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Identification of a 3-β-homoalanine Conjugate of Brusatol with Reduced Toxicity in Mice.

Nicky Hwang, Yonggang Pei, Jason Clement, Erle S Robertson, Yanming Du,

Brusatol, a quassinoid natural product, is effective against multiple diseases including hematologic malignancies as we reported recently by targeting the PI3Kγ isoform, but toxicity limits its further development. Herein, we report the synthesis of a series of conjugates of brusatol with amino acids and short peptides through its enolic hydroxyl ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, :127553]

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Synthesis and Biological Evaluation of Radioiodinated 3-Phenylcoumarin Derivatives Targeting Myelin in Multiple Sclerosis.

Hiroyuki Watanabe, Shiori Sakai, Shimpei Iikuni, Yoichi Shimizu, Hisashi Shirakawa, Shuji Kaneko, Masahiro Ono,

Myelin is a lipid multilayer involved in the rate of nerve transmission, and its loss is a pathological feature of multiple sclerosis in brains. Since in vivo imaging of myelin may be useful for drug development, early diagnosis, and monitoring the disease stage, we designed, synthesized, and evaluated eight novel ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, :127562]

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Sulfamic acid catalyzed synthesis of new 3,5-[(sub)phenyl]-1H-pyrazolebearing N1-isonicotinoyl: and their pharmacological activity evaluation.

Jayashri D Bhirud, Rajendra D Patil, Hemant P Narkhede,

A sustainable synthesis of new 3,5-[(sub)phenyl]-1H-pyrazole bearing N1-isonicotinoyl derivatives from substituted chalcones and isoniazid by using sulfamic acid and their pharmacological activity evaluationis reported. An anti-oxidant study is performed by using DPPH assay. In vitro anti-mycobacterial activity of compounds bearing R/R'=4-CH3/4-F and 3-OCH3/4-Cl showed complete inhibition (99%) at the MIC ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, :127558]

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Synthesis of non-nucleoside anti-viral cyclopropylcarboxacyl hydrazones and initial anti-HSV-1 structure-activity relationship studies.

James McNulty, Chanti Babu Dokuburra, Leonardo D'Aiuto, Matthew Demers, Lora McClain, Paolo Piazza, Kelly Williamson, Wenxiao Zheng, Vishwajit L Nimgaonkar,

The synthesis of a lead anti-viral cyclopropyl carboxy acyl hydrazone 4F17 (5) and three sequential arrays of structural analogues along with the initial assessment and optimization of the antiviral pharmacophore against the herpes simplex virus type 1 (HSV-1) are reported. ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, :127559]

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Benzylidene thiazolidinediones: Synthesis, in vitro investigations of antiproliferative mechanisms and in vivo efficacy determination in combination with Imatinib.

Hardik Joshi, Vijay Patil, Kalpana Tilekar, Neha Upadhyay, Vikram Gota, C S Ramaa,

Thiazolidinedione (TZD) has been an interesting scaffold due to its proven antidiabetic activity and encouraging findings in anticancer drug discovery. We synthesised benzylidene thiazolidinedione derivatives which exhibited excellent antiproliferative effects in chronic myeloid leukemic cells K562 and the most active compounds 3t and 3x had GI50 value of 0.9 and ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, :127561]

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Discovery of a Series of Ester-substituted NLRP3 Inflammasome Inhibitors.

David Harrison, Nicolas Boutard, Krzysztof Brzozka, Marta Bugaj, Stefan Chmielewski, Anna Cierpich, John R Doedens, Charles-Henry R Y Fabritius, Christopher A Gabel, Michal Galezowski, Piotr Kowalczyk, Oleksandr Levenets, Magdalena Mroczkowska, Katarzyna Palica, Roderick A Porter, David Schultz, Marta Sowinska, Grzegorz Topolnicki, Piotr Urbanski, Jakub Woyciechowski, Alan P Watt,

The NLRP3 inflammasome is a component of the innate immune system involved in the production of proinflammatory cytokines. Aberrant activation by a wide range of exogenous and endogenous signals can lead to chronic, low-grade inflammation. It has attracted a great deal of interest as a drug target due to the ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, :127560]

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Rhopaladins' analogue (E)-2-aroyl-4-(4-fluorobenzylidene)- 5-oxopyrrolidines inhibit proliferation, promote apoptosis and down-regulation of E6/E7 mRNA in cervical cancer.

