Bioorganic & Medicinal Chemistry

Synthesis of five and six-membered heterocycles bearing an arylpiperazinylalkyl side chain as orally active antinociceptive agents ()
Publication date: Available online 2 September 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Claudia Vergelli, Giovanna Ciciani, Agostino Cilibrizzi, Letizia Crocetti, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Gabriella Guerrini, Antonella Iacovone, Maria Paola Giovannoni A number of heterocycles bearing an arylpiperazinylalkyl side chain and structurally related to the previously described lead ET1 (4-amino-6-methyl-2-[3-(4-p-tolylpiperazin-1-yl)propyl]-5-vinylpyridazin-3(2H)-one) was synthesized and tested for their antinociceptive activity in Writhing Test. Many compounds, tested at doses of 20-40 mg/kg po were able to reduce the number of abdominal constrictions by more than 47% and, in same cases, the potency is comparable to lead ET1 as for 5e, 24a, 27b and 27c. The analgesia induced by the active compounds was completely prevented by pretreatment with α 2-antagonist yohimbine, confirming the involvement of the adrenergic system in the mechanism of action for these new compounds. Graphical abstract image
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Editorial board ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17
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Graphical contents list ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17
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Pyrroloaryls and pyrroloheteroaryls: Inhibitors of the HIV fusion/attachment, reverse transcriptase and integrase ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Rahul V. Patel, Se Won Park Heterocyclic compounds execute a very important role in drug design and discovery. This article provides the basic milestones of the research for pyrroloaryl and pyrroloheteroaryl based components targeting HIV viral replication cycle. Anti-HIV activity is elaborated for several classes of pyrrolo-compounds as pyrrolopyridines, pyrrolopyrimidines, pyrrolopyridazines, pyrrolobenzodiazepinones, pyrrolobenzothiazepines, pyrrolobenzoxazepinones, pyrrolophenanthridines, pyrroloquinoxalines, pyrrolotriazines, pyrroloquinolines, pyrrolopyrazinones, pyrrolothiatriazines, arylthiopyrroles and pyrrolopyrazolones targeting two essential HIV enzymes, reverse transcriptase and integrase as well as attachment/fusion of HIV virons to the host CD-4 cell. Such attempts were resulted in a discovery of highly potent anti-HIV agents suitable for clinical trials, for example, BMS-378806, BMS-585248, BMS-626529, BMS-663068, BMS-488043 and BMS-663749, etc. as anti-HIV attachment agents, triciribine, QX432, BI-1 and BI-2 as HIV RT inhibitors which are in preclinical or clinical development. Mechanism of action of compounds presented in this article towards the suppression of HIV attachment/fusion as well as against the activities of HIV enzymes reverse transcriptase and integrase has been discussed. Relationships of new compounds’ molecular framework and HIV viral target has been overviewed in order to facilitate further construction of promising anti-HIV agents in future drug discovery process. Graphical abstract image
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Synthesis and evaluation of arylpiperazine-reverse amides as biased dopamine D3 receptor ligands ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Yongkai Cao, Suresh Paudel, Xiaowei Zhang, Kyeong-Man Kim, Seung Hoon Cheon The dopamine D3 receptor (D3R) preferential ligands have been universally adopted as a strategy for the treatment of drug addiction and other neuropsychiatric disorders due to fewer side effects. However, the high sequence homology between D3R and the D2 receptor (D2R) challenges the development of D3R-biased compounds. Herein, we design and synthesize a novel series of reverse amide-piperazine hybrid ligands and evaluate their biological affinities in vitro. Compound 4d was found to be the most potent D3R-selective ligand among these hybrid derivatives. Molecular modeling revealed that extracellular loop 1 (EL1) and loop 2 (EL2) of D3R together likely contribute to D3R selectivity over D2R. In particular, Gly94 in EL1 of D3R may act as a molecular determinant for D3R specificity. Graphical abstract image
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Synthesis, biological evaluation and docking study of maleimide derivatives bearing benzenesulfonamide as selective COX-2 inhibitors and anti-inflammatory agents ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Sandip D. Firke, Sanjay B. Bari A series of maleimide analogs bearing benzenesulfonamide were synthesized (4a–r). The anti-inflammatory activity of synthesized derivatives was evaluated using carrageenan induced rat paw edema model. COX-1 and COX-2 potency was evaluated through in vitro cyclooxygenase assays. The results revealed that, compounds 4a, 4h, 4j, 4k and 4r had potent COX-2 percentage inhibition as well as in vivo anti-inflammatory activity. The potent compound 4j was docked into the COX-2 active site to determine the probable binding model. The results of in vivo and in vitro studies demonstrate that phenyl ring with electron withdrawing groups on maleimide ring would generate more potent anti-inflammatory agents. Thus, these compounds can serve as potential leads for further anti-inflammatory studies. Graphical abstract image
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1,5-Disubstituted benzimidazoles that direct cardiomyocyte differentiation from mouse embryonic stem cells ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Karl J. Okolotowicz, Paul Bushway, Marion Lanier, Cynthia Gilley, Mark Mercola, John R. Cashman Cardiomyopathy is the leading cause of death worldwide. Despite progress in medical treatments, heart transplantation is one of the only current options for those with infarcted heart muscle. Stem cell differentiation technology may afford cell-based therapeutics that may lead to the generation of new, healthy heart muscle cells from undifferentiated stem cells. Our approach is to use small molecules to stimulate stem cell differentiation. Herein, we describe a novel class of 1,5-disubstituted benzimidazoles that induce differentiation of stem cells into cardiac cells. We report on the evaluation in vitro for cardiomyocyte differentiation and describe structure–activity relationship results that led to molecules with drug-like properties. The results of this study show the promise of small molecules to direct stem cell lineage commitment, to probe signaling pathways and to develop compounds for the stimulation of stem cells to repair damaged heart tissue. Graphical abstract image
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Discovery of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as potent RORγt inverse agonists ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Yonghui Wang, Ting Yang, Qian Liu, Yingli Ma, Liuqing Yang, Ling Zhou, Zhijun Xiang, Ziqiang Cheng, Sijie Lu, Lisa A. Orband-Miller, Wei Zhang, Qianqian Wu, Kathleen Zhang, Yi Li, Jia-Ning Xiang, John D. Elliott, Stewart Leung, Feng Ren, Xichen Lin A novel series of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as RORγt inverse agonists was discovered. Binding mode analysis of a RORγt partial agonist (2c) revealed by co-crystal structure in RORγt LBD suggests that the inverse agonists do not directly interfere with the interaction between H12 and the RORγt LBD. Detailed SAR exploration led to identification of potent RORγt inverse agonists such as 3m with a pIC50 of 8.0. Selected compounds in the series showed reasonable activity in Th17 cell differentiation assay as well as low intrinsic clearance in mouse liver microsomes. Graphical abstract image
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A new small molecule inhibitor of soluble guanylate cyclase ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Filipa Mota, Paul Gane, Kathryn Hampden-Smith, Charles K. Allerston, John Garthwaite, David L. Selwood Soluble guanylate cyclase (sGC) is a haem containing enzyme that regulates cardiovascular homeostasis and multiple mechanisms in the central and peripheral nervous system. Commonly used inhibitors of sGC activity act through oxidation of the haem moiety, however they also bind haemoglobin and this limits their bioavailability for in vivo studies. We have discovered a new class of small molecule inhibitors of sGC and have characterised a compound designated D12 (compound 10) which binds to the catalytic domain of the enzyme with a K D of 11μM in a SPR assay. Graphical abstract image
