15,141 results match your criteria Bioorg. Med. Chem.[Journal]


Design synthesis and evaluation of novel aldose reductase inhibitors: The case of indolyl-sulfonyl-phenols.

Bioorg Med Chem 2020 Aug 4;28(15):115575. Epub 2020 Jun 4.

Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54214 Thessaloniki, Greece. Electronic address:

Therapeutic interventions with aldose reductase inhibitors appear to be a promising approach to major pathological conditions (i.e. neuropathy/angiopathy related to chronic hyperglycemia, chronic inflammation and cancer). Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115575DOI Listing

Design, synthesis and biological activity of novel substituted 3-benzoic acid derivatives as MtDHFR inhibitors.

Bioorg Med Chem 2020 Aug 20;28(15):115600. Epub 2020 Jun 20.

Laboratory of Design and Synthesis of Bioactive Substances (LAPESSB), Faculty of Pharmaceutical Sciences, University of São Paulo, Prof. Lineu Prestes Avenue, 580, Bl.13, São Paulo, SP, Brazil. Electronic address:

The enzyme dihydrofolate reductase from M.tuberculosis (MtDHFR) has a high unexploited potential to be a target for new drugs against tuberculosis (TB), due to its importance for pathogen survival. Preliminary studies have obtained fragment-like molecules with low affinity to MtDHFR which can potentially become lead compounds. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115600DOI Listing

Design, synthesis and biological evaluation of novel 6-phenyl-1,3a,4,10b-tetrahydro-2H-benzo[c]thiazolo[4,5-e]azepin-2-one derivatives as potential BRD4 inhibitors.

Bioorg Med Chem 2020 Aug 20;28(15):115601. Epub 2020 Jun 20.

Center of Drug Discovery, State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address:

Bromodomain-containing protein 4 (BRD4) is a key epigenetic regulator in cancer, and inhibitors targeting BRD4 exhibit great anticancer activity. By replacing the methyltriazole ring of the BRD4 inhibitor I-BET-762 with an N-methylthiazolidone heterocyclic ring, fifteen novel BRD4 inhibitors were designed and synthesized. Compound 13f had a hydrophobic acetylcyclopentanyl side chain, showing the most potent BRD4 inhibitory activity in the BRD4-BD1 inhibition assay (IC value of 110 nM), it also significantly suppressed the proliferation of MV-4-11 cells with high BRD4 level (IC value of 0. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115601DOI Listing

Tetrazoles as anticancer agents: A review on synthetic strategies, mechanism of action and SAR studies.

Bioorg Med Chem 2020 Aug 20;28(15):115599. Epub 2020 Jun 20.

Department of Pharmaceutical Sciences and Natural Products, School of Basic and Applied Sciences, Central University of Punjab, Bathinda 151 001, India. Electronic address:

Cancer is a leading cause of death worldwide. Even after the availability of numerous drugs and treatments in the market, scientists and researchers are focusing on new therapies because of their resistance and toxicity issues. The newly synthesized drug candidates are able to demonstrate in vitro activity but are unable to reach clinical trials due to their rapid metabolism and low bioavailability. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115599DOI Listing

Structural studies of triazole inhibitors with promising inhibitor effects against antibiotic resistance metallo-β-lactamases.

Bioorg Med Chem 2020 Aug 18;28(15):115598. Epub 2020 Jun 18.

The Norwegian Structural Biology Centre (NorStruct), Department of Chemistry, Faculty of Science and Technology, UiT The Arctic University of Norway, N-9037 Tromsø, Norway. Electronic address:

Metallo-β-lactamases (MBLs) are an emerging cause of bacterial antibiotic resistance by hydrolysing all classes of β-lactams except monobactams, and the MBLs are not inhibited by clinically available serine-β-lactamase inhibitors. Two of the most commonly encountered MBLs in clinical isolates worldwide - the New Delhi metallo-β-lactamase (NDM-1) and the Verona integron-encoded metallo-β-lactamase (VIM-2) - are included in this study. A series of several NH-1,2,3-triazoles was prepared by a three-step protocol utilizing Banert cascade reaction as the key step. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115598DOI Listing

Green asymmetric synthesis of epoxypeptidomimetics and evaluation as human cathepsin K inhibitors.

Bioorg Med Chem 2020 Aug 17;28(15):115597. Epub 2020 Jun 17.

Centre of Excellence for Research on Sustainable Chemistry, Department of Chemistry, Federal University of São Carlos, 13565-905 São Carlos, SP, Brazil; School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, 14040-903 Ribeirão Preto, SP, Brazil. Electronic address:

Cathepsin K (CatK) is a cysteine protease known for its potent collagenolytic activity, being recognized as an important target to the development of therapies for the treatment of bone disorders. Epoxypeptidomimetics have been reported as potent inhibitors of cathepsins, thus in this work we present a green synthesis of new peptidomimetics by using a one-pot asymmetric epoxidation/Ugi multicomponent reaction. The compounds were evaluated against CatK showing selectivity when compared with cathepsin L, with an inhibition profile in the low micromolar IC range. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115597DOI Listing

Amide derivatives of Gallic acid: Design, synthesis and evaluation of inhibitory activities against in vitro α-synuclein aggregation.

