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Bioorganic & Medicinal Chemistry

Junjun Tian, Leen Vandermosten, Steve Peigneur, Lien Moreels, Jef Rozenski, Jan Tytgat, Piet Herdewijn, Philippe E Van den Steen, Steven De Jonghe
Astemizole is a H1-antagonist endowed with antimalarial activity, but has hERG liabilities. Systematic structural modifications of astemizole led to the discovery of analogues that display very potent activity as inhibitors of the growth of the Plasmodium parasite, but show a decreased hERG inhibition, when compared to astemizole. These compounds can be used as starting point for the development of a new class of antimalarials.
October 7, 2017: Bioorganic & Medicinal Chemistry
Sona Mohammadi-Ostad-Kalayeh, Vjaceslavs Hrupins, Sabine Helmsen, Frank Stahl, Thomas Scheper, Matthias Preller, Frank Surup, Marc Stadler, Andreas Kirschning, Carsten Zeilinger
A facile method for testing ATP binding in a highly miniaturized microarray environment using human HSP70 and DnaK from Mycobacterium tuberculosis as biological targets is reported. Supported by molecular modelling studies we demonstrate that the position of the fluorescence label on ATP has a strong influence on the binding to human HSP70. Importantly, the label has to be positioned on the adenine ring and not to the terminal phosphate group. Unlabelled ATP displaced bound Cy5-ATP from HSP70 in the micromolar range...
October 7, 2017: Bioorganic & Medicinal Chemistry
Masaki Kita, Kota Yamagishi, Kota Tsuchiya, Yu Seguchi, Hiroki Nakane, Hideo Kigoshi
The antitumor and actin-depolymerizing marine macrolide aplyronine A (ApA) synergistically binds to tubulin in association with actin, and prevents spindle formation and mitosis. While the crystal structure of the actin ApA complex was solved in 2006, its interaction with the tubulin heterodimer has not been clarified. To investigate the binding modes of ApA as a unique protein-protein interaction (PPI)-inducer between these two cytoskeletal proteins, we prepared its photoaffinity acetylene and fluorescent derivatives with the aid of molecular modeling studies for probe design...
October 4, 2017: Bioorganic & Medicinal Chemistry
Vasudha Abbhi, Lovneet Saini, Srishti Mishra, Gautam Sethi, Alan Prem Kumar, Poonam Piplani
Rho kinase inhibitors (ROCK II) play a key role in glaucoma management attributed to their IOP lowering ability and neuroprotective effects. In the present study, a series of novel benzimidazole derivatives (9a-m) has been synthesized and evaluated for their IOP lowering, Rho kinase inhibitory and antioxidant properties. The synthesized compounds were found to be lipophilic and showed a significant IOP lowering effect both in the treated and the contralateral eye comparable to the reference standard fasudil...
October 4, 2017: Bioorganic & Medicinal Chemistry
Francisco Estévez-Sarmiento, Mercedes Said, Ignacio Brouard, Francisco León, Celina García, José Quintana, Francisco Estévez
Flavonoids are naturally occurring polyphenolic compounds and are among the most promising anticancer agents. A series of flavonols and their 3-methyl ether derivatives were synthesized and assessed for cytotoxicity. It was found that 3'-hydroxy-3,4'-dimethoxyflavone (flavonoid 7a) displayed strong cytotoxicity against human SK-MEL-1 melanoma cells and blocked tubulin polymerization, but had no significant cytotoxic effects against quiescent or proliferating human peripheral blood mononuclear cells. Our analyses showed that flavonoid 7a induces G2-M cell cycle arrest and apoptosis in melanoma cells which is associated with cytochrome c release and activation of both extrinsic and intrinsic apoptotic pathways of cell death...