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Exploring new Probenecid-based carbonic anhydrase inhibitors: Synthesis, biological evaluation and docking studies ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Adriano Mollica, Roberto Costante, Atilla Akdemir, Simone Carradori, Azzurra Stefanucci, Giorgia Macedonio, Mariangela Ceruso, Claudiu T. Supuran Novel Probenecid-based amide derivatives, incorporating different natural amino acids, were synthesized and assayed to test their effect on the human carbonic anhydrase (hCA, EC 4.2.1.1) transmembrane isoforms hCA IX and XII over the ubiquitous isoforms hCA I and II. Most of them presented a complete loss of hCA II inhibition (Kis>10,000nM) and strong inhibitory activity against hCA IX and XII in the nanomolar range with respect to the parent compound. A residual activity against hCA I was observed for some of them. These biological results have been explained by docking studies within the active sites of the four studied human carbonic anhydrases (with or without the zinc-bound water) and helped us to better comprehend the rationale behind the design of tertiary sulfonamide compounds as potent but atypical inhibitors of specific isoforms of human carbonic anhydrase. Graphical abstract image
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Photoaffinity labeling studies of the carbohydrate-binding proteins with different affinities ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Kaori Sakurai, Shimpei Ozawa, Tamayo Yamaguchi Photoaffinity labeling has been used as a promising approach to detection and isolation of carbohydrate-binding proteins, which are typically characterized by low binding affinity and selectivity. When there are several specific binding proteins, it is desirable that a photoaffinity probe is capable of simultaneously crosslinking them and that the crosslinking yields depend on the relative binding affinities. In this study, we describe the design and synthesis of carbohydrate photoaffinity probes and their ability to capture lectins of different binding affinities. Graphical abstract image
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Tight binding enantiomers of pre-clinical drug candidates ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Gary B. Evans, Scott A. Cameron, Andreas Luxenburger, Rong Guan, Javier Suarez, Keisha Thomas, Vern L. Schramm, Peter C. Tyler MTDIA is a picomolar transition state analogue inhibitor of human methylthioadenosine phosphorylase and a femtomolar inhibitor of Escherichia coli methylthioadenosine nucleosidase. MTDIA has proven to be a non-toxic, orally available pre-clinical drug candidate with remarkable anti-tumour activity against a variety of human cancers in mouse xenografts. The structurally similar compound MTDIH is a potent inhibitor of human and malarial purine nucleoside phosphorylase (PNP) as well as the newly discovered enzyme, methylthioinosine phosphorylase, isolated from Pseudomonas aeruginosa. Since the enantiomers of some pharmaceuticals have revealed surprising biological activities, the enantiomers of MTDIH and MTDIA, compounds 1 and 2, respectively, were prepared and their enzyme binding properties studied. Despite binding less tightly to their target enzymes than their enantiomers compounds 1 and 2 are nanomolar inhibitors. Graphical abstract image
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Ribosome-targeting antibiotics as inhibitors of oncogenic microRNAs biogenesis: Old scaffolds for new perspectives in RNA targeting ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Thi Phuong Anh Tran, Duc Duy Vo, Audrey Di Giorgio, Maria Duca MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression at the post-transcriptional level. It is now well established that the overexpression of some miRNAs (oncogenic miRNAs) is responsible for initiation and progression of human cancers and the discovery of new molecules able to interfere with their production and/or function represents one of the most important challenges of current medicinal chemistry of RNA ligands. In this work, we studied the ability of 18 different antibiotics, known as prokaryotic ribosomal RNA, to bind to oncogenic miRNA precursors (stem-loop structured pre-miRNAs) in order to inhibit miRNAs production. In vitro inhibition, binding constants, thermodynamic parameters and binding sites were investigated and highlighted that aminoglycosides and tetracyclines represent interesting pre-miRNA ligands with the ability to inhibit Dicer processing. Graphical abstract image
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Carbon nanotubes supported tyrosinase in the synthesis of lipophilic hydroxytyrosol and dihydrocaffeoyl catechols with antiviral activity against DNA and RNA viruses ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Giorgia Botta, Bruno Mattia Bizzarri, Adriana Garozzo, Rossella Timpanaro, Benedetta Bisignano, Donatella Amatore, Anna Teresa Palamara, Lucia Nencioni, Raffaele Saladino Hydroxytyrosol and dihydrocaffeoyl catechols with lipophilic properties have been synthesized in high yield using tyrosinase immobilized on multi-walled carbon nanotubes by the Layer-by-Layer technique. All synthesized catechols were evaluated against a large panel of DNA and RNA viruses, including Poliovirus type 1, Echovirus type 9, Herpes simplex virus type 1 (HSV-1), Herpes simplex virus type 2 (HSV-2), Coxsackievirus type B3 (Cox B3), Adenovirus type 2 and type 5 and Cytomegalovirus (CMV). A significant antiviral activity was observed in the inhibition of HSV-1, HSV-2, Cox B3 and CMV. The mechanism of action of the most active dihydrocaffeoyl derivative was investigated against a model of HSV-1 infection. Graphical abstract image
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Heterocyclic chalcone activators of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) with improved in vivo efficacy ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Nicole Lounsbury, George Mateo, Brielle Jones, Srinivas Papaiahgari, Rajash K. Thimmulappa, Christiana Teijaro, John Gordon, Kenneth Korzekwa, Min Ye, Graham Allaway, Magid Abou-Gharbia, Shyam Biswal, Wayne Childers Nrf2 activators represent a good drug target for designing agents to treat diseases associated with oxidative stress. Building upon previous work, we designed and prepared a series of heterocyclic chalcone-based Nrf2 activators with reduced lipophilicity and, in some cases, greater in vitro potency compared to the respective carbocyclic scaffold. These changes resulted in enhanced oral bioavailability and a superior pharmacodynamic effect in vivo. Graphical abstract image
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Synthesis, binding, nuclease resistance and cellular uptake properties of 2′-O-acetalester-modified oligonucleotides containing cationic groups ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Annabelle Biscans, Sonia Rouanet, Jean-Rémi Bertrand, Jean-Jacques Vasseur, Christelle Dupouy, Françoise Debart We report on the synthesis and properties of oligonucleotides (ONs) with 2′-O-acetalester modifications containing cationic side chains in a prodrug-like approach. In the aim to improve cell penetration and nuclease resistance, various different amino- or guanidino-acetalester were grafted to 2′-OH of uridine and the corresponding phosphoramidites were incorporated into ONs. Introduction of 2′-O-(2-aminomethyl-2-ethyl)butyryloxymethyl (AMEBuOM) modification into 2′-OMe ONs leads to high resistance towards enzymatic degradation and to destabilization of duplexes with complementary RNA strand. Spontaneous uptake experiments of a twelve-mer containing ten 2′-O-AMEBuOM-U units into A673 cells showed moderate internalization of ON within the cells whereas substantial internalization of the corresponding lipophilic 2′-O-pivaloyloxymethyl ON was observed for the first time. Graphical abstract image