Bioorg Med Chem 2020 Aug 17;28(15):115596. Epub 2020 Jun 17.

College of Pharmacy, Xinxiang Medical University, Jinsui Road 601, 453003 Xinxiang, China. Electronic address:

Gallic acid (GA), a natural phenolic acid, has received numerous attention because of its anti-oxidative, anti-inflammatory, and anti-cancer activity. More importantly, GA can act as an efficient inhibitor of α-Synuclein (α-Syn) aggregation at early stages. Nevertheless, some evidences suggest that GA is unlikely to cross the blood-brain barrier because of its high hydrophilicity. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115596DOI Listing

Design and synthesis of peptide-based chimeric molecules to induce degradation of the estrogen and androgen receptors.

Bioorg Med Chem 2020 Aug 12;28(15):115595. Epub 2020 Jun 12.

National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan; Graduate School of Medical Health Sciences, Yokohama City University, Yokohama, Kanagawa 230-0045, Japan. Electronic address:

Peptide-based inducers of estrogen receptor (ER) α and androgen receptor (AR) degradations via the ubiquitin-proteasome system (UPS) were developed. The designated inducers were composed of two biologically active scaffolds: the helical peptide PERM3, which is an LXXLL-like mimic of the coactivator SRC-1, and various small molecules (MV1, LCL161, VH032, and POM) that bind to E3 ligases (IAPs, VHL, and cereblon, respectively), to induce ubiquitylation of nuclear receptors that bind to SRC-1. All of the synthesized chimeric E3 ligand-containing molecules induced the UPS-mediated degradation of ERα and AR. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115595DOI Listing

New coumarin/sulfocoumarin linked phenylacrylamides as selective transmembrane carbonic anhydrase inhibitors: Synthesis and in-vitro biological evaluation.

Bioorg Med Chem 2020 Aug 18;28(15):115586. Epub 2020 Jun 18.

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India; Department of Chemistry, Anwarul Uloom College, 11-3-918, New Malleypally, Hyderabad 500001, T. S., India. Electronic address:

Two novel series of phenylacrylamide linked coumarins and sulfocoumarins (6a-p, 8a-i, and 14a-g) were synthesized and evaluated against four physiologically relevant human carbonic anhydrases (hCAs, EC 4.2.1. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115586DOI Listing

Synthetic and therapeutic perspectives of nitrogen containing heterocycles as anti-convulsants.

Bioorg Med Chem 2020 Aug 13;28(15):115585. Epub 2020 Jun 13.

Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Ghal Kalan, Ferozpur G.T. Road MOGA-142001, Punjab, India. Electronic address:

Epilepsy is one of the commonly prevailing neurological disorders. According to the reports, it is evident that about 80% of the epileptic cases have been observed in developing countries. Although there are many drugs with significant potency available in the market; still there is an issue of selectivity and toxicity. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115585DOI Listing

Phenyltriazole-functionalized sulfamate inhibitors targeting tyrosyl- or isoleucyl-tRNA synthetase.

Bioorg Med Chem 2020 Aug 5;28(15):115580. Epub 2020 Jun 5.

Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49 box 1030, 3000 Leuven, Belgium. Electronic address:

Antimicrobial resistance is considered as one of the major threats for the near future as the lack of effective treatments for various infections would cause more deaths than cancer by 2050. The development of new antibacterial drugs is considered as one of the cornerstones to tackle this problem. Aminoacyl-tRNA synthetases (aaRSs) are regarded as good targets to establish new therapies. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115580DOI Listing

Structural manipulation of aporphines via C10 nitrogenation leads to the identification of new 5-HTR ligands.

Bioorg Med Chem 2020 Aug 5;28(15):115578. Epub 2020 Jun 5.

Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA; Program in Biochemistry, CUNY Graduate Center, 365 5(th) Avenue, New York, NY 10016, USA; Program in Chemistry, CUNY Graduate Center, 365 5(th) Avenue, New York, NY 10016, USA. Electronic address:

Aporphine alkaloids containing a C10 nitrogen motif were synthesized and evaluated for affinity at 5-HTR, 5-HTR, 5-HTR and 5-HTR. Three series of racemic aporphines were investigated: 1,2,10-trisubstituted, C10 N-monosubstituted and compounds containing a C10 benzofused aminothiazole moiety. The 1,2,10-trisubstituted series of compounds as a group displayed modest selectivity for 5-HTR and also had moderate 5-HTR affinity. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115578DOI Listing

Synthesis and evaluation of F labeled crizotinib derivative [F]FPC as a novel PET probe for imaging c-MET-positive NSCLC tumor.

