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PubMed Journal Database | Bioorganic & medicinal chemistry letters RSS

07:24 EDT 20th July 2019 | BioPortfolio

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Showing PubMed Articles 1–25 of 361 from Bioorganic & medicinal chemistry letters

Backbone modifications in peptidic inhibitors of flaviviral proteases.

The NS2B-NS3 protease is a promising target for the development of drugs against dengue virus (DENV), West Nile virus (WNV) and related flaviviruses. We report the systematic variation of the peptide backbone of the two lead compounds Bz-Arg-Lys-d-Phg-NH and Bz-Arg-Lys-d-Phg(OBn)-NH. While inhibitory activity against WNV protease was generally decreased, the inhibitory potency against DENV protease could be conserved and increased in several peptidomimetics, particularly in those containing a (NMe)arginine ...

Development of substituted pyrido3,2-dpyrimidines as potent and selective dihydrofolate reductase inhibitors for pneumocystis pneumonia infection.

Pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii (pj) can lead to serious health consequences in patients with an immunocompromised system. Trimethoprim (TMP), used as first-line therapy in combination with sulfamethoxazole, is a selective but only moderately potent pj dihydrofolate reductase (pjDHFR) inhibitor, whereas non-clinical pjDHFR inhibitors, such as, piritrexim and trimetrexate are potent but non-selective pjDHFR inhibitors. To meet the clinical needs for a potent and selective pjDHFR...

Identification of substituted benzothiazole sulfones as potent and selective inhibitors of endothelial lipase.

A low level of high density lipoprotein (HDL) is an independent risk factor for cardiovascular disease. HDL reduces inflammation and plays a central role in reverse cholesterol transport, where cholesterol is removed from peripheral tissues and atherosclerotic plaque. One approach to increase plasma HDL is through inhibition of endothelial lipase (EL). EL hydrolyzes phospholipids in HDL resulting in reduction of plasma HDL. A series of benzothiazole sulfone amides was optimized for EL inhibition potency, li...

Synthesis and biological evaluation of acylthiourea against DUSP1 inhibition.

Structure based virtual screening attempts to discover DUSP1 inhibitors have yielded a scaffold featuring benzoxazole and acylthiourea pharmacophore. A series of its analogues were synthesized to explore structure activity relationship (SAR) of DUSP1 inhibition.

Design, synthesis and biological evaluation of benzimidazole derivatives as novel human Pin1 inhibitors.

In this work, a series of novel benzimidazole derivatives were designed and synthesized as Pin1 inhibitors. Protease-coupled assay was used to investigate the Pin1 inhibitory potency of all synthesized compounds. Thirteen of them showed preferable Pin1 inhibitory effects with IC values lower than 5 μM, and 12a, 15b, 15d and 16c exhibited the most promising Pin1 inhibitory activity at low micromolar level (0.33-1.00 μM) than the positive control compound Juglone. Flow cytometry results showed that trea...

Corrigendum to 'Synthesis and biological evaluation of Doxorubicin-containing conjugate targeting PSMA' Bioor. Med. Chem. Lett. 29/10 (2019) 1246-1255.

Synthesis and biological evaluation of F-18 labeled tetrahydroisoquinoline derivatives targeting orexin 1 receptor.

Orexin 1 receptor (OXR) is thought to be involved in various body functions, including arousal maintenance and emotional control, but the full details of its function remain unknown. OXR imaging with positron emission tomography (PET) would be useful in elucidating the orexin system including OXR, but no PET probes targeting OXR have been reported. We, therefore, designed and synthesized tetrahydroisoquinoline (THIQ) derivatives as novel PET probes targeting OXR, and evaluated their utility. In an in vitro ...

Structure guided drug design to develop kallikrein 5 inhibitors to treat Netherton syndrome.

The connection between Netherton syndrome and overactivation of epidermal/dermal proteases particularly KLK5 has been well established. To treat sufferers of this severe condition we wished to develop a topical KLK5 inhibitor in order to normalise epidermal shedding and reduce the associated inflammation and itching. In this paper we describe structure-based optimisation of a series of brightly coloured weak KLK5 inhibitors into colourless, non-irritant molecules with good KLK5 activity and selectivity over...

Design, synthesis of orally bioavailable novel anaplastic lymphoma kinase (ALK) inhibitor diphenylaminopyrimidine analogs and efficacy study on NCI-H2228 xenografts mice model.