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Phosphate-modified analogues of m7GTP and m7Gppppm7G—Synthesis and biochemical properties ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Marcin Ziemniak, Joanna Kowalska, Maciej Lukaszewicz, Joanna Zuberek, Katarzyna Wnek, Edward Darzynkiewicz, Jacek Jemielity The synthesis and biochemical properties of 17 new mRNA cap analogues are reported. Six of these nucleotides are m7GTP derivatives, whereas 11 are ‘two headed’ tetraphosphate dinucleotides based on a m7Gppppm7G structure. The compounds contain either a boranophosphate or phosphorothioate moiety in the nucleoside neighbouring position(s) and some of them possess an additional methylene group between β and γ phosphorus atoms. The compounds were prepared by divalent metal chloride-mediated coupling of an appropriate m7GMP analogue with a given P1,P2-di(1-imidazolyl) derivative. The analogues were evaluated as tools for studying cap-dependent processes in a number of biochemical assays, including determination of affinity to eukaryotic initiation factor eIF4E, susceptibility to enzymatic hydrolysis, and translational efficiency in vitro. The results indicate that modification in the phosphate chain can increase binding to cap-interacting proteins and provides higher resistance to degradation. Furthermore, modified derivatives of m7GTP were found to be potent inhibitors of cap-dependent translation in cell free systems. Graphical abstract image
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Galantamine derivatives with indole moiety: Docking, design, synthesis and acetylcholinesterase inhibitory activity ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Mariyana Atanasova, Georgi Stavrakov, Irena Philipova, Dimitrina Zheleva, Nikola Yordanov, Irini Doytchinova The inhibitors of acetylcholinesterase are the main therapy against Alzheimer’s disease. Among them, galantamine is the best tolerated and the most prescribed drug. In the present study, 41 galantamine derivatives with known acetylcholinesterase inhibitory activities expressed as IC50 were selected from the literature and docked into a recombinant human acetylcholinesterase by GOLD. A linear relationship between GoldScores and pIC50 values was found and used to design and predict novel galantamine derivatives with indole moiety in the side chain. The four best predicted compounds were synthesized and tested for inhibitory activity. All of them were between 11 and 95 times more active than galantamine. The novel galantamine derivatives with indole moiety have dual site binding to the enzyme—the galantamine moiety binds to the catalytic anionic site and the indole moiety binds to peripheral anionic site. Additionally, the indole moiety of one of the novel inhibitors binds in a region, close to the peripheral anionic site of the enzyme, where the Ω-loop of amyloid beta peptide adheres to acetylcholinesterase. This compound emerges as a promising lead compound for multi-target anti-Alzheimer therapy not only because of the strong inhibitory activity, but also because it is able to block the amyloid beta deposition on acetylcholinesterase. Graphical abstract image
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Synthesis and biological evaluation of (3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone selective CB2 inverse agonist ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Chaela S. Presley, Suni M. Mustafa, Ammaar H. Abidi, Bob M. Moore Cannabinoid receptor 2 (CB2) selective agonists and inverse agonists possess significant potential as therapeutic agents for regulating inflammation and immune function. Although CB2 agonists have received the greatest attention, it is emerging that inverse agonists also manifest anti-inflammatory activity. In process of designing new cannabinoid ligands we discovered that the 2,6-dihydroxy-biphenyl-aryl methanone scaffold imparts inverse agonist activity at CB2 receptor without functional activity at CB1. To further explore the scaffold we synthesized a series of (3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone analogs and evaluated the CB1 and CB2 affinity, potency, and efficacy. The studies reveal that an aromatic C ring is required for inverse agonist activity and that substitution at the 4 position is optimum. The resorcinol moiety is required for optimum CB2 inverse agonist activity and selectivity. Antagonist studies against CP 55,940 demonstrate that the compounds 41 and 45 are noncompetitive antagonists at CB2. Graphical abstract image
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Sulfation modulates the cell uptake, antiradical activity and biological effects of flavonoids in vitro: An examination of quercetin, isoquercitrin and taxifolin ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Lenka Roubalová, Kateřina Purchartová, Barbora Papoušková, Jan Vacek, Vladimír Křen, Jitka Ulrichová, Jiří Vrba Quercetin 3′-O-sulfate is one of the main metabolites of the natural flavonoid quercetin in humans. This study was designed to prepare quercetin 3′-O-sulfate (1), isoquercitrin 4′-O-sulfate (2) and taxifolin 4′-O-sulfate (3) by the sulfation of quercetin, isoquercitrin (quercetin 3-O-glucoside) and taxifolin (2,3-dihydroquercetin) using the arylsulfate sulfotransferase from Desulfitobacterium hafniense, and to examine the effect of sulfation on selected biological properties of the flavonoids tested. We found that flavonoid sulfates 1–3 were weaker DPPH radical scavengers than the corresponding nonsulfated flavonoids, and that 1–3, unlike quercetin, did not induce the expression of either heme oxygenase-1 in RAW264.7 cells or cytochrome P450 1A1 in HepG2 cells. In both cell types, the cell uptake of compounds 1–3 was much lower than that of quercetin, but comparable to that of the glycoside isoquercitrin. Moreover, HPLC/MS metabolic profiling in HepG2 cells showed that flavonoid sulfates 1–3 were metabolized to a limited extent compared to the nonsulfated compounds. We conclude that sulfation of the tested flavonoids reduces their antiradical activity, and affects their cell uptake and biological activity in vitro. Graphical abstract image
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Guanidinium compounds with sub-micromolar activities against Mycobacterium tuberculosis. Synthesis, characterization and biological evaluations ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Hugues Massimba-Dibama, Maxime Mourer, Patricia Constant, Mamadou Daffé, Jean-Bernard Regnouf-de-Vains Seven polycharged species, incorporating 1, 2, 3, 4 and 6 guanidine arms organized around a benzene core were synthesized and assayed as anti-mycobacterial agents against Mycobacterium tuberculosis. They display MIC values comprised between 25 and 12.5μM (close to ethambutol EMB) for the mono- and the hexa-substituted derivatives, and 0.8μM (close to isoniazid and streptomycin) for the tri-substituted derivative. The three bi- and the tetra-substituted analogs displayed MIC values of ca. 6.5–3.0μM. The latter were also evaluated against the isoniazid-resistant MYC5165 strain, resulting in highly interesting micromolar or sub-micromolar MIC, ca. 4–125 times more active than isoniazid. These preliminary results are attractive for the development of new anti-TB agents. Graphical abstract image
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Antimalarial benzoheterocyclic 4-aminoquinolines: Structure–activity relationship, in vivo evaluation, mechanistic and bioactivation studies ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Dennis S.B. Ongarora, Natasha Strydom, Kathryn Wicht, Mathew Njoroge, Lubbe Wiesner, Timothy J. Egan, Sergio Wittlin, Ulrik Jurva, Collen M. Masimirembwa, Kelly Chibale A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure–activity relationship studies led to the identification of highly promising analogues, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively. Graphical abstract image