Bioorg Med Chem 2020 Aug 30;28(15):115577. Epub 2020 May 30.

Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, China; Institute of Nuclear Medicine, Fudan University, Shanghai, China; Shanghai Institute of Medical Imaging, Shanghai, China. Electronic address:

c-MET-positive NSCLC is an important subtype accounting for about 5%~22% of lung cancer. NSCLC patients with activating c-MET are intensively sensitive to c-MET selective receptor tyrosine kinase (RTK) inhibitors, so we aimed to develop a specific PET probe targeting to c-MET-positive NSCLC for potential patients screened by PET/CT. Herein, PET tracer F-radiolabeled crizotinib derivative ([F]FPC) was successfully achieved through a simple one-step F-labeling method. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115577DOI Listing

Synthesis of ureido thioglycosides as novel insect β‑N‑acetylhexosaminidase OfHex1 inhibitors.

Bioorg Med Chem 2020 Aug 23;28(15):115602. Epub 2020 Jun 23.

Department of Pesticide Chemistry, College of Science, China Agricultural University, Beijing, China. Electronic address:

The insect β-N-acetylhexosaminidase OfHex1 from Ostrinia furnacalis (one of the most destructive agricultural pests) has been considered as a promising pesticide target. In this study, a series of novel and readily available ureido thioglycosides were designed and synthesized based on the catalytic mechanism and the co-crystal structures of OfHex1 with substrates. After evaluation via enzyme inhibition experiments, thioglycosides 11c and 15k were found to have inhibitory activities against OfHex1 with the K values of 25. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115602DOI Listing

Strategies towards potent trypanocidal drugs: Application of Rh-catalyzed [2 + 2 + 2] cycloadditions, sulfonyl phthalide annulation and nitroalkene reactions for the synthesis of substituted quinones and their evaluation against Trypanosoma cruzi.

Bioorg Med Chem 2020 Aug 30;28(15):115565. Epub 2020 May 30.

Institute of Exact Sciences, Department of Chemistry, Federal University of Minas Gerais, CEP 31270-901, Belo Horizonte, MG, Brazil. Electronic address:

Rhodium-catalyzed [2 + 2 + 2] cycloadditions, sulfonyl phthalide annulations and nitroalkene reactions have been employed for the synthesis of 56 quinone-based compounds. These were evaluated against Trypanosoma cruzi, the parasite that causes Chagas disease. The reactions described here are part of a program that aims to utilize modern, versatile and efficient synthetic methods for the one or two step preparation of trypanocidal compounds. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115565DOI Listing

6,6'-Aryl trehalose analogs as potential Mincle ligands.

Bioorg Med Chem 2020 Jul 31;28(14):115564. Epub 2020 May 31.

Department of Chemistry and Biochemistry, University of Montana, 32 Campus Drive, Missoula, MT 59812, United States; Center for Translational Medicine, University of Montana, 32 Campus Drive, Missoula, MT 59812, United States. Electronic address:

6,6'-Aryl trehalose derivatives have been synthesized with a view towards identifying novel Th-17-inducing vaccine adjuvants based on the high affinity Mincle ligand Brartemicin. The initial structure-activity relationships of these novel trehalose-based compounds were investigated. All compounds have been evaluated for their ability to engage the Mincle receptor and induce a potential pro-Th17 cytokine profile from human peripheral blood mononuclear cells based on IL-6 production in human peripheral blood mononuclear cells. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115564DOI Listing

Design, synthesis and evaluation of carbamate-linked uridyl-based inhibitors of human ST6Gal I.

Bioorg Med Chem 2020 Jul 24;28(14):115561. Epub 2020 May 24.

Molecular Horizons and School of Chemistry & Molecular Bioscience, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia. Electronic address:

Sialic acid at the terminus of cell surface glycoconjugates is a critical element in cell-cell recognition, receptor binding and immune responses. Sialyltransferases (ST), the enzymes responsible for the biosynthesis of sialylated glycans are highly upregulated in cancer and the resulting hypersialylation of the tumour cell surface correlates strongly with tumour growth, metastasis and drug resistance. Inhibitors of human STs, in particular human ST6Gal I, are thus expected to be valuable chemical tools for the discovery of novel anticancer drugs. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115561DOI Listing

Fibroblast growth factor receptor modulators employing diamines with reduced phospholipidosis-inducing potential.

Bioorg Med Chem 2020 Jul 24;28(14):115562. Epub 2020 May 24.

Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.