Xiu-Lian Zhu, Xiao-Qiong Tian, Huan-Huan Xu, Hong-Mei Wang, Qin-Hua Chen, Xiao-Hua Zeng,

The occurrence and development of cervical cancer threaten women's life and health, HPV-induced cervical cancer is a major health issue among women. We synthesized three Rhopaladins' analogue (E)-2-aroyl-4-(4-fluorobenzylidene)-5-oxopyrrolidines via a tandem Ugi 4CC/SN cyclization with pyrrolidone as a core structure. In addition, the cytotoxicity of these new compounds in the ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, :127554]

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3-(Cyclopropylmethyl)-7-((4-(4-[11C]methoxyphenyl)piperidin-1-yl)methyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine: Synthesis and preliminary evaluation for PET imaging of metabotropic glutamate receptor subtype 2.

Katsushi Kumata, Yiding Zhang, Masanao Ogawa, Yusuke Kurihara, Wakana Mori, Kuan Hu, Masayuki Fujinaga, Nobuki Nengaki, Ming-Rong Zhang,

Selective metabotropic glutamate receptor 2 (mGluR2) inhibitors have been demonstrated to show therapeutic effects by improving alleviating symptoms of schizophrenic patients in clinical studies. Herein we report the synthesis and preliminary evaluation of a 11C-labeled positron emission tomography (PET) tracer originating from a mGluR2 inhibitor, 3-(cyclopropylmethyl)-7-((4-(4-methoxyphenyl)piperidin-1-yl)methyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (CMTP, 1a). [11C]CMTP ([11C]1a) ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, 30(23):127555]

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Design, synthesis and biological evaluation of novel heptamethine cyanine dye-erlotinib conjugates as antitumor agents.

Xiaoguang Yang, Zhuang Hou, Dun Wang, Yanhua Mou, Chun Guo,

Epidermal growth factor receptor tyrosine kinase (EGFR-TK) has been proved as a target for the treatment of non-small cell lung cancer (NSCLC) with specific gene mutations. However, EGFR-TK inhibitors (EGFR-TKIs) need to enter cancer cells and then competitively interact with the active site of tyrosine kinase receptors to suppress the ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, :127557]

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Design of a dual ERK5 kinase activation and autophosphorylation inhibitor to block cancer stem cell activity.

Samanth R Kedika, Satya P Shukla, D Gomika Udugamasooriya,

The importance of ERK5 kinase signaling in tumorigenicity, metastasis, and drug resistance of cancer stem cells (CSCs) has been recognized recently, and we report a unique dual inhibitor that blocks binding of the ERK5 activator and ERK5 autophosphorylation simultaneously. The conventional ATP-binding site inhibitors have not yet yielded expected level ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, :127552]

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The synthesis and anti-tumour properties of novel 4-substituted phthalazinones as Aurora B kinase inhibitors.

Xiu-Juan Zhang, Yu Xu, Hong-Xia Mou, Shuai Wang, Shu-Yi Hao, Shi-Wu Chen,

A series of novel 4-substituted phthalazinones as Aurora B kinase inhibitors was synthesized and evaluated the anti-proliferative activities against A549, HCT116, MCF-7 and HepG2 cells. 1-(4-(2-((4-Oxo-3,4-dihydrophthalazin-1-yl)amino)ethyl) phenyl)-3-(3-(trifluoromethyl)phenyl)urea (17b) exhibited the most potent anti-proliferative activity against HCT116 cells with IC50 value of 4.35 ± 1.21 μM, as well as the moderate Aurora B inhibitory ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, 30(23):127556]

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Mycophenolic anilides as broad specificity inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitors.

Seungheon Lee, Angela Ku, Mohana Rao Vippila, Yong Wang, Minjia Zhang, Xingyou Wang, Lizbeth Hedstrom, Gregory D Cuny,

Inosine-5'-monophosphate dehydrogenase (IMPDH) is a potential target for microorganisms. However, identifying inhibitor design determinants for IMPDH orthologs continues to evolve. Herein, a series of mycophenolic anilide inhibitors of Cryptosporidium parvum and human IMPDHs are reported. Furthermore, molecular docking of 12 (e.g. SH-19; CpIMPDH Ki,app = 0.042 ± 0.015 µM, HsIMPDH2 ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, :127543]

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Synthesis and biofilm inhibition studies of 2-(2-amino-6-arylpyrimidin-4-yl)quinazolin-4(3H)-ones.