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Design, chemical synthesis and biological evaluation of 3-spiromorpholinone/3-spirocarbamate androsterone derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 3 ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Guy Bertrand Djigoué, Lucie Carolle Kenmogne, Jenny Roy, René Maltais, Donald Poirier 17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a key enzyme involved in the biosynthesis of testosterone and dihydrotestosterone. These hormones are known to stimulate androgen-dependent prostate cancer. In order to generate effective inhibitors of androgen biosynthesis without androgenic effect, we synthesized a new family of 3-spiromorpholinone and 3-spirocarbamate androsterone derivatives bearing diversified hydrophobic groups. We also tested their inhibitory activity in a microsomal fraction of 17β-HSD3-containing rat testes, and their androgenic effect on androgen-sensitive LAPC-4 cells. From our first structure–activity relationship (SAR) study, we noted that compound 7e inhibited 17β-HSD3 (77% at 0.1μM) compared to our reference compound RM-532-105 (76% at 0.1μM), but exhibited a residual androgenic effect. A library of 7e analogue compounds was next synthesized in order to generate compounds with reduced androgenic activity. In this new SAR study, the sulfonamide compound 7e21 and the carboxamide compound 7e22 inhibited 17β-HSD3 (IC50 =28 and 88nM, respectively). These two compounds were not androgenic and not cytotoxic even at the highest concentration tested, but their inhibitory activity decreased in intact LNCaP cells overexpressing 17β-HSD3 (LNCaP[17β-HSD3]). Structural modifications of these two lead compounds could however be tested to produce a second generation of 17β-HSD3 inhibitors. Graphical abstract image
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Highly potent artemisinin-derived dimers and trimers: Synthesis and evaluation of their antimalarial, antileukemia and antiviral activities ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Christoph Reiter, Tony Fröhlich, Lisa Gruber, Corina Hutterer, Manfred Marschall, Cornelia Voigtländer, Oliver Friedrich, Barbara Kappes, Thomas Efferth, Svetlana B. Tsogoeva New pharmaceutically active compounds can be obtained by modification of existing drugs to access more effective agents in the wake of drug resistance amongst others. To achieve this goal the concept of hybridization was established during the last decade. We employed this concept by coupling two artemisinin-derived precursors to obtain dimers or trimers with increased in vitro activity against Plasmodiumfalciparum 3D7 strain, leukemia cells (CCRF-CEM and multidrug-resistant subline CEM/ADR5000) and human cytomegalovirus (HCMV). Dimer 4 (IC50 of 2.6nM) possess superior antimalarial activity compared with its parent compound artesunic acid(3) (IC50 of 9.0nM). Dimer 5 and trimers 6 and 7 display superior potency against both leukemia cell lines (IC50 up to 0.002μM for CCRF-CEM and IC50 up to 0.20μM for CEM/ADR5000) and are even more active than clinically used doxorubicin (IC50 1.61μM for CEM/ADR5000). With respect to anti-HCMV activity, trimer 6 is the most efficient hybrid (IC50 0.04μM) outperforming ganciclovir (IC50 2.6μM), dihydroartemisinin(IC50 >10μM) and artesunic acid (IC50 3.8μM). Graphical abstract image
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Molecular dynamics and density functional studies on the metabolic selectivity of antipsychotic thioridazine by cytochrome P450 2D6: Connection with crystallographic and metabolic results ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Katsunori Sasahara, Akira Mashima, Tatsusada Yoshida, Hiroshi Chuman CYP2D6, a cytochrome P450 isoform, significantly contributes to the metabolism of many clinically important drugs. Thioridazine (THD) is one of the phenothiazine-type antipsychotics, which exhibit dopamine D2 antagonistic activity. THD shows characteristic metabolic profiles compared to other phenothiazine-type antipsychotics such as chlorpromazine. The sulfur atom attached to the phenothiazine ring is preferentially oxidized mainly by CYP2D6, that is, the 2-sulfoxide is a major metabolite, and interestingly this metabolite shows more potent activity against dopamine D2 receptors than THD. On the other hand, the formation of this metabolite causes many serious problems for its clinical use. Wójcikowski et al. (Drug Metab. Dispos. 2006, 34, 471) reported a kinetic study of THD formed by CYP2D6. Recently, Wang et al. (J. Biol. Chem. 2012, 287, 10834 and J. Biol. Chem. 2015, 290, 5092) revealed the crystallographic structure of THD with CYP2D6. In the current study, the binding and reaction mechanisms at the atomic and electronic levels were computationally examined based on the assumption as to whether or not the different crystallographic binding poses correspond to the different metabolites. The binding and oxidative reaction steps in the whole metabolic process were investigated using molecular dynamics and density functional theory calculations, respectively. The current study demonstrated the essential importance of the orientation of the substrate in the reaction center of CYP2D6 for the metabolic reaction. Graphical abstract image
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Structural and computational study on inhibitory compounds for endonuclease activity of influenza virus polymerase ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Satoshi Fudo, Norio Yamamoto, Michiyoshi Nukaga, Takato Odagiri, Masato Tashiro, Saburo Neya, Tyuji Hoshino Seasonal epidemics and occasional pandemics caused by influenza viruses are global threats to humans. Since the efficacy of currently approved drugs is limited by the emerging resistance of the viruses, the development of new antiviral drugs is still demanded. Endonuclease activity, which lies in the influenza polymerase acidic protein N-terminal domain (PAN), is a potent target for novel antiviral agents. Here, we report the identification of some novel inhibitors for PAN endonuclease activity. The binding mode of one of the inhibitory compounds to PAN was investigated in detail by means of X-ray crystal structure analysis and molecular dynamics (MD) simulation. It was observed in the crystal structure that three molecules of the same kind of inhibitor were bound to one PAN. One of the three molecules is located at the active site and makes a chelation to metal ions. Another molecule is positioned at the space adjacent to the metal-chelated site. The other molecule is located at a site slightly apart from the metal-chelated site, causing a conformational change of Arg124. The last binding site was not observed in previous crystallographic studies. Hence, the stability of inhibitor binding was examined by performing 100-ns MD simulation. During the MD simulation, the three inhibitor molecules fluctuated at the respective binding sites at different amplitudes, while all of the molecules maintained interactions with the protein. Molecular mechanics/generalized Born surface area (MM/GBSA) analysis suggested that the molecule in the last binding site has a higher affinity than the others. Structural information obtained in this study will provide a hint for designing and developing novel potent agents against influenza viruses. Graphical abstract image
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Novel metal chelating molecules with anticancer activity. Striking effect of the imidazole substitution of the histidine–pyridine–histidine system ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Taha F.S. Ali, Kana Iwamaru, Halil Ibrahim Ciftci, Ryoko Koga, Masahiro Matsumoto, Yasunori Oba, Hiromasa Kurosaki, Mikako Fujita, Yoshinari Okamoto, Kazuo Umezawa, Mitsuyoshi Nakao, Takuichiro Hide, Keishi Makino, Jun-ichi Kuratsu, Mohamed Abdel-Aziz, Gamal El-Din A.A. Abuo-Rahma, Eman A.M. Beshr, Masami Otsuka Previously we have reported a metal chelating histidine–pyridine–histidine system possessing a trityl group on the histidine imidazole, namely HPH-2Trt, which induces apoptosis in human pancreatic adenocarcinoma AsPC-1 cells. Herein the influence of the imidazole substitution of HPH-2Trt was examined. Five related compounds, HPH-1Trt, HPH-2Bzl, HPH-1Bzl, HPH-2Me, and HPH-1Me were newly synthesized and screened for their activity against AsPC-1 and brain tumor cells U87 and U251. HPH-1Trt and HPH-2Trt were highly active among the tested HPH compounds. In vitro DNA cleavage assay showed both HPH-1Trt and HPH-2Trt completely disintegrate pUC19 DNA. The introduction of trityl group decisively potentiated the activity. Graphical abstract image