SUN13837 (1), a fibroblast growth factor receptor modulator, has been an attractive candidate for treating neurodegenerative diseases. However, one of its metabolites, N-benzyl-4-(methylamino)piperidine (BMP), turned out to possess phospholipidosis-inducing potential (PLIP) in vitro. To obtain SUN13837 analogs with reduced phospholipidosis risk, we replaced BMP with other diamines possessing low PLIP. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115562DOI Listing

Synthesis and evaluation of new 1-oxa-8-azaspiro[4.5]decane derivatives as candidate radioligands for sigma-1 receptors.

Bioorg Med Chem 2020 Jul 23;28(14):115560. Epub 2020 May 23.

Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China. Electronic address:

We report the design, synthesis, and evaluation of a series of 1-oxa-8-azaspiro[4.5]decane and 1,5-dioxa-9-azaspiro[5.5]undecane derivatives as selective σ receptor ligands. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115560DOI Listing

N-Substituted benzimidazole scaffold for farnesoid X receptor (FXR) agonists accompanying prominent selectivity against vitamin D receptor (VDR).

Bioorg Med Chem 2020 Jul 23;28(14):115512. Epub 2020 May 23.

Graduate School of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan; Faculty of Clinical Nutrition, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan. Electronic address:

As a cellular bile acid sensor, farnesoid X receptor (FXR) participates in regulation of bile acid, lipid and glucose homeostasis, and liver protection. With respect to the bone metabolism, FXR positively regulates bone metabolism through both bone formation and resorption of the bone remodeling pathways. Some of FXR agonists possessing isoxazole moiety are undergoing clinical trials for the treatment of non-alcoholic steatohepatitis. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115512DOI Listing

Bisphosphonate esters interact with HMG-CoA reductase membrane domain to induce its degradation.

Bioorg Med Chem 2020 Jul 31;28(14):115576. Epub 2020 May 31.

Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113 0032, Japan. Electronic address:

HMG-CoA reductase (HMGCR) is a rate-limiting enzyme in the cholesterol biosynthetic pathway, and its catalytic domain is the well-known target of cholesterol-lowering drugs, statins. HMGCR is subject to layers of negative feedback loops; excess cholesterol inhibits transcription of the gene, and lanosterols and oxysterols accelerate degradation of HMGCR. A class of synthetic small molecules, bisphosphonate esters exemplified by SR12813, has been known to induce accelerated degradation of HMGCR and reduce the serum cholesterol level. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115576DOI Listing

Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.

Bioorg Med Chem 2020 Jul 7;28(14):115546. Epub 2020 May 7.

University of Florida, Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), College of Pharmacy, 1345 Center Dr., Gainesville, FL 32610, United States. Electronic address:

G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115546DOI Listing

2β-3,4-Unsaturated sialic acid derivatives: Synthesis optimization, and biological evaluation as Newcastle disease virus hemagglutinin-neuraminidase inhibitors.

Bioorg Med Chem 2020 Jul 24;28(14):115563. Epub 2020 May 24.

Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Piazza Malan 2, San Donato Milanese, 20097 Milan, Italy; University of Vita-Salute San Raffaele, Milan, Italy. Electronic address:

The optimization of the synthetic protocol to obtain the 3,4-unsaturated sialic acid derivatives, through the fine-tuning of both the Ferrier glycosylation conditions and the subsequent hydrolysis work-up, is herein reported. The accomplishment of the desired β-anomers and some selected α-ones, in pure form, led us to evaluate their specific inhibitory activity towards NDV-HN and human sialidase NEU3. Importantly, the resulting data allowed the identification, for the first time, of three active 3,4-unsaturated sialic acid analogs, showing IC values against NDV-HN in the micromolar range. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115563DOI Listing

Discovery of novel potent GPR40 agonists containing imidazo[1,2-a]pyridine core as antidiabetic agents.

Bioorg Med Chem 2020 Jul 2;28(13):115574. Epub 2020 Jun 2.

Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address:

Free fatty acid receptor 1 (FFA1 or GPR40) has been studied for many years as a target for the treatment of type 2 diabetes mellitus. In order to increase potency and reduce hepatotoxicity, a series of novel compounds containing imidazo[1,2-a]pyridine scaffold as GPR40 agonist were synthesized. Compound I-14 was identified as an effective agonist as shown by the conspicuous drop in blood glucose in normal and diabetic mice. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115574DOI Listing

Versatile near-infrared fluorescent probe for in vivo detection of Aβ oligomers.

Bioorg Med Chem 2020 Jul 12;28(13):115559. Epub 2020 May 12.