Anaplastic lymphoma kinase (ALK) is an attractive therapeutic target for the treatment of non-small cell lung cancer (NSCLC). Within our ALK drug discovery program, we identified novel deuterated 2,4-diarylamino pyrimidine compounds as potent ALK inhibitors. The compound 11 showed better in vitro activity and in vivo efficacy with good pharmacokinetic profile. In vivo efficacy of compound 11 was better than standard drug ceritinib in NCI-H2228 xenograft mice model.

Synthesis and in vitro biological evaluation of new P2X7R radioligands Chalo-GSK1482160 analogs.

The reference standards halo-GSK1482160 (F-, Br-, and I-) and their corresponding precursors desmethyl-halo-GSK1482160 (F-, Br-, and I-) were synthesized from (S)-1-methyl-5-oxopyrrolidine-2-carboxylic acid or (S)-5-oxopyrrolidine-2-carboxylic acid and 2-halo-3-(trifluoromethyl)benzylamine (F-, Br-, and I-) in one step with 45-93% yields. The target tracers [C]halo-GSK1482160 (F-, Br-, and I-) were prepared from desmethyl-halo-GSK1482160 (F-, Br-, and I-) with [C]CHOTf under basic conditions (NaOH-NaCO, sol...

Identification and SAR exploration of a novel series of Legumain inhibitors.

This letter describes the development of a series of potent and selective small molecule Legumain inhibitors suitable as chemical probes for in vitro experiments. Our previous research had identified a dipeptide inhibitor utilizing a semi-reversible cyano warhead that generated 2, a cell active inhibitor. This work explores an alternative P2-P3 linker and further SAR exploration of the P3 group which led to the identification of 16i, a highly potent inhibitor with excellent physiochemical properties.

Xylo-C-nucleosides with a pyrrolo2,1-f1,2,4triazin-4-amine heterocyclic base: Synthesis and antiproliferative properties.

The synthesis of a xylo-C-nucleoside containing pyrrolo[2,1-f][1,2,4]triazin-4-amine as nucleobase along with that of its 1'-cyano analogue is described. Among different experimental conditions explored in order to optimize a key debenzylation step in the presented synthetic route, it was found that palladium catalyzed hydrogen transfer allowed for obtaining the target compounds in good yields. The resulting mixture of epimers was separated and each was characterized by NOESY NMR experiments. In vitro antip...

Discovery of a class of highly potent Janus Kinase 1/2 (JAK1/2) inhibitors demonstrating effective cell-based blockade of IL-13 signaling.

Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a s...

Synthesis and evaluation of histamine H receptor ligand based on lactam scaffold as agents for treating neuropathic pain.

The synthesis and H receptor ligand of a new series of lactam derivatives are reported. The new compounds were evaluated in vitro in H and H receptor-binding assays. The structure-activity relationship led us to the promising derivative 2-methyl-7-(3-morpholinopropoxy)-3,4-dihydroisoquinolin-1(2H)-one (11). The compound with highest affinity and greatest selectivity were further profiled, In addition, compound 11 exerted dose-dependent anti-nociceptive effects in the formalin test. These characteristics sug...

Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2.

Janus Kinase 2 (JAK2) is a kind of intracellular non-receptor protein tyrosine kinase and has been certified as an important target for the treatment of myeloproliferative neoplasms and rheumatoid arthritis. However, the low selectivity and potential safety issues restrict the clinical applications of JAK2 inhibitors. Here we found that crizotinib showed good inhibitory activity against JAK2 by enzymatic assays (IC = 27 nM). Then we carried out structure-based drug design and synthesized a series of c...

Synthesis of diphenoxyadamantane alkylamines with pharmacological interest.

In this work, the synthesis and the pharmacological evaluation of diphenoxyadamantane alkylamines Ia-f and IIa-f is described. The new diphenoxy-substituted adamantanes share structural features present in trypanocidal and antitubercular agents. 1-Methylpiperazine derivative Ia is the most potent against T. brucei compound, whilst its hexylamine congener IIf exhibits a significant antimycobacterial activity.

Design, synthesis, and biological evaluation of novel pyrrolo1,2-apyrazine derivatives.

A pyrrolo[1,2-a]pyrazine-based chemical territory was expanded via construction of new chemical library with distinctive substitution patterns, which was made possible by regiodivergent electrophilic acylation followed by aldol condensation. Biological screening of the compounds in this class revealed that the viability of human lymphoma U937 cells was strongly inhibited by 6b with a methoxy group at the o-position of the aromatic ring, but not by compounds 6t-w bearing a halogen at the o-position. Furtherm...

Peptide-based covalent inhibitors of MALT1 paracaspase.