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Discovery and structure of a new inhibitor scaffold of the autophagy initiating kinase ULK1 ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Michael B. Lazarus, Kevan M. Shokat Energy homeostasis in eukaryotic cells is a complex and fundamental process that is misregulated in several human diseases. A key component of energy regulation is a process called autophagy that involves the recycling of cellular components. There has been much recent interest in studying the mechanism of autophagy to understand an important cellular process and to evaluate the therapeutic potential in targeting autophagy. Activation of a kinase called ULK1 initiates autophagy by driving downstream pathways that lead to the formation of double membrane bound vesicles that surround the cellular contents that are to be degraded. Here, we report the discovery of an inhibitor of ULK1 with improved selectivity and a high-resolution crystal structure of the compound bound to the kinase, which will be useful tools for studying autophagy in cells. Graphical abstract image
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Computer-aided identification, synthesis, and biological evaluation of novel inhibitors for botulinum neurotoxin serotype A ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Yu-Han Gary Teng, William T. Berger, Natasha M. Nesbitt, Kunal Kumar, Trent E. Balius, Robert C. Rizzo, Peter J. Tonge, Iwao Ojima, Subramanyam Swaminathan Botulinum neurotoxins (BoNTs) are among the most potent biological toxin known to humans, and are classified as Category A bioterrorism agents by the Centers for Disease Control and prevention (CDC). There are seven known BoNT serotypes (A–G) which have been thus far identified in literature. BoNTs have been shown to block neurotransmitter release by cleaving proteins of the soluble NSF attachment protein receptor (SNARE) complex. Disruption of the SNARE complex precludes motor neuron failure which ultimately results in flaccid paralysis in humans and animals. Currently, there are no effective therapeutic treatments against the neurotoxin light chain (LC) after translocation into the cytosols of motor neurons. In this work, high-throughput in silico screening was employed to screen a library of commercially available compounds from ZINC database against BoNT/A-LC. Among the hit compounds from the in silico screening, two lead compounds were identified and found to have potent inhibitory activity against BoNT/A-LC in vitro, as well as in Neuro-2a cells. A few analogs of the lead compounds were synthesized and their potency examined. One of these analogs showed an enhanced activity than the lead compounds. Graphical abstract image
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2- and 3-Fluoro-3-deazaneplanocins, 2-fluoro-3-deazaaristeromycins, and 3-methyl-3-deazaneplanocin: Synthesis and antiviral properties ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Chong Liu, Qi Chen, John D. Gorden, Stewart W. Schneller The 3-deaza analogs of the naturally occurring adenine-based carbocyclic nucleosides aristeromycin and neplanocin possess biological properties that have not been optimized. In that direction, this paper reports the strategic placement of a fluorine atom at the C-2 and C-3 positions and a methyl at the C-3 site of the 3-deazaadenine ring of the aforementioned compounds. The synthesis and S-adenosylhomocysteine hydrolase inhibitory and antiviral properties of these targets are described. Some, but not all, compounds in this series showed significant activity toward herpes, arena, bunya, flavi, and orthomyxoviruses. Graphical abstract image
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Antimalarial activity of prodrugs of N-branched acyclic nucleoside phosphonate inhibitors of 6-oxopurine phosphoribosyltransferases ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Dana Hocková, Zlatko Janeba, Lieve Naesens, Michael D. Edstein, Marina Chavchich, Dianne T. Keough, Luke W. Guddat Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the human and Plasmodium falciparum 6-oxopurine phosphoribosyltransferases (PRTs), key enzymes of the purine salvage pathway. Chemical modifications, based on the crystal structures of several inhibitors in complex with the human PRTase, led to the design of a new class of inhibitors—the aza-ANPs. Because of the negative charges of the phosphonic acid moiety, their ability to cross cell membranes is, however, limited. Thus, phosphoramidate prodrugs of the aza-ANPs were prepared to improve permeability. These prodrugs arrest parasitemia with IC50 values in the micromolar range against Plasmodium falciparum-infected erythrocyte cultures (both chloroquine-sensitive and chloroquine-resistant Pf strains). The prodrugs exhibit low cytotoxicity in several human cell lines. Thus, they fulfill two essential criteria to qualify them as promising antimalarial drug leads. Graphical abstract image
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Design and synthesis of dithiocarbamate linked β-carboline derivatives: DNA topoisomerase II inhibition with DNA binding and apoptosis inducing ability ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Ahmed Kamal, Manda Sathish, V. Lakshma Nayak, Vunnam Srinivasulu, Botla Kavitha, Yellaiah Tangella, Dinesh Thummuri, Chandrakant Bagul, Nagula Shankaraiah, Narayana Nagesh A series of new β-carboline-dithiocarbamate derivatives bearing phenyl, dithiocarbamate and H/methyl substitutions at position-1, 3 and 9, respectively, were designed and synthesized. These derivatives 8a–l and 13a–l and their starting precursors (7a–d and 12a–d) have been evaluated for their in vitro cytotoxic activity on selected human cancer cell lines. Among the derivatives tested, 7c, 12c, 8a, 8d, 8i, 8j, 8k, 8l and 13d–l exhibited considerable cytotoxicity against most of the tested cancer cell lines (IC50 <10μM). Interestingly, most of the derivatives (8a–l and 13a–l) exhibited enhanced activity than their precursors (7a–d and 12a–d), which indicates that the combination of dithiocarbamate with β-carboline enhances the cytotoxicity of 8a–l and 13a–l. Moreover, the derivatives 8j and 13g exhibited significant cytotoxic activity with IC50 values of 1.34μM and 0.79μM on DU-145 cancer cells, respectively. Further, the induction of apoptosis by these derivatives was confirmed by Annexin V-FITC and Hoechst staining assays. However, both biophysical as well as molecular docking studies suggested a combilexin-type of interaction between these derivatives and DNA, unlike simple β-carbolines. With a view to understand their mechanism of action, DNA topoisomerase II (topo II) inhibition assay was also performed. Overall, the present study emphasizes the importance of linking a dithiocarbamate moiety to the β-carboline scaffold for exhibiting profound activity. Graphical abstract image
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Novel diazabicycloalkane delta opioid agonists ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Giovanni Loriga, Paolo Lazzari, Ilaria Manca, Stefania Ruiu, Matteo Falzoi, Gabriele Murineddu, Mirko Emilio Heiner Bottazzi, Giovanni Pinna, Gérard Aimè Pinna Here we report the investigation of diazabicycloalkane cores as potential new scaffolds for the development of novel analogues of the previously reported diazatricyclodecane selective delta (δ) opioid agonists, as conformationally constrained homologues of the reference δ agonist (+)-4-[(αR)-α((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80). In particular, we have simplified the diazatricyclodecane motif of δ opioid agonist prototype 1a with bridged bicyclic cores. 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[3.3.1]nonane, 3,9-diazabicyclo[4.2.1]nonane, and 3,10-diazabicyclo[4.3.1]decane were adopted as core motifs of the novel derivatives. The compounds were synthesized and biologically assayed as racemic (3–5) or diastereoisomeric (6,7) mixtures. All the novel compounds 3–7 showed δ agonism behaviour and remarkable affinity to δ receptors. Amongst the novel derivatives, 3,8-diazabicyclo[3.2.1]octane based compound 4 evidenced improved δ affinity and selectivity relative to SNC80. Graphical abstract image