State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 21198, China. Electronic address:

Amyloid-β oligomers (AβOs) enrichment in brain is highly related to Alzheimer's pathogenesis, but tracing them in the brain by imaging technique is still a great challenge due to their heterogeneity and metastability. Herein, a new near-infrared (NIR) fluorescent probe, namely, PTO-41, was designed and synthesized to specifically target AβOs. PTO-41 possesses excellent functional properties including optimal fluorescent properties (emission maxima at 680 nm upon interacting with AβOs), high affinity (K = 349 nM), low cell toxicity, desirable lipophilicity (log P = 2. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115559DOI Listing

Investigation into the influence of an acrylic acid acceptor in organic D-π-A sensitizers against phototoxicity.

Bioorg Med Chem 2020 Jul 19;28(13):115558. Epub 2020 May 19.

Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan. Electronic address:

Photodynamic therapy (PDT) is a non-invasive, selective, and cost-effective cancer therapy. We previously reported that thiophene-based organic D-π-A sensitizers consist of an electron-donating (D) moiety, a π-conjugated bridge (π) moiety, and an electron-accepting (A) moiety, and are readily accessible and stable templates for photosensitizers that could be used in PDT. In addition, acrylic acid acceptor-containing photosensitizers exert a high level of phototoxicity. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115558DOI Listing

A critical update on the strategies towards modulators targeting androgen receptors.

Bioorg Med Chem 2020 Jul 12;28(13):115554. Epub 2020 May 12.

Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China. Electronic address:

Prostate cancer is the most common carcinoma of the male urinary system in developed countries. Androgen deprivation therapy has been commonly used in the treatment of prostate cancer for decades, but most patients will inevitably develop into more aggressive castration-resistant prostate cancer. Therefore, novel strategies are urgent to address this resistance mechanism. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115554DOI Listing

Synthesis, cytotoxicity, and in vivo antitumor activity study of parthenolide semicarbazones and thiosemicarbazones.

Bioorg Med Chem 2020 Jul 19;28(13):115557. Epub 2020 May 19.

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

Parthenolide is an important sesquiterpene lactone with potent anticancer activities. In order to further improve its biological activity, a series of parthenolide semicarbazone or thiosemicarbazone derivatives was synthesized and evaluated for their anticancer activity. Derivatives were tested in vitro against 5 human tumor cell lines, and many of these showed higher cytotoxicity than parthenolide. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115557DOI Listing
July 2020
2.793 Impact Factor

Broad assessment of bioactivity of a collection of spiroindane pyrrolidines through "cell painting".

Bioorg Med Chem 2020 Jul 19;28(13):115547. Epub 2020 May 19.

Department of Medicinal Chemistry, University of Kansas, Lawrence, 66045 KS, United States. Electronic address:

A collection of small molecules has been synthesized by composing photo-cycloaddition, C-H functionalization, and N-capping strategies. Multidimensional biological fingerprints of molecules comprising this collection have been recorded as changes in cell and organelle morphology. This untargeted, phenotypic approach allowed for a broad assessment of biological activity to be determined. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115547DOI Listing

Synthesis and evaluation of heterocycle structures as potential inhibitors of Mycobacterium tuberculosis UGM.

Bioorg Med Chem 2020 Jul 2;28(13):115579. Epub 2020 Jun 2.

Laboratoire Synthèse et Isolement de Molécules Bioactives (SIMBA, EA 7502), Université de Tours, Faculté de Pharmacie, Parc de Grandmont, 31 Avenue Monge, 37200 Tours, France. Electronic address:

In this study, we screen three heterocyclic structures as potential inhibitors of UDP-galactopyranose mutase (UGM), an enzyme involved in the biosynthesis of the cell wall of Mycobacterium tuberculosis. In order to understand the binding mode, docking simulations are performed on the best inhibitors. Their activity on Mycobacterium tuberculosis is also evaluated. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115579DOI Listing

Computational-aided design of a library of lactams through a diversity-oriented synthesis strategy.

Bioorg Med Chem 2020 Jun 4;28(12):115539. Epub 2020 May 4.

Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy; Interdepartmental Center for Preclinical Development of Molecular Imaging (CISPIM), University of Florence, Viale Morgagni 85, 50134 Florence, Italy. Electronic address:

Small molecule libraries for virtual screening are becoming a well-established tool for the identification of new hit compounds. As for experimental assays, the library quality, defined in terms of structural complexity and diversity, is crucial to increase the chance of a successful outcome in the screening campaign. In this context, Diversity-Oriented Synthesis has proven to be very effective, as the compounds generated are structurally complex and differ not only for the appendages, but also for the molecular scaffold. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115539DOI Listing

Discovery of N-substituted-3-phenyl-1,6-naphthyridinone derivatives bearing quinoline moiety as selective type II c-Met kinase inhibitors against VEGFR-2.

Bioorg Med Chem 2020 Jun 12;28(12):115555. Epub 2020 May 12.

Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, China. Electronic address:

New N-substituted-3-phenyl-1,6-naphthyridinone derivatives are designed and synthesized, based on structural modification of our previously reported compound 3. Extensive enzyme-based SAR studies and PK evaluation led to the discovery of compound 4r, with comparable c-Met potency to that of Cabozantinib and high VEGFR-2 selectivity, while Cabozantinib displayed no VEGFR-2 selectivity. More importantly, at oral doses of 45 mg/kg (Q. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115555DOI Listing

Cytosolic delivery of peptidic STAT3 SH2 domain inhibitors.

Bioorg Med Chem 2020 Jun 4;28(12):115542. Epub 2020 May 4.

Department of Chemistry, Tufts University, Medford, MA 02155, United States. Electronic address:

The signal transducer and activator of transcription 3 (STAT3) protein is constitutively activated in several cancers. STAT3 activity can be blocked by inhibiting its Src Homology 2 (SH2) domain, but phosphotyrosine and its isosteres have poor bioavailability. In this work, we develop peptide-based inhibitors of STAT3-SH2 by combining chemical strategies that have proven effective for targeting other SH2 domains. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294595PMC

Design, synthesis, and evaluation of a novel macrocyclic anti-EV71 agent.

Bioorg Med Chem 2020 Jun 8;28(12):115551. Epub 2020 May 8.

State Key Laboratory of Drug Lead Compound Research, WuXi AppTec (Shanghai) Co., Ltd., Shanghai, China.

We describe here the design, synthesis, and evaluation of a macrocyclic peptidomimetic as a potent agent targeting enterovirus A71 (EV71). The compound has a 15-membered macrocyclic ring in a defined conformation. Yamaguchi esterification reaction was used to close the 15-membered macrocycle instead of the typical Ru-catalyzed ring-closing olefin metathesis reaction. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115551DOI Listing

Rational design, synthesis and biological evaluation of novel multitargeting anti-AD iron chelators with potent MAO-B inhibitory and antioxidant activity.

Bioorg Med Chem 2020 Jun 11;28(12):115550. Epub 2020 May 11.

Collaborative Innovation Centre of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, PR China; College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, PR China. Electronic address:

A series of (3-hydroxypyridin-4-one)-coumarin hybrids were developed and investigated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through the incorporation of iron-chelating and monoamine oxidase B (MAO-B) inhibition. This combination endowed the hybrids with good capacity to inhibit MAO-B as well as excellent iron-chelating effects. The pFe values of the compounds were ranging from 16. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115550DOI Listing

Genetically encoded protein labeling and crosslinking in living Pseudomonas aeruginosa.

Bioorg Med Chem 2020 Jun 6;28(12):115545. Epub 2020 May 6.

Beijing National Laboratory for Molecular Sciences, Synthetic and Functional Biomolecules Center, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Beijing 100871, China. Electronic address:

Pseudomonas aeruginosa (PA) is a major human pathogen for hospital-acquired infections. We report the genetic code expansion of this opportunistic pathogen by using the pyrrolysyl-tRNA synthetase-tRNA system, which enabled the genetic and site-specific incorporation of unnatural amino acids bearing bioorthogonal handles or photo-affinity groups into proteins in PA. This strategy allowed us to conduct bioorthogonal labeling and imaging of flagella, as well as site-specific photo-affinity capturing of interactions between a Type III secretion effector and its chaperone inside living bacteria. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115545DOI Listing

Synthesis of novel 3,5,6-trisubstituted 2-pyridone derivatives and evaluation for their anti-inflammatory activity.

Bioorg Med Chem 2020 Jun 12;28(12):115549. Epub 2020 May 12.

Departamento de Química, Universidade Estadual de Maringá (UEM), 87030-900 Maringá, PR, Brazil. Electronic address:

The inflammatory response is the reaction of living tissue to an injury of a foreign nature, such as infection and irritants, and occurs as part of the body's natural defence response. Compounds capable of inhibiting cyclooxygenase (COX) enzymes, especially COX-2, have great potential as anti-inflammatory agents. Herein we present the regioselective synthesis of 49 novel compounds based on the 2-pyridone nucleus. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115549DOI Listing

The synthesis and biological evaluation of nucleobases/tetrazole hybrid compounds: A new class of phosphodiesterase type 3 (PDE3) inhibitors.

Bioorg Med Chem 2020 Jun 5;28(12):115540. Epub 2020 May 5.

Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran. Electronic address:

Spired by the chemical structure of Cilostazol, a selective phosphodiesterase 3A (PDE3A) inhibitor, several novel hybrid compounds of nucleobases (uracil, 6-azauracil, 2-thiuracil, adenine, guanine, theophylline and theobromine) and tetrazole were designed and successfully synthesized and their inhibitory effects on PDE3A as well as their cytotoxicity on HeLa and MCF-7 cancerous cell lines were studied. Obtained results show the linear correlation between the inhibitory effect of synthesized compounds and their cytotoxicity. In some cases, the PDE3A inhibitory effects of synthesized compounds are higher than the Cilostazol. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115540DOI Listing

Bisbenzylisoquinoline alkaloids and P-glycoprotein function: A structure activity relationship study.

