsomal stability. However, compound 1 had poor solubility. We then carried out further structural modification at the C2and the C6positions of thieno[2,3-d]pyrimidine scaffold. Compound 13b, which possesses a thiazole moiety at the C2position, exhibited better antiproliferative activity than compound 1 and showed increased solubility and moderate microsomal stability. These results indicate that compound 13b could be a promising potential FLT inhibitor for AML chemotherapy.
- Oh, Changmok,Kim, Hyuntae,Kang, Jong Soon,Yun, Jieun,Sim, Jaejun,Kim, Hwan-Mook,Han, Gyoonhee
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- Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D2 receptor
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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
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p. 474 - 490
(2019/03/07)
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- Identification of 4-methoxythieno[2,3-d]pyrimidines as FGFR1 inhibitors
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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.
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p. 152 - 162
(2020/06/02)
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- 4-Substituted thieno[2,3-d]pyrimidines as potent antibacterial agents: Rational design, microwave-assisted synthesis, biological evaluation and molecular docking studies
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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
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p. 1115 - 1121
(2017/10/06)
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- Stimulation of cortical bone formation with thienopyrimidine based inhibitors of Notum Pectinacetylesterase
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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.
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p. 1525 - 1528
(2016/07/27)
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- Design and synthesis of novel protein kinase CK2 inhibitors on the base of 4-aminothieno[2,3-d]pyrimidines
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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.
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p. 148 - 160
(2016/04/05)
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- Substituted thienopyrimidinamine compound with insecticidal and acaricidal activity, and application thereof
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The invention discloses an application of a substituted thienopyrimidinamine compound represented by general formula I shown in the specification as an insecticidal and acaricidal agent. All substituent groups in the formula I are defined as in the specification. The compound has wide-spectrum insecticidal and acaricidal activity, is highly effective to lepidoptera pests, Homoptera pests and mites, has especially good activity on aphids, carminespider mites, diamondback moths and armyworms, and has a very good control effect under a very low dosage.
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- Thienopyrimidylurea compound, and preparation method and applications thereof
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The invention belongs to the field of organic synthesis, and discloses a thienopyrimidylurea compound, and applications thereof. The thienopyrimidylurea compound is represented by formula (I), wherein R1 and R2 are used for respectively representing a group independently selected from H, and C1-6 alkyl groups, or a C5-8 aliphatic ring formed via bonding of R1 with R2, R3 is used for representing a group selected from H, C1-6 alkyl groups, and C1-6 halogenated alkyl groups, and R4 is used for representing a group selected from H, halogens, and C1-6 alkyl groups. The thienopyrimidylurea compound possesses excellent activity in inhibiting tumour cell proliferation.
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Paragraph 0114-0118
(2017/04/22)
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- Design, synthesis & evaluation of condensed 2H-4-arylaminopyrimidines as novel antifungal agents
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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.
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p. 166 - 175
(2014/04/03)
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- Novel dual use of formamide-POCl3 mixture for the efficient, one-pot synthesis of condensed 2 H-pyrimidin-4-amine libraries under microwave irradiation
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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
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p. 719 - 727
(2013/01/15)
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- IRAK INHIBITORS AND USES THEREOF
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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.
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(2012/07/28)
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- Convenient and efficient synthesis of some novel fused thieno pyrimidines using gewald's reaction
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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
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p. 2835 - 2851
(2011/09/12)
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- COMPOUND HAVING TGF-BETA INHIBITORY ACTIVITY AND PHARMACEUTICAL COMPOSITION CONTAINING SAME
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The present invention provides compounds of formula (I) or compounds of formula (II) and pharmaceutically acceptable salts or solvates thereof. An objective of the present invention is to provide compounds having TGF2 inhibitory activity.
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(2010/11/24)
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