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Discovery of a series of novel compounds with moderate anti-hepatitis C virus NS3 protease activity in vitro ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Fangyuan Shi, Yingjie Zhang, Wenfang Xu The hepatitis C virus (HCV) NS3/4A protease that plays an important role in the viral life cycle has been proven to be an excellent target for the discovery of anti-HCV drugs. Enlightened by some P2-triazole and amide compounds, which had been found as HCV NS3 protease inhibitors, we designed and synthesized a series of novel compounds by incorporating different amino acid residues in P1/P1′ and P3/P3′ position to develop novel antiviral agents. The result of enzyme inhibition assay indicated that all the designed compounds showed moderate anti-HCV NS3 protease activity. On the basis of the biological result, a detailed structure–activity relationship (SAR) was derived and discussed. Graphical abstract image
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Optimization of 3-aryl-3-ethoxypropanoic acids and discovery of the potent GPR40 agonist DS-1558 ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Rieko Takano, Masao Yoshida, Masahiro Inoue, Takeshi Honda, Ryutaro Nakashima, Koji Matsumoto, Tatsuya Yano, Tsuneaki Ogata, Nobuaki Watanabe, Masakazu Hirouchi, Takako Kimura, Narihiro Toda GPR40 agonists stimulate insulin secretion only under the presence of high glucose concentration. Based on this mechanism, GPR40 agonists are believed to be promising novel insulin secretagogues with low risk of hypoglycemia. The optimizations of 3-aryl-3-ethoxypropanoic acids were performed to improve in vitro activity. We discovered compound 29r (DS-1558), (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid, which was confirmed to have an enhancing effect on glucose-dependent insulin secretion after intravenous glucose injection in SD rats. Graphical abstract image
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Optimization of permethyl ningalin B analogs as P-glycoprotein inhibitors ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Zhen Wang, Iris L.K. Wong, Fu Xing Li, Chao Yang, Zhen Liu, Tao Jiang, Ting Fu Jiang, Larry M.C. Chow, Sheng Biao Wan In the present study, a total of 9 novel permethyl ningalin B analogs have been synthesized and evaluated for their P-gp modulating activity in a P-gp overexpressed breast cancer cell line LCC6MDR. Among these derivatives, compound 12 with dimethoxy groups at rings A and B and tri-substitution at ring C with ortho-methoxyethylmorpholine, meta-bromo and para-benzyloxy groups displays the most potent P-gp modulating activity with EC50 of 423nM to reverse paclitaxel resistance. It is non-toxic towards L929 fibroblast with IC50 greater than 100μM and with selective index greater than 236. Its mechanism to reverse P-gp mediated drug resistance is by virtue of inhibiting transport activity of P-gp, restoring intracellular drug accumulation and eventually chemosensitizing the cancer cells to anticancer drug again. Moreover, compound 12 showed better solubility (405ng/mL) than hit compound 1 in phosphate buffer (pH 4.0). In summary, our study demonstrates that permethyl ningalin B derivative 12 is non-toxic and efficient P-gp inhibitor that is a potential candidate to be used clinically to reverse P-gp mediated cancer drug resistance. Graphical abstract image
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Ethylenedioxy homologs of N-methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) and its corresponding cathinone analog methylenedioxymethcathinone: Interactions with transporters for serotonin, dopamine, and norepinephrine ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Fabio Del Bello, Farhana Sakloth, John S. Partilla, Michael H. Baumann, Richard A. Glennon N-Methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA; ‘Ecstasy’; 1) and its β-keto analog methylone (MDMC; 2) are popular drugs of abuse. Little is known about their ring-expanded ethylenedioxy homologs. Here, we prepared N-methyl-(3,4-ethylenedioxyphenyl)-2-aminopropane (EDMA; 3), both of its optical isomers, and β-keto EDMA (i.e., EDMC; 4) to examine their effects at transporters for serotonin (SERT), dopamine (DAT), and norepinephrine (NET). In general, ring-expansion of the methylenedioxy group led to a several-fold reduction in potency at all three transporters. With respect to EDMA (3), S(+)3 was 6-fold, 50-fold, and 8-fold more potent than its R(−) enantiomer at SERT, DAT, and NET, respectively. Overall, in the absence of a β-carbonyl group, the ethylenedioxy (i.e., 1,4-dioxane) substituent seems better accommodated at SERT than at DAT and NET. Graphical abstract image
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Addition of niclosamide to palladium(II) saccharinate complex of terpyridine results in enhanced cytotoxic activity inducing apoptosis on cancer stem cells of breast cancer ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Didem Karakas, Buse Cevatemre, Nazlihan Aztopal, Ferda Ari, Veysel Turan Yilmaz, Engin Ulukaya Wnt signaling is one of the core signaling pathways of cancer stem cells (CSCs). It is re-activated in CSCs and plays essential role in the survival, self-renewal and proliferation of these cells. Therefore, we aimed to evaluate the cytotoxic effects of palladium(II) complex which is formulated as [PdCl(terpy)](sac)2H2O and its combination with niclosamide which is an inhibitor of Wnt signaling pathway associated with breast cancer stem cells. Characteristic cell surface markers (CD44+/CD24−) were determined by flow cytometry in CSCs. ATP viability assay was used to determine the cytotoxic activity. The mode of cell death was evaluated morphologically using fluorescence microscopy and biochemically using M30 ELISA assay as well as performing qPCR. Our study demonstrated that the combination of niclosamide (1.5μM) and Pd(II) complex (12.5, 25 and 50μM) at 48h has enhanced cytotoxic activity resulted from the induction of apoptosis (indicated by the presence of pyknotic nuclei, increments in M30 and over expression of proapoptotic genes of TNFRSF10A and FAS). Importantly, the addition of niclosamide resulted in the suppression of autophagy (proved by the decrease in ATG5 gene levels) that might have contributed to the enhanced cytotoxicity. In conclusion, the application of this combination may be regarded as a novel and effective approach for the treatment of breast cancer due to its promising cytotoxic effect on cancer stem cells that cause recurrence of the disease. Graphical abstract image
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The influence of the C5 substituent on the 2-thiouridine desulfuration pathway and the conformational analysis of the resulting 4-pyrimidinone products ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Paulina Bartos, Katarzyna Ebenryter-Olbinska, Elzbieta Sochacka, Barbara Nawrot In recent years, increasing attention has been focused on the posttranscriptional modifications present in transfer RNAs (tRNAs), which have been suggested to constitute another level of regulation of gene expression. The most representative among them are the 5-substituted 2-thiouridines (R5S2U), which are located in the wobble position of the anticodon and play a fundamental role in the tuning of the translation process. On the other hand, sulfur-containing biomolecules are the primary site for the attack of reactive oxygen species (ROS). We have previously demonstrated that under in vitro conditions that mimic oxidative stress in the cell, the S2U alone or bound to an RNA chain undergoes desulfuration to yield uridine and 4-pyrimidinone nucleoside (H2U) products. The reaction is pH- and concentration-dependent. In this study, for the first time, we demonstrate that the substituent at the C5 position of the 2-thiouracil ring of R5S2Us influences the desulfuration pathway, and thus the products ratio. As the substituent R changes, the amount of R5H2U increases in the order H–>CH3O–>CH3OC(O)CH2–>HOC(O)CH2NHCH2–≈ CH3NHCH2–, and this effect is more pronounced at lower pH. The conformational analysis of the resulting R5H2U products indicates that independent of the nature of the R5 substituent, the R5H2U nucleosides predominantly adopt a C2′-endo sugar ring conformation, as opposed to the preferred C3′-endo conformation of the parent R5S2Us. Graphical abstract image