Bioorg Med Chem 2020 Jun 11;28(12):115553. Epub 2020 May 11.

Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. Electronic address:

Conflicts with the notion that specific substrate interactions were required in the control of reaction path in active transport systems, P-glycoprotein showed extraordinarily low specificity. Therefore, overexpression P-glycoprotein excluded a large number of anticancer agents from cancer cells, and multidrug resistance happened. Several kinds of bisbenzylisoqunoline alkaloids were reported to modulate P-glycoprotein function and reverse drug resistance. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115553DOI Listing

Immunomodulation-mediated anticancer activity of a novel compound from Brugmansia suaveolens leaves.

Bioorg Med Chem 2020 Jun 11;28(12):115552. Epub 2020 May 11.

School of Health Sciences, University of Petroleum and Energy Studies, Energy Acres, Bidholi, Via Premnagar, Uttrakhand 248007, India. Electronic address:

Immunomodulation activity-guided fractionation of ethanol extract of Brugmansia suaveolens leaves was carried out to isolate a novel compound SUPH036-022A (1) by co-culturing the test fraction/compound activated PBMC with MCF7 and A549 cancer cell lines. Assessment of immune markers in PBMC, and analysis of apoptosis markers and cell cycle was carried out for cancer cells. The structure of the isolated compound was elucidated by spectral analysis. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115552DOI Listing
June 2020
2.793 Impact Factor

Discovery of a novel indole pharmacophore for the irreversible inhibition of myeloperoxidase (MPO).

Bioorg Med Chem 2020 Jun 12;28(12):115548. Epub 2020 May 12.

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, United States. Electronic address:

Myeloperoxidase (MPO) activity and subsequent generation of hypochlorous acid has been associated with the killing of host-invading microorganisms (e.g. bacteria, viruses, and fungi). Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115548DOI Listing

Design, synthesis and biological evaluation of novel pyrrolo[2,3-d]pyrimidine as tumor-targeting agents with selectivity for tumor uptake by high affinity folate receptors over the reduced folate carrier.

Bioorg Med Chem 2020 Jun 6;28(12):115544. Epub 2020 May 6.

Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States. Electronic address:

Tumor-targeted 6-substituted pyrrolo[2,3-d]pyrimidine benzoyl compounds based on 2 were isosterically modified at the 4-carbon bridge by replacing the vicinal (C11) carbon by heteroatoms N (4), O (5) or S (6), or with an N-substituted formyl (7), trifluoroacetyl (8) or acetyl (9). Replacement with sulfur (6) afforded the most potent KB tumor cell inhibitor, ~6-fold better than the parent 2. In addition, 6 retained tumor transport selectivity via folate receptor (FR) α and -β over the ubiquitous reduced folate carrier (RFC). Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327796PMC
June 2020
2.793 Impact Factor

Discovery of ORN0829, a potent dual orexin 1/2 receptor antagonist for the treatment of insomnia.

Bioorg Med Chem 2020 Jul 11;28(13):115489. Epub 2020 Apr 11.

Discovery Research Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan. Electronic address:

Here, we present the design, synthesis, and SAR of dual orexin 1 and 2 receptor antagonists, which were optimized by balancing the antagonistic activity for orexin receptors and lipophilicity. Based on the prototype compound 1, ring construction and the insertion of an additional heteroatom into the resulting ring led to the discovery of orexin 1 and 2 receptor antagonists, which were 3-benzoyl-1,3-oxazinane derivatives. Within these derivatives, (-)-3h enabled a high dual orexin receptor antagonistic activity and a low lipophilicity. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115489DOI Listing

Corrigendum to "A truncated RHAMM protein for discovering novel therapeutic peptides" [Bioorg. Med. Chem. 26 (2018) 5194-5203].

Bioorg Med Chem 2020 Jul 16;28(13):115543. Epub 2020 May 16.

Department of Chemistry, Western University, London, Ontario, Canada; Cancer Research Laboratory Program, Lawson Health Research Institute and London Regional Cancer Program, London Health Sciences Center, London, Ontario, Canada; Department of Oncology, Western University, London, Ontario, Canada; Department of Medical Imaging, Western University, London, Ontario, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.bmc.2020.115543DOI Listing

Design, synthesis and SAR study of bridged tricyclic pyrimidinone carboxamides as HIV-1 integrase inhibitors.

Bioorg Med Chem 2020 Jul 4;28(13):115541. Epub 2020 May 4.

Departments of Discovery Chemistry and Molecular Technologies, 5 Research Parkway, Wallingford, CT 06492, USA; Assembly Biosciences, Inc. 331 Oyster Point Blvd, San Francisco, CA 94080, USA.