Sivappa Rasapalli, Zachary F Murphy, Vamshikrishna Reddy Sammeta, James A Golen, Alexander W Weig, Roberta J Melander, Christian Melander, Prathyushakrishna Macha, Milana C Vasudev,

Synthesis of novel 4(3H)-quinazolinonyl aminopyrimidine derivatives has been achieved via quinazolinonyl enones which in turn were obtained from 2-acyl-4(3H)-quinazolinone. They have been assayed for biofilm inhibition against Gram-positive (methicillin-resistant Staphylococcus aureus (MRSA)) and Gram-negative bacteria (Acinetobacter baumannii). The analogues with 2,4,6-trimethoxy phenyl, 4-methylthio phenyl, and 3-bromo phenyl substituents (5h, 5j ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, 30(23):127550]

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Antifungal Polybrominated Proxyphylline Derivative Induces Candida albicans Calcineurin Stress Response in Galleria mellonella.

Małgorzata Gizińska, Anna Staniszewska, Michalina Kazek, Mirosława Koronkiewicz, Łukasz Kuryk, Małgorzata Milner-Krawczyk, Joanna Baran, Paweł Borowiecki, Monika Staniszewska,

Candida albicans CNB1 plays a role in the response in vitro and in vivo to stress generated by PB-WUT-01, namely 1,3-dimethyl-7-(2-((1-(3-(perbromo-2H-benzo[d][1,2,3]triazol-2-yl)propyl)-1H-1,2,3-triazol-4-yl)methoxy)propyl)-1H-purine-2,6(3H,7H)-dione. The antifungal mechanism involved the calcineurin pathway-regulated genes SAP9-10. Galleria mellonella treated with PB-WUT-01 (at 0.64 µg/mg) showed limited candidiasis and remained within the highest survival rates. The molecular ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, :127545]

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Structural basis for producing selective MAP2K7 inhibitors.

Yuka Murakawa, Shirly Valter, Haim Barr, Nir London, Takayoshi Kinoshita,

Mitogen-activated protein kinase kinase 7 (MAP2K7) in the c-Jun N-terminal kinase signal cascade is an attractive drug target for a variety of diseases. The selectivity of MAP2K7 inhibitors against off-target kinases is a major barrier in drug development. We report a crystal structure of MAP2K7 complexed with a potent covalent ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, 30(22):127546]

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Exploring efficacy of Natural-derived Acetylphenol Scaffold Inhibitors for α-Glucosidase: synthesis, in vitro and in vivo biochemical studies.

Xiao Yu, Fan Zhang, Ting Liu, Zhigang Liu, Qingjian Dong, Ding Li,

The discovery of novel α-glucosidase inhibitors and anti-diabetic candidates from natural or natural-derived products represents an attractive therapeutic option. Here, a collection of acetylphenol analogues derived from paeonol and acetophenone were synthesized and evaluated for their α-glucosidase inhibitory activity. Most of derivatives, such as 9a - 9e, 9i, 9m - ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, :127528]

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Synthesis of metronidazole based thiazolidinone analogs as promising antiamoebic agents.

Mohammad Fawad Ansari, Afreen Inam, Kamal Ahmad, Shehnaz Fatima, Subhash M Agarwal, Amir Azam,

Metronidazole and its derivatives are widely used for the treatment of amoebiasis. However, metronidazole is considered as the standard drug but it has many side effects. The present study describes the synthesis of a series of metronidazole based thiazolidinone analogs via Knoevenagel condensation of 4-[2-(2-methyl-5-nitro-1H-imidazole-1-yl)ethoxy]benzaldehyde 1 with various thiazolidinone derivatives ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, :127549]

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Discovery of 1-(1H-Indazol-4-yl)-3-((1-Phenyl-1H-Pyrazol-5-yl)methyl) Ureas as Potent and Thermoneutral TRPV1 Antagonists.

Jin Mi Kang, Sun Ok Kwon, Jihyae Ann, Peter M Blumberg, Heejin Ha, Young Dong Yoo, Robert Frank-Foltyn, Bernhard Lesch, Gregor Bahrenberg, Hannelore Stockhausen, Thomas Christoph, Jeewoo Lee,

A series of 1-indazol-3-(1-phenylpyrazol-5-yl)methyl ureas were investigated as hTRPV1 antagonists. The structure-activity relationship study was conducted systematically for both the indazole A-region and the 3-trifluoromethyl/t-butyl pyrazole C-region to optimize the antagonism toward the activation by capsaicin. Among them, the antagonists 26, 50 and 51 displayed highly potent antagonism with Ki(CAP) ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, :127548]

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Biochemical, cellular and structural characterization of novel and selective ERK3 inhibitors.

