20 results match your criteria thienopyrimidine analogues

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Novel thienopyrimidine analogues as potential metabotropic glutamate receptors inhibitors and anticancer activity: Synthesis, In-vitro, In-silico, and SAR approaches.

Bioorg Chem 2021 Apr 16;109:104729. Epub 2021 Feb 16.

Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, P.O. Box 11795, Cairo, Egypt; Center of Scientific Excellence "Helwan Structural Biology Research, (HSBR)", Helwan University, Cairo 11795, Egypt.

There is a continuous need in drug development approach for synthetic anticancer analogues with new therapeutic targets to diminish chemotherapeutic resistance of cancer cells. This study presents new group of synthetic thienopyrimidine analogues (1-9) aims as mGluR-1 inhibitors with anticancer activity. In-vitro antiproliferative assessment was carried out using viability assay against cancer cell lines (MCF-7, A-549 and PC-3) compared to WI-38 normal cell line. Read More

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Identification of BRaf-Sparing Amino-Thienopyrimidines with Potent IRE1α Inhibitory Activity.

ACS Med Chem Lett 2020 Dec 16;11(12):2389-2396. Epub 2020 Oct 16.

Genentech Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.

Amino-quinazoline BRaf kinase inhibitor was identified from a library screen as a modest inhibitor of the unfolded protein response (UPR) regulating potential anticancer target IRE1α. A combination of crystallographic and conformational considerations were used to guide structure-based attenuation of BRaf activity and optimization of IRE1α potency. Quinazoline 6-position modifications were found to provide up to 100-fold improvement in IRE1α cellular potency but were ineffective at reducing BRaf activity. Read More

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December 2020

A Thieno[2,3- d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D Receptor.

J Med Chem 2019 01 15;62(1):174-206. Epub 2018 May 15.

Department of Biological Sciences, Bridge Institute , University of Southern California , Los Angeles , California 90089 , United States.

Recently, a novel negative allosteric modulator (NAM) of the D-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. Read More

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January 2019

Design and synthesis of novel annulated thienopyrimidines as phosphodiesterase 5 (PDE5) inhibitors.

Arch Pharm (Weinheim) 2018 May 14;351(5):e1800018. Epub 2018 Apr 14.

Faculty of Pharmacy and Biotechnology, Department of Pharmaceutical Chemistry, German University in Cairo, Cairo, Egypt.

Novel cycloalkene-fused thienopyrimidine analogues with enhanced phosphodiesterase 5 (PDE5) inhibitory properties are presented. The structure of the reported scaffold was modulated through variation of the terminal cycloalkene ring size, as well as by varying the substituents at position 4 through the attachment of different groups including aniline, benzylamine, cyclohexylethylamine, methyl/acetyl/aryl piperazines, and aryl hydrazones. Compound 15Y with a benzylamine substituent and cycloheptene as terminal ring showed the highest PDE5 inhibitory activity with an IC value as low as 190 nM and with good selectivity versus PDE7 and PDE9. Read More

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Discovery of new thienopyrimidine derivatives as potent and orally efficacious phosphoinositide 3-kinase inhibitors.

Bioorg Med Chem 2018 02 23;26(3):637-646. Epub 2017 Dec 23.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address:

A series of new thienopyrimidine derivatives has been discovered as potent PI3K inhibitors. The systematic SAR studies for these analogues are described. Among them, 8a and 9a exhibit nanomolar enzymatic potencies and sub-micromolar cellular anti-proliferative activities. Read More

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February 2018

Addressing the Metabolic Stability of Antituberculars through Machine Learning.

ACS Med Chem Lett 2017 Oct 14;8(10):1099-1104. Epub 2017 Sep 14.

Department of Pharmacology, Physiology, and Neuroscience, Rutgers University-New Jersey Medical School, Newark, New Jersey 07103, United States.