The design, synthesis and structure-activity relationships associated with a series of bridged tricyclic pyrimidinone carboxamides as potent inhibitors of HIV-1 integrase strand transfer are described. Structural modifications to these molecules were made in order to examine the effect on potency towards wild-type and clinically-relevant resistant viruses. The [3. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115541DOI Listing

Discovery and structure-activity relationships study of positive allosteric modulators of the M muscarinic acetylcholine receptor.

Bioorg Med Chem 2020 Jul 30;28(13):115531. Epub 2020 Apr 30.

Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.

The M muscarinic acetylcholine receptor (mAChR) is a member of the family of mAChRs, which are associated with a variety of physiological functions including the contraction of various smooth muscle tissues, stimulation of glandular secretion, and regulation of a range of cholinergic processes in the central nerve system. We report here the discovery and a comprehensive structure--activity relationships (SARs) study of novel positive allosteric modulators (PAMs) of the M mAChR through a high throughput screening (HTS) campaign. Compound 9 exhibited potent in vitro PAM activity towards the M mAChR and significant enhancement of muscle contraction in a concentration-dependent manner when applied to isolated smooth muscle strips of rat bladder. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115531DOI Listing
July 2020
2.793 Impact Factor

Synthesis and biological evaluation of triazolyl-substituted benzyloxyacetohydroxamic acids as LpxC inhibitors.

Bioorg Med Chem 2020 Jul 25;28(13):115529. Epub 2020 Apr 25.

Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems. Electronic address:

The bacterial deacetylase LpxC is a promising target for the development of antibiotics selectively combating Gram-negative bacteria. To improve the biological activity of the reported benzyloxyacetohydroxamic acid 9 ((S)-N-hydroxy-2-{2-hydroxy-1-[4-(phenylethynyl)phenyl]ethoxy}acetamide), its hydroxy group was replaced by a triazole ring. Therefore, in divergent syntheses, triazole derivatives exhibiting rigid and flexible lipophilic side chains, different configurations at their stereocenter, and various substitution patterns at the triazole ring were synthesized, tested for antibacterial and LpxC inhibitory activity, and structure-activity relationships were deduced based on docking and binding energy calculations. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115529DOI Listing

Sulfonamide-based 4-anilinoquinoline derivatives as novel dual Aurora kinase (AURKA/B) inhibitors: Synthesis, biological evaluation and in silico insights.

Bioorg Med Chem 2020 Jul 25;28(13):115525. Epub 2020 Apr 25.

Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia; Department of Pharmaceutical Organic Chemistry, Beni-Suef University, Beni-Suef 62514, Egypt. Electronic address:

Aurora kinases (AURKs) were identified as promising druggable targets for targeted cancer therapy. Aiming at the development of novel chemotype of dual AURKA/B inhibitors, herein we report the design and synthesis of three series of 4-anilinoquinoline derivatives bearing a sulfonamide moiety (5a-d, 9a-d and 11a-d). The % inhibition of AURKA/B was determined for all target quinolines, then compounds showed more than 50% inhibition on either of the enzymes, were evaluated further for their IC on the corresponding enzyme. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115525DOI Listing
July 2020
2.793 Impact Factor

Structure-activity relationship analyses of fusidic acid derivatives highlight crucial role of the C-21 carboxylic acid moiety to its anti-mycobacterial activity.

Bioorg Med Chem 2020 Jul 25;28(13):115530. Epub 2020 Apr 25.

Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa; Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa. Electronic address:

Fusidic acid (FA) is a potent congener of the fusidane triterpenoid class of antibiotics. Structure-activity relationship (SAR) studies suggest the chemical structure of FA is optimal for its antibacterial activity. SAR studies from our group within the context of a drug repositioning approach in tuberculosis (TB) suggest that, as with its antibacterial activity, the C-21 carboxylic acid group is indispensable for its anti-mycobacterial activity. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115530DOI Listing
July 2020
2.793 Impact Factor

Exploring tryptamine conjugates as pronucleotides of phosphate-modified 7-methylguanine nucleotides targeting cap-dependent translation.

Bioorg Med Chem 2020 Jul 25;28(13):115523. Epub 2020 Apr 25.

Centre of New Technologies, University of Warsaw, S. Banacha 2c, 02-097 Warsaw, Poland. Electronic address:

Eukaryotic translation initiation factor 4E (eIF4E) is overexpressed in many cancers deregulating translational control of the cell cycle. mRNA 5' cap analogs targeting eIF4E are small molecules with the potential to counteract elevated levels of eIF4E in cancer cells. However, the practical utility of typical cap analogs is limited because of their reduced cell membrane permeability. Read More

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http://dx.doi.org/10.1016/j.bmc.2020.115523DOI Listing
July 2020
2.793 Impact Factor