October 3, 2017: Bioorganic & Medicinal Chemistry
Matteo Staderini, Alicia Megia-Fernandez, Kevin Dhaliwal, Mark Bradley
Optical medical imaging is a rapidly growing area of research and development that offers a multitude of healthcare solutions both diagnostically and therapeutically. In this review, some of the most recently described peptide-based optical probes are reviewed with a special emphasis on their in vivo use and potential application in a clinical setting.
September 30, 2017: Bioorganic & Medicinal Chemistry
Marcelo Fiori Marchiori, Thalita B Riul, Leandro Oliveira Bortot, Peterson Andrade, Getúlio G Junqueira, Giuseppina Foca, Nunzianna Doti, Menotti Ruvo, Marcelo Dias-Baruffi, Ivone Carvalho, Vanessa Leiria Campo
The synthesis of the O-3 triazole-linked galactosyl arylsulfonamides 1-7 as potential inhibitors of Trypanosoma cruzi cell invasion is described. These target compounds were synthesized by Cu(I)-catalysed azide-alkyne cycloaddition reaction ('click chemistry') between different azide arylsulfonamides and the alkyne-based sugar 3-O-propynyl-βGalOMe. Inhibition assays of T. cruzi cell invasion with compounds 1-7 showed reduced values of infection index (∼20) for compounds 3 and 5, bearing the corresponding 5-methylisoxazole and 2,4-dimethoxypyrimidine groups, which also presented higher binding affinities to galectin-3 (EC50 17-18 μM) in Corning Epic label-free assays...
September 30, 2017: Bioorganic & Medicinal Chemistry
Shimaa A H Abdel Monaim, Yahya E Jad, Ayman El-Faham, Beatriz G de la Torre, Fernando Albericio
It looks that a new era of antimicrobial peptides (AMPs) started with the discovery of teixobactin, which is a "head to side-chain" cyclodepsipeptide. It was isolated from a soil gram-negative b-proteobacteria by means of a revolutionary technique. Since there, several groups have developed synthetic strategies for efficient synthesis of this peptide and its analogues as well. Herein, all chemistries reported as well as the biological activity of the analogues are analyzed. Finally, some inputs regarding new trends for the next generation of analogues are discussed...
September 30, 2017: Bioorganic & Medicinal Chemistry
Maria V Papadopoulou, William D Bloomer, Howard S Rosenzweig
Twenty three 3-nitrotriazole- and five nitroimidazole-based compounds, mostly amides, were screened for antitubercular activity against Mycobacterium tuberculosis H37Rv (Mtb H37Rv) under aerobic or low oxygen conditions, intracellular activity in murine J774 macrophages or THP-1 cells, activity against resistant Mtb strains as well as cytotoxicity in normal cells. Compounds with a Minimum Inhibitory Concentration (MIC) less than 10μM and 10-50μM were characterized as active and moderately active, respectively, whereas compounds with a MIC >50μM were characterized inactive...
September 28, 2017: Bioorganic & Medicinal Chemistry
Mohammed Akhter Hossain, Ross A D Bathgate
Peptidomimetics are designed to overcome the poor pharmacokinetics and pharmacodynamics associated with the native peptide or protein on which they are based. The design of peptidomimetics starts from developing structure-activity relationships of the native ligand-target pair that identify the key residues that are responsible for the biological effect of the native peptide or protein. Then minimization of the structure and introduction of constraints are applied to create the core active site that can interact with the target with high affinity and selectivity...
September 27, 2017: Bioorganic & Medicinal Chemistry
Hua-Li Yang, Pei Cai, Qiao-Hong Liu, Xue-Lian Yang, Si-Qiang Fang, Yan-Wei Tang, Cheng Wang, Xiao-Bing Wang, Ling-Yi Kong
A series of salicyladimine derivatives were designed, synthesized and evaluated as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that some derivatives possessed significant inhibitory activities against amyloid-β (Aβ) aggregation and human monoamine oxidase B (hMAO-B) as well as remarkable antioxidant effects and low cell toxicity. The optimal compound, 5, exhibited excellent potency for inhibition of self-induced Aβ1-42 aggregation (91...