We present the first prospective application of our mouse liver microsomal (MLM) stability Bayesian model. CD117, an antitubercular thienopyrimidine tool compound that suffers from metabolic instability (MLM < 1 min), was utilized to assess the predictive power of our new MLM stability model. The S-substituent was removed, a set of commercial reagents was utilized to construct a virtual library of 411 analogues, and our MLM stability model was applied to prioritize 13 analogues for synthesis and biological profiling. Read More

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October 2017

C-Nucleosides To Be Revisited.

Erik De Clercq

J Med Chem 2016 Mar 29;59(6):2301-11. Epub 2015 Oct 29.

Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, B-3000 Leuven, Belgium.

Two new C-nucleoside analogues, BCX4430, an imino-C-nucleoside, and GS-6620, a phosphoramidate derivative of 1'-cyano-2'-C-methyl-4-aza-7,9-dideazaadenosine C-nucleoside, have been recently described as effective against filovirus infections (Marburg) and hepatitis C virus (HCV), respectively. The first C-nucleoside analogues were described about half a century ago. The C-nucleoside pseudouridine is a natural component of RNA, and various other C-nucleoside analogues have been reported previously for their antiviral and/or anticancer potential, the most prominent being pyrazofurin, tiazofurin, and selenazofurin. Read More

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Rational Design of Orthogonal Multipolar Interactions with Fluorine in Protein-Ligand Complexes.

J Med Chem 2015 Sep 6;58(18):7465-74. Epub 2015 Sep 6.

Department of Pathology, University of Michigan , Ann Arbor, Michigan 48109, United States.

Multipolar interactions involving fluorine and the protein backbone have been frequently observed in protein-ligand complexes. Such fluorine-backbone interactions may substantially contribute to the high affinity of small molecule inhibitors. Here we found that introduction of trifluoromethyl groups into two different sites in the thienopyrimidine class of menin-MLL inhibitors considerably improved their inhibitory activity. Read More

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September 2015

Identification of a thienopyrimidine derivatives target by a kinome and chemical biology approach.

Arch Pharm Res 2015 Sep 18;38(9):1575-81. Epub 2015 Jul 18.

Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seoul, 120-749, Republic of Korea.

Target identification through chemical biology has been considered one of the most efficient approaches for drug discovery. Thienopyrimidine derivatives were designed to discover potent IκB kinase β (IKKβ) inhibitors based on a known IKKβ inhibitor library. Most of the thienopyrimidine derivatives inhibited nitric oxide and tumor necrosis factor alpha, which are downstream of the NF-κB signaling pathway, but not IKKβ. Read More

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September 2015

Truncated structures used in search for new lead compounds and in a retrospective analysis of thienopyrimidine-based EGFR inhibitors.

Eur J Med Chem 2015 Apr 4;94:175-94. Epub 2015 Mar 4.

Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address:

An approach for optimization of epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors using truncated thienopyrimidine structures combined with enzymatic assay has been evaluated. This was done by synthesis and EGFR activity measurement of a series of fragment structures and their corresponding drug-model analogues. On average, the activity of the drug-like structures increased a ten-fold as compared to the fragments. Read More

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Discovery of thienopyrimidine-based FLT3 inhibitors from the structural modification of known IKKβ inhibitors.

Bioorg Med Chem Lett 2014 Jun 24;24(12):2655-60. Epub 2014 Apr 24.

Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea; Department of Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea. Electronic address:

Inactivation of the NF-κB signaling pathway by inhibition of IKKβ is a well-known approach to treat inflammatory diseases such as rheumatoid arthritis and cancer. Thienopyrimidine-based analogues were designed through modification of the known IKKβ inhibitor, SPC-839, and then biologically evaluated. The resulting analogues had good inhibitory activity against both nitric oxide and TNF-α, which are well-known inflammatory responses generated by activated NF-κB. Read More

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Thienopyrimidine bisphosphonate (ThPBP) inhibitors of the human farnesyl pyrophosphate synthase: optimization and characterization of the mode of inhibition.