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Chemoenzymatic synthesis and cytotoxicity of oenanthotoxin and analogues ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Sven Sommerwerk, Lucie Heller, Bianka Siewert, René Csuk We developed a synthetic scheme for the synthesis of naturally occurring (14R)-oenanthotoxin and several analogs. Key-steps of this synthesis were an efficient homo-coupling of alkynes and a chemoenzymatic resolution of racemic oenanthotoxin using novozyme 435 and vinyl acetate. The compounds were screened for their cytotoxic activity using a photometric sulforhodamine B assays and several human tumor cell lines. Oenanthotoxin and many derivatives thereof were cytotoxic to tumor cell lines as well as to non-malignant mouse fibroblasts. The highest activity was determined for human ovarian cancer cells A2780 with EC50 =3.8μM. Graphical abstract image
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A P450 fusion library of heme domains from Rhodococcus jostii RHA1 and its evaluation for the biotransformation of drug molecules ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Justyna K. Kulig, Claudia Spandolf, Ralph Hyde, Antonio C. Ruzzini, Lindsay D. Eltis, Gunnar Grönberg, Martin A. Hayes, Gideon Grogan The actinomycete Rhodococcus jostii RHA1 contains a multitude of oxygenase enzymes, consonant with its remarkable activities in the catabolism of hydrophobic xenobiotic compounds. In the interests of identifying activities for the transformation of drug molecules, we have cloned genes encoding 23 cytochrome P450 heme domains from R. jostii and expressed them as fusions with the P450 reductase domain (RhfRED) of cytochrome P450Rhf from Rhodococcus sp. NCIMB 9784. Fifteen of the fusions were expressed in the soluble fraction of Escherichia coli Rosetta (DE3) cells. Strains expressing the fusions of RhfRED with genes ro02604, ro04667, ro11069, ro11320, ro11277, ro08984 and ro04671 were challenged with 48 commercially available drugs revealing many different activities commensurate with P450-catalyzed hydroxylation and demethylation reactions. One recombinant strain, expressing the fusion of P450 gene ro11069 (CYP257A1) with RhfRED, and named Ro07-RhfRED, catalyzed the N-demethylation of diltiazem and imipramine. This observation was in accord with previous reports of this enzyme’s activity as a demethylase of alkaloid substrates. Ro07-RhfRED was purified and characterised, and applied in cell-free biotransformations of imipramine (7μM) giving a 63% conversion to the N-desmethyl product. Graphical abstract image
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Synthesis, biological evaluation and molecular modeling of new tetrahydroacridine derivatives as potential multifunctional agents for the treatment of Alzheimer’s disease ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Marek Bajda, Jakub Jończyk, Barbara Malawska, Kamila Czarnecka, Małgorzata Girek, Paulina Olszewska, Joanna Sikora, Elżbieta Mikiciuk-Olasik, Robert Skibiński, Anna Gumieniczek, Paweł Szymański A novel series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with 4-dimethylaminobenzoic acid moiety was synthesized and tested towards inhibition of cholinesterases and amyloid β aggregation. Target compounds were designed as dual binding site cholinesterase inhibitors able to bind to both the catalytic and the peripheral site of the enzyme and therefore potentially endowed with other properties. The obtained derivatives were very potent inhibitors of both cholinesterases (EeAChE, EqBChE) with IC50 values ranging from sub-nanomolar to nanomolar range, and the inhibitory potency of the most promising agents was higher than that of the reference drugs (rivastigmine and tacrine). The kinetic studies of the most active compound 3a revealed competitive type of AChE inhibition. Moreover, all target compounds were more potent inhibitors of human AChE than tacrine with the most active compound 3b (IC50 =19nM). Compound 3a was also tested and displayed inhibitory potency against AChE-induced Aβ 1–42 aggregation (80.6% and 91.3% at 50μM and 100μM screening concentration, respectively). Moreover, cytotoxicity assay performed on A549 cells did not indicate toxicity of this agent. Compound 3a is a promising candidate for further development of novel multi-functional agents in the therapy of AD. Graphical abstract image
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Synthesis and carbonic anhydrase I, II, IX and XII inhibitory activity of sulfamates incorporating piperazinyl-ureido moieties ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Cenzo Congiu, Valentina Onnis, Alessandro Deplano, Gianfranco Balboni, Mariangela Ceruso, Claudiu T. Supuran A series of sulfamates were synthesized using as lead compound SLC-0111, a sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in Phase I clinical trials. The new derivatives incorporated ureido moieties as spacers between the benzene sulfamate fragment which binds the zinc ion from the active site, and the tail of the inhibitor, but the urea moieties were part of a substituted piperazine ring system. The derivatives (and some of their phenol precursors) were tested for the inhibition of the cytosolic, hCA I and II (off target isoforms) and the trans-membrane, tumor-associated hCA IX and XII enzymes (anticancer drug targets). Generally hCA I was not effectively inhibited, whereas many low nanomolar inhibitors were evidenced against hCA II (K Is in the range of 1.0–94.4nM), IX (K Is in the range of 0.91–36.9nM), and XII (K Is in the range of 1.0–84.5nM). The best substitution fragments at the piperazine ring included the following moieties: 3-methylphenyl, 2,3-dimethylphenyl, 4-methoxyphenyl, 6-arylpyrimidine-2-yl. Graphical abstract image
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Evaluation of transition-state mimics in a superior BACE1 cleavage sequence as peptide-mimetic BACE1 inhibitors ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Yasunao Hattori, Kazuya Kobayashi, Ayaka Deguchi, Yukie Nohara, Tomomi Akiyama, Kenta Teruya, Akira Sanjoh, Atsushi Nakagawa, Eiki Yamashita, Kenichi Akaji A superior substrate sequence for BACE1 containing transition-state mimics at the scissile site was evaluated as a protease inhibitor. Hydroxymethylcarbonyl (HMC) and hydroxyethylamine (HEA) isosteres were selected as the transition state mimics, and incorporated into the scissile site of the superior sequence covering the P4 to P1’ sites (Glu-Ile-Thi-Thi*Nva; *denotes the cleavage site). Isosteres having different absolute configurations of the hydroxyl group were synthesized separately, and the effect of the configuration was evaluated. Configuration of the hydroxyl group of each isostere showed a marked effect on the inhibitory activity; anti-configuration to the scissile site substituent had potent inhibitory activity in an HMC-type inhibitor, whereas anti-configuration of HEA-type inhibitors showed no inhibitory activity. Structural evaluations based on X-ray crystallographic analyses of recombinant BACE1 in complex with each inhibitor provided insights into the protein–ligand interactions, especially at the prime sites. Graphical abstract image