September 27, 2017: Bioorganic & Medicinal Chemistry
Michael W Pennington, Andrzej Czerwinski, Raymond S Norton
Peptides are recognized as being highly selective, potent and relatively safe as potential therapeutics. Peptides isolated from the venom of different animals satisfy most of these criteria with the possible exception of safety, but when isolated as single compounds and used at appropriate concentrations, venom-derived peptides can become useful drugs. Although the number of venom-derived peptides that have successfully progressed to the clinic is currently limited, the prospects for venom-derived peptides look very optimistic...
September 23, 2017: Bioorganic & Medicinal Chemistry
Susumu Yamaki, Hiroyoshi Yamada, Akira Nagashima, Mitsuhiro Kondo, Yoshiaki Shimada, Keitaro Kadono, Kosei Yoshihara
Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted structural optimization of the glycine amide derivative 1, which we previously reported as a novel VAP-1 inhibitor, to improve stability in dog and monkey plasma, and aqueous solubility. By chemical modification of the right part in the glycine amide derivative, we identified the carbamimidoylcarbamate derivative 20c, which showed stability in dog and monkey plasma while maintaining VAP-1 inhibitory activity...
September 23, 2017: Bioorganic & Medicinal Chemistry
Masanobu Nagano, Nancy Carrillo, Nobumasa Otsubo, Wataru Hakamata, Hitoshi Ban, Roberta P Fuller, Nasir K Bashiruddin, Carlos F Barbas
Vaccination is a reliable method of prophylaxis and a crucial measure for public health. However, the majority of vaccines cannot be administered orally due to their degradation in the harsh gut environment or inability to cross the GI tract. In this study, we report the first proof-of-concept study of orally producible chemically programmed antibodies via specific conjugation of adaptor ligands to endogenous antibodies, in vivo. Pre-immuniztion with 2,4-dinitrophenyl (DNP), or the reactive hapten, 1,3-diketone (DK), or a novel reactive hapten, vinyl sulfone (VS) in mice, followed by oral administration of adaptor ligands composed of the hapten and biotin to the pre-immunized mice resulted in successful in vivo formation of the biotin-hapten-antibody complexes within 2h...
September 23, 2017: Bioorganic & Medicinal Chemistry
Jéssica Venância Faria, Percilene Fazolin Vegi, Ana Gabriella Carvalho Miguita, Maurício Silva Dos Santos, Nubia Boechat, Alice Maria Rolim Bernardino
The pyrazole nucleus is an aromatic azole heterocycle with two adjacent nitrogen atoms. Pyrazole derivatives have exhibited a broad spectrum of biological activities, and approved pyrazole-containing drugs include celecoxib, antipyrine, phenylbutazone, rimonabant, and dipyrone. Many research groups have synthesized and evaluated pyrazoles against several biological agents. This review examines recent publications relating the structures of pyrazoles with their corresponding biological activities.
September 23, 2017: Bioorganic & Medicinal Chemistry
Heajin Lee, Ralf Landgraf, James N Wilson
A fluorescent probe targeting the ERBB2 receptor tyrosine was designed, synthesized and evaluated as reporter of ERBB2 dynamics in overexpressing BT474, i.e. Her2(+), cells. Two cyanoquinazoline (CQ) probes modeled after type-I (CQ1) or active state and type-II (CQ2) or inactive state inhibitors were designed and synthesized with extended π systems that impart binding-induced, turn-on fluorescence. Solution spectroscopy revealed that CQ1 exhibited attractive photophysical properties and displayed turn-on emission in the presence of purified, soluble ERBB2 kinase domain, while CQ2 was found to be non-emissive, likely due to quenching via a photoinduced electron transfer mechanism...