J Med Chem 2013 Oct 3;56(20):7939-50. Epub 2013 Oct 3.

Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montreal, Quebec, Canada H3A 0B8.

Human farnesyl pyrophosphate synthase (hFPPS) controls the post-translational prenylation of small GTPase proteins that are essential for cell signaling, cell proliferation, and osteoclast-mediated bone resorption. Inhibition of hFPPS is a clinically validated mechanism for the treatment of lytic bone diseases, including osteoporosis and cancer related bone metastases. A new series of thienopyrimidine-based bisphosphonates (ThP-BPs) were identified that inhibit hFPPS with low nanomolar potency. Read More

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October 2013

Synthesis of some novel thieno[3,2-d]pyrimidines as potential cytotoxic small molecules against breast cancer.

Chem Pharm Bull (Tokyo) 2013 29;61(6):637-47. Epub 2013 Mar 29.

Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

A variety of novel thieno[3,2-d]pyrimidines with different decorating functional groups were synthesized as a part of a study aiming to enrich the arsenal of chemotherapeutic agents for the treatment of cancer. The design of synthetic molecules based on DNA-interchelating properties by hydrogen bond formation. The reported compounds herein are: 4-aminothienopyrimidine derivatives 4a, b and their 4-substituted phenylamino analogues 8a, b; 4-thienopyrimidin-4-ones 5a, b; N-alkyl thienopyrimidin-4-ones 6a-g; 4-chlorothienopyrimidines 7a, b and thienopyrimidoquinazolinones 9a, b which are the structural mimics of 8a, b. Read More

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December 2013

Thieno analogues of RNA nucleosides: a detailed theoretical study.

J Phys Chem B 2012 Jul 25;116(26):7618-26. Epub 2012 Jun 25.

Theoretical Sciences Unit, Jawaharlal Nehru Center for Advanced Scientific Research, Jakkur P.O., Bangalore 560064, India.

We use first-principles density functional theory calculations to investigate the structural, energetic, bonding aspects, and optical properties of recently synthesized thieno-analogues of RNA nucleosides. The results are compared against the findings obtained for both the natural nucleosides as well as available experimental data. We find that the modified nucleosides form the hydrogen bonded Watson-Crick (WC) base pairing with similar H-bonding energy as obtained for the natural nucleosides. Read More

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Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization.

Eur J Med Chem 2012 Jun 17;52:205-12. Epub 2012 Mar 17.

Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kai Yuan Avenue, Guangzhou Science Park, Guangzhou 510530, China.

We previously reported a highly potent DPP-IV inhibitor 6 with low in vivo efficacy. While trying to maintain consistent in vitro and in vivo biological activity, we initiated a pharmacokinetic property-driven optimization to improve the metabolic stability and permeability of inhibitor 6. A simple scaffold replacement of thienopyrimidine with pyrrolopyrimidine (21a) led to significantly improved metabolic stability (4% vs. Read More

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Synthesis of substituted thieno[2,3-d]pyrimidine-2,4-dithiones and their S-glycoside analogues as potential antiviral and antibacterial agents.

Eur J Med Chem 2010 Sep 2;45(9):4026-34. Epub 2010 Jun 2.

Photochemistry Department (Heterocyclic& Nucleosides Group), National Research Centre, 12622 Dokki, Cairo, Egypt.

Previously, we synthesized and evaluated several thienopyrimidine derivatives containing heterocyclic ring substituents linked to the pyrimidine-2-thione nucleus at C-2 by a two- to four-atom spacer as potential anti-HIV-1 and antimicrobial agents. Also, from the literature, S-substituted pyrimidin-4-ones A and B exhibited interesting anti-HIV-1 activity. To further investigate the synthesis, tools and biological activities, we synthesized several new thienopyrimidine derivatives derived from thieno[2,3-d]-pyrimidine-2,4-dithione (3a,b) The compounds were designed to comprise the heterocyclic substituents directly linked to the thienopyrimidines nucleus at C-2. Read More

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September 2010

Preparation of a 7-arylthieno[3,2-d]pyrimidin-4-amine library.