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Synthesis of CNS active thyrotropin-releasing hormone (TRH)-like peptides: Biological evaluation and effect on cognitive impairment induced by cerebral ischemia in mice ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Chhuttan L. Meena, Avinash Thakur, Prajwal P. Nandekar, Abhay T. Sangamwar, Shyam S. Sharma, Rahul Jain Thyrotropin-releasing hormone (TRH)-like peptides were synthesized by replacing critical histidine and pGlu residues in the native peptide. The peptides were evaluated in vitro for receptor binding activity assay and in the cell functional assay; the peptides exhibit selective basal signaling agonist behavior toward TRH-R2. For example, peptides 8a, 8b, 8c, 8f, 8h, 8l and 12d activated TRH-R2 with potency (EC50) of 0.53μM, 0.048μM, 0.05μM, 0.006μM, 0.31μM, 0.034μM and 0.004μM, respectively. In contrast for signaling activation of TRH-R1, the same peptide required higher concentration of 19.35μM, 3.98μM, 2.54μM, 0.287μM, 11.28μM, 0.986μM and 0.944μM, respectively. The results showed that peptides were 36.5, 82.9, 50.8, 47.8, 36.3, 32.6 and 235-fold selective to TRH-R2 receptor subtype. The peptides were investigated for CNS activity at 10μmol/kg in pentobarbital-induced sleep assay study. Peptides 8c (16.5±1.4min) and 8l (16.5±2.1min) displayed excellent CNS activity. In an in vivo study, peptide 8c did not cause significant change in the rat plasma TSH levels. The peptide 8c was further investigated for neuroprotective potential, and significantly reduced infracts volume and neurological score in the focal cerebral ischemia model in mice. Peptide 8c also significantly lowered MDA levels, indicating reduction of oxidative and enhanced percentage cell survival in CA1 region, when compared to ischemic brain. Graphical abstract image
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Imine/amide–imidazole conjugates derived from 5-amino-4-cyano-N1-substituted benzyl imidazole: Microwave-assisted synthesis and anticancer activity via selective topoisomerase-II-α inhibition ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Arvind Negi, Jimi Marin Alex, Suyog M. Amrutkar, Ashish T. Baviskar, Gaurav Joshi, Sandeep Singh, Uttam C. Banerjee, Raj Kumar Microwave-accelerated synthesis and anticancer activity of novel imine/amide–imidazole conjugates derived from 5-amino-4-cyano-N1-substituted benzyl imidazole against a panel of seven cancer cell lines are reported for the first time. Compounds ARK-4, 10 and 12 in the series show promising in vitro anti proliferative activity with low micromolar IC50 values against A-459 (lung), Hep-G2 (liver) and H-460 (liver) cancer cell lines. Compounds caused the increase in ROS levels as well as mitochondrial membrane depolarization, which might induce apoptosis. Further, mechanistic interventions on biological and molecular modeling data supported that compounds inhibited topoisomerase-II selectively. Graphical abstract image
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Modification of N-(6-(2-methoxy-3-(4-fluorophenylsulfonamido)pyridin-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetamide as PI3Ks inhibitor by replacement of the acetamide group with alkylurea ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Xiao-Meng Wang, Shuai Mao, Lei Cao, Xiao-Xiao Xie, Min-Hang Xin, Jia-Fang Lian, Yong-Xiao Cao, San-Qi Zhang N-(6-(2-Methoxy-3-(4-fluorophenylsulfonamido)pyridin-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetamide exhibits remarkable anticancer effects and toxicity when orally administrated. In present study, alkylurea moiety replaced the acetamide group in the compound and a series of 1-alkyl-3-(6-(2-methoxy-3-sulfonylaminopyridin-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)urea derivatives were synthesized. The antiproliferative activities of the synthesized compounds in vitro were evaluated against four human cancer cell lines. Several compounds with potent antiproliferative activities were tested for their acute oral toxicity and their inhibitory activity against PI3Ks and mTOR. The results indicate that the compound attached a alkylurea or 2-(dialkylamino)ethylurea moiety at the 2-position of [1,2,4]triazolo[1,5-a]pyridine can retain the antiproliferative activity and the inhibitory activity against PI3Ks and mTOR. In addition, their acute oral toxicity reduced dramatically. Moreover, the results also indicate that compound 1e can efficaciously inhibit tumor growth in a mice S180 model. These findings suggest that title compounds can serve as potent PI3K inhibitors and effective anticancer agents with low toxicity. Graphical abstract image
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Antiproliferative and apoptosis-inducing activities of novel naphthalimide–cyclam conjugates through dual topoisomerase (topo) I/II inhibition ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Shaoying Tan, Deheng Sun, Jiankun Lyu, Xiao Sun, Fangshu Wu, Qiang Li, Yiqi Yang, Jianxu Liu, Xin Wang, Zhuo Chen, Honglin Li, Xuhong Qian, Yufang Xu A novel series of naphthalimide–cyclam conjugates were designed and synthesized. Among them, compounds 4c, 4d, 8c and 8d which bearing long lipophilic alkyl chains, displayed comparable or more potent cytotoxic activities against human tumor cell lines than amonafide. Furthermore, the four compounds were proved to possess strong inhibition against both topoisomerase I and II. The representative compound 8c exhibited moderate DNA intercalation activity. Molecular modeling studies identified the possible interaction of compound 8c with the molecular target by forming topoisomerase/DNA/drug ternary complex. Finally, derivatives with long lipophilic alkyl chains could efficiently induce apoptosis. Graphical abstract image
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A-ring substituted 17β-arylsulfonamides of 17β-aminoestra-1,3,5(10)-trien-3-ol as highly potent reversible inhibitors of steroid sulfatase ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Yaser A. Mostafa, Braden Kralt, Praveen P.N. Rao, Scott D. Taylor Steroid sulfatase (STS) catalyzes the hydrolysis of the sulfate ester group in biologically inactive sulfated steroids to give biologically active steroids. Inhibitors of STS are considered to be potential therapeutics for treating hormone-dependent cancers such as ER+ breast cancer. A series of 4-substituted 17β-arylsulfonamides of 17β-aminoestra-1,3,5(10)-trien-3-ol were prepared and examined as STS inhibitors. The presence of a NO2 or Br at the 2-position of the A-ring resulted in a decrease in potency compared to their A-ring-unsubstituted counterparts. However the presence of a nitro group or fluorine atom at the 4-position of the A-ring resulted in an increase in potency and one of these compounds exhibited a K i app value of 1nM. Modeling studies provided insight into how these compounds interact with active site residues. The anti-proliferative activity of the 3′-Br, 3′-CF3, 4-NO2-3′-Br and 4-NO2-3′-CF3 derivatives were examined using the NCI 60-cell-line panel and found to have mean graph midpoint values of 1.9–3.4μM. Graphical abstract image
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Synthesis, nicotinic acetylcholine receptor binding, in vitro and in vivo pharmacology properties of 3′-(substituted pyridinyl)-deschloroepibatidine analogs ()
Publication date: 1 September 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 17 Author(s): Pauline W. Ondachi, Zhuo Ye, Ana H. Castro, Charles W. Luetje, M. Imad Damaj, S. Wayne Mascarella, Hernán A. Navarro, F. Ivy Carroll Over the last several years we have synthesized and studied the in vitro and in vivo nAChR pharmacological properties of epibatidine (4) analogs. In this study we report the synthesis, nAChR in vitro and in vivo pharmacological properties of 3′-(substituted pyridinyl)-deschloroepibatidine analogs (5a–e and 6a–e). All of the analogs had high binding affinity for α4β2∗-nAChRs. Several of the analogs were potent antagonists of α4β2-nAChRs in in vitro efficacy tests and were potent antagonists of nicotine-induced antinociception in the mouse tail-flick test. Compound 6b had a K i =0.13nM in the binding assay, 25- and 46-fold selectivity for the α4β2∗-nAChR relative to the α3β4- and α7-nAChR, respectively, in the in vitro efficacy test and an AD50 =0.13μg/kg in the tail-flick test. Combined with favorable calculated physiochemical properties compared to varenicline, our findings suggest that 6b should be considered for development as a potential pharmacotherapy for treating nicotine addiction and other CNS disorders. Graphical abstract image
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