Potent and selective substrate-based covalent inhibitors of MALT1 protease were developed from the tetrapeptide tool compound Z-VRPR-fmk. To improve cell permeability, we replaced one arginine residue. We further optimized a series of tripeptides and identified compounds that were potent in both a GloSensor reporter assay measuring cellular MALT1 protease activity, and an OCI-Ly3 cell proliferation assay. Example compounds showed good overall selectivity towards cysteine proteases, and one compound was sele...

Modulation of mitochondrial dysfunction for treatment of disease.

Mitochondrial dysfunction is a causative and/or exacerbating feature of many pathologies. We discuss below approaches to modulate mitochondrial dysfunction that involve (1) increasing their energetic efficiency by targeting gene expression regulators such as PPAR or AMPK, (2) using antioxidant compounds to reduce the toxic reactive oxygen species mitochondria produce under stress, or (3) modulating aspects on the innate mitochondrial quality control system. The latter comprise linked processes of biogenesis...

Discovery of niclosamide and its O-alkylamino-tethered derivatives as potent antibacterial agents against carbapenemase-producing and/or colistin resistant Enterobacteriaceae isolates.

Carbapenemase-producing Enterobacteriaceae (CPE) represents the most worrisome evolution of the antibiotic resistance crisis, which is almost resistant to most of available antibiotics. This situation is getting even worse particularly due to the recent emergence of colistin resistance. Herein, niclosamide, an FDA-approved traditional drug, and its novel O-alkylamino-tethered derivatives were discovered as new and potent antibacterial agents against carbapenemase-producing and/or colistin resistant Enteroba...

Advanced protocol to functionalize CaP bioceramic surface with peptide sequences and effect on murine pre-osteoblast cells proliferation.

To bring osteoinductive properties to calcium phosphate (CaP) bioceramics, a silicon-substituted hydroxyapatite was functionalized by integrin-adhesive cyclic-pentapeptides (c-(DfKRG)). A new two-step protocol was set up to immobilize peptides at low and controlled density on the ceramic surface and limit contamination by adsorbed molecules. To this aim, a spacer bearing c-(DfKRG)-S-PEG-NHS molecule was synthesized and bonded to an organosilane previously covalently bonded to the ceramic surface. The functi...

Identification, design and synthesis of novel pyrazolopyridine influenza virus nonstructural protein 1 antagonists.

Nonstructural protein 1 (NS1) plays a crucial function in the replication, spread, and pathogenesis of influenza virus by inhibiting the host innate immune response. Here we report the discovery and optimization of novel pyrazolopyridine NS1 antagonists that can potently inhibit influenza A/PR/8/34 replication in MDCK cells, rescue MDCK cells from cytopathic effects of seasonal influenza A strains, reverse NS1-dependent inhibition of IFN-β gene expression, and suppress the slow growth phenotype in NS1-expr...

HSP60/10 chaperonin systems are inhibited by a variety of approved drugs, natural products, and known bioactive molecules.

All living organisms contain a unique class of molecular chaperones called 60 kDa heat shock proteins (HSP60 - also known as GroEL in bacteria). While some organisms contain more than one HSP60 or GroEL isoform, at least one isoform has always proven to be essential. Because of this, we have been investigating targeting HSP60 and GroEL chaperonin systems as an antibiotic strategy. Our initial studies focused on applying this antibiotic strategy for treating African sleeping sickness (caused by Trypanosoma...

Enhanced cytotoxicity of gold porphyrin complexes after inclusion in cyclodextrin scaffolds adsorbed on polyethyleneimine-coated gold nanoparticles.

A new gold nanoparticle-based construct has been designed to hydrophobic drugs delivery into cancer cells. Cyclodextrin scaffolds adsorbed on polyethyleneimine-coated gold nanoparticles (AuNP@PEI@CD) have been used to encapsulate hydrophobic tetrapyrrolic compounds consisting of gold complexes of 5,10,15,20-tetraphenyl porphyrin (AuTPPCl) and 5-(4-acetoxyphenyl)-10,15,20-triphenyl porphyrin (AuTPPOAcCl). These two nanoparticles have been tested for their cytotoxic activities against the two colorectal cance...

Efficient chemoenzymatic synthesis of UDP-α-6-N-glucose.

A novel chemo-enzymatic synthetic method for UDP-α-6-N-glucose was developed by combining the versatility of chemical synthesis and natural enzyme stereo-selectivity of Bifidobacterium longum (BLUSP). This flexible and efficient platform expanded the substrate scope for UDP-sugars on an improved scale, particularly for UDP-sugar substrates containing bioorthogonal functional groups.


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