J Comb Chem 2007 May-Jun;9(3):431-6. Epub 2007 Mar 8.

Key Laboratory of Asymmetric Synthesis & Chirotechnology of Sichuan Province and Union Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China.

A focused kinase library of 7-arylthieno[3,2-d]pyrimidin-4-amine analogues is readily prepared via solution-phase parallel synthesis. This strategy relies on a key cyclization of a 3-aminothiophene-2-carboxamide with a formamide to construct the thienopyrimidine core. Further elaborations of this core via substitution and Suzuki coupling reactions allow the introduction of other diversity points. Read More

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Synthesis of new iso-C-nucleoside analogues from 2-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-alpha-D-altropyranosid-3-yl)ethanal.

Carbohydr Res 2005 Mar;340(4):547-55

Institut für Chemie, Universität Rostock, D-18051 Rostock, Germany.

Treatment of 2-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-alpha-D-altropyranosid-3-yl)ethanal with malononitrile, cyanoacetamide and 2-cyano-N-(4-methoxyphenyl)acetamide, respectively, in the presence of aluminium oxide yielded 2-cyano-4-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-alpha-D-altropyranosid-3-yl)crotonic acid derivatives. Cyclization with sulfur and triethylamine was performed to synthesize the 2-amino-5-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-alpha-D-altropyranosid-3-yl)thiophene-3-carbonic acid derivatives, which were treated with triethyl orthoformate/ammonia and triethyl orthoformate, respectively, to furnish 6-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-alpha-D-altropyranosid-3-yl)thieno[2.3-d]pyrimidine derivatives. Read More

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[[(Arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone derivatives as high-affinity, selective 5-HT1A receptor ligands.

J Med Chem 1997 Feb;40(4):574-85

Dipartimento di Scienze Farmaceutiche, Università di Catania, Italy.

A series of 2-[[(4-aryl-1-piperazinyl)alkyl]thio]thieno[2,3-d]pyrimidin-4 (1H)-one and 3-substituted 2-[[(4-aryl-1-piperazinyl)alky]thio]thieno[2,3-d]pyrimidin-4 (3H)-one derivatives was prepared and evaluated for in vitro 5-HT1A receptor affinity by radioligand binding assays; the selectivity for 5-HT1A receptors rather than alpha 1-adrenoceptors was also examined (ratio of the IC50 alpha 1 to IC50 5-HT1A). The binding tests gave indications about the best features of the [(arylpiperazinyl)alkyl]thio moiety and of the substituents on the thiophene and pyrimidinone rings for efficacious and selective 5-HT1A ligands. The most effective derivative for displacing [3H]-8-OH-DPAT from rat hippocampal membranes was the 3-amino-2-[[3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl]thio]-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one (70) (IC50 = 0. Read More

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February 1997

[Anti-AIDS thienopyrimidine nucleosides].

J Pharm Belg 1995 Mar-Jun;50(2-3):121-61

Centre d'Etudes et de Recherche sur le Médicament de Normandie UFR des Sciences Pharmaceutiques, Université de Caen, France.

In response to the AIDS epidemic, the discovery of antiviral agents has been focused on the synthesis of nucleoside analogues. The basis moiety of these pyrimidine nucleosides were thieno and thiano[3,2-d]pyrimidine-2,4-dione possibly substituted on 7 position by methyl or aryl groups, 6,7-dihydrothieno[3,2-d]pyrimidin-4-one, bicyclic heterocycles including an uracil moiety. The first part of organic chemistry work has provided cyclic and acyclic N-nucleosides after adaptation of Vorbrüggen and Niedballa method. Read More

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October 1995
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