September 23, 2017: Bioorganic & Medicinal Chemistry
Yoshihiro Banno, Shigekazu Sasaki, Makoto Kamata, Jun Kunitomo, Yasufumi Miyamoto, Hidenori Abe, Naohiro Taya, Satoru Oi, Masanori Watanabe, Tomoko Urushibara, Masatoshi Hazama, Shin-Ichi Niwa, Saku Miyamoto, Akira Horinouchi, Ken-Ichi Kuroshima, Nobuyuki Amano, Shin-Ichi Matsumoto, Shinichiro Matsunaga
The discovery of a novel series of β-methyltryptophan (β MeTrp) derivatives as selective and orally active non-peptide somatostatin receptor 2 (SSTR2) agonists for the treatment of Type 2 diabetes is described. In our previous research, Compound A, β-MeTrp derivative with highly potent and selective SSTR2 agonistic activity IC50 (SSTR2/SSTR5)=0.3/>100 (nM), was identified asa drug candidate for treatment of Type 2 diabetes which lowers significantly plasma glucose level in Wistar fatty rats in its oral administrations...
September 21, 2017: Bioorganic & Medicinal Chemistry
Yosuke Igata, Noriko Saito-Tarashima, Daiki Matsumoto, Kazuyuki Sagara, Noriaki Minakawa
A convenient strategy to purify oligonucleotides (ONs) synthesized by solid phase synthesis on an automatic DNA/RNA synthesizer was described. By attaching a photocleavable azide linker as the last phosphoramidite unit in the ON synthesis, only the desired full-length sequence was 'caught' on a controlled pore glass (CPG) resin possessing an aza-dimethoxycyclooctyne (DIBAC) derivative. Washing the resulting CPG resin to remove all unbounded species, the subsequent photoirradiation allowed the pure ONs to be 'released' without leaving any chemical modifications on native ON structure or chemical reagents from the solid phase ON synthesis...
September 21, 2017: Bioorganic & Medicinal Chemistry
Kentaro Ohno, Daiki Sugiyama, Leo Takeshita, Takashi Kanamori, Yoshiaki Masaki, Mitsuo Sekine, Kohji Seio
6-O-(2-Nitrobenzyl)guanosine and 4-O-(2-nitrobenzyl)uridine triphosphates ((NB)GTP, (NB)UTP) were synthesized, and their biochemical and photophysical properties were evaluated. We synthesized (NB)UTP using the canonical triphosphate synthesis method and (NB)GTP from 2',3'-O-TBDMS guanosine via a triphosphate synthesis method by utilizing mild acidic desilylation conditions. Deprotection of the nitrobenzyl group in (NB)GTP and (NB)UTP proceeded within 60s by UV irradiation at 365nm. Experiments using (NB)GTP or (NB)UTP in T7-RNA transcription reactions showed that (NB)GTP could be useful for the photocontrol of transcription by UV irradiation...
September 21, 2017: Bioorganic & Medicinal Chemistry
Galina F Makhaeva, Sofya V Lushchekina, Natalia P Boltneva, Olga G Serebryakova, Elena V Rudakova, Alexey A Ustyugov, Sergey O Bachurin, Alexander V Shchepochkin, Oleg N Chupakhin, Valery N Charushin, Rudy J Richardson
We investigated the inhibitory activity of 4 groups of novel acridine derivatives against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carboxylesterase (CaE) using the methods of enzyme kinetics and molecular docking. Antioxidant activity of the compounds was determined using the 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS(+)) radical decolorization assay as their ability to scavenge free radicals. Analysis of the esterase profiles and antiradical activities of the acridine derivatives showed that 9-aryl(heteroaryl)-N-methyl-9,10-dihydroacridines have a high radical-scavenging activity but low potency as AChE and BChE inhibitors, whereas 9-aryl(heteroaryl)-N-methyl-acridinium tetrafluoroborates effectively inhibit cholinesterases but do not exhibit antiradical activity...
September 20, 2017: Bioorganic & Medicinal Chemistry
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