Ulrich Grädler, Michael Busch, Birgitta Leuthner, Michael Raba, Lars Burgdorf, Martin Lehmann, Nina Linde, Christina Esdar,

Triazolo[4,5-d]pyrimidin-5-amines were identified from kinase selectivity screening as novel ERK3 inhibitors with sub-100 nanomolar potencies in a biochemical assay using MK5 as substrate and with an attractive kinase selectivity profile. ERK3 crystal structures clarified the inhibitor binding mode in the ATP pocket with impact on A-loop, GC-loop and αC-helix conformations ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, 30(22):127551]

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Synthesis of indole-tethered [1,3,4]thiadiazolo and [1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one hybrids as anti-pancreatic cancer agents.

Lalitha Gummidi, Nagaraju Kerru, Paul Awolade, Asif Raza, Arun K Sharma, Parvesh Singh,

New indole-tethered [1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (8a-j) and [1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one hybrids (9a-e) were synthesized using [4+2] cycloaddition reactions of functionalized 1,3-diazabuta-1,3-dienes with indole-ketenes. All molecular hybrids were structurally characterized by spectroscopic techniques (IR, NMR, and HRMS) and screened for their anti-pancreatic cancer activity in vitro. The [1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one hybrids (9a-e) showed stronger anti-pancreatic cancer activity ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, 30(22):127544]

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Dihydrodibenzothiepine: Promising hydrophobic pharmacophore in the influenza cap-dependent endonuclease inhibitor.

Yoshiyuki Taoda, Masayoshi Miyagawa, Toshiyuki Akiyama, Kenji Tomita, Yasushi Hasegawa, Ryu Yoshida, Takeshi Noshi, Takao Shishido, Makoto Kawai,

This work describes a set of discovery research studies of an influenza cap-dependent endonuclease (CEN) inhibitor with a carbamoyl pyridone bicycle (CAB) scaffold. Using influenza CEN inhibitory activity, antiviral activity and pharmacokinetic (PK) parameters as indices, structure activity relationships (SAR) studies were performed at the N-1 and N-3 positions on ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, 30(22):127547]

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Structure-activity relationships of GPX4 inhibitor warheads.

John K Eaton, Laura Furst, Luke L Cai, Vasanthi S Viswanathan, Stuart L Schreiber,

Direct inhibition of GPX4 requires covalent modification of the active-site selenocysteine. While phenotypic screening has revealed that activated alkyl chlorides and masked nitrile oxides can inhibit GPX4 covalently, a systematic assessment of potential electrophilic warheads with the capacity to inhibit cellular GPX4 has been lacking. Here, we survey more than ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, :127538]

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Synthesis and Biological Evaluation of 5'-C-Methyl Nucleotide Prodrugs for Treating HCV Infections.

Madhuri Dasari, Peipei Ma, Stephen C Pelly, Savita K Sharma, Dennis C Liotta,

Nucleotide prodrugs are of great clinical interest for treating a variety of viral infections due to their ability to target tissues selectively and to deliver relatively high concentrations of the active nucleotide metabolite intracellularly. However, their clinical successes have been limited, oftentimes due to unwanted in vivo metabolic processes that ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, :127539]

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Characterization of SPK 98, a Torin2 analog, as ATR and mTOR dual kinase inhibitor.

Rashmi Bhakuni, Althaf Shaik, Bhanu Priya, Sivapriya Kirubakaran,

A series of Torin2, a second-generation ATP-competitive inhibitor, analogues were biologically characterized to identify their potential for ATR and mTOR kinase inhibition. Compound SPK 98 was observed to inhibit ATR/mTOR kinase selectively over ATM kinase in HCT116 cell line. In addition to that, SPK 98 on 30 min incubation with ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, :127517]

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Design, synthesis and evaluation of novel indirubin-based N-hydroxybenzamides, N-hydroxypropenamides and N-hydroxyheptanamides as histone deacetylase inhibitors and antitumor agents.

Duong Tien Anh, Pham-The Hai, Do Thi Mai Dung, Phan Thi Phuong Dung, Le-Thi-Thu Huong, Eun Jae Park, Hye Won Jun, Jong Soon Kang, Joo-Hee Kwon, Truong Thanh Tung, Sang-Bae Han, Nguyen-Hai Nam,

Several novel indirubin-based N-hydroxybenzamides, N-hydropropenamides and N-hydroxyheptanamides (4a-h, 7a-h, 10a-h) were designed using a fragment-based approach with structural features extracted from several previously reported HDAC inhibitors, such as SAHA (vorinostat), MGCD0103 (mocetinostat), nexturastat A and PXD-101 (belinostat). The biological results reveal that our compounds showed excellent cytotoxicity toward three common ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, 30(22):127537]

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