Bioorganic & Medicinal Chemistry

Discovery and structure-activity relationship studies of irreversible benzisothiazolinone-based inhibitors against Staphylococcus aureus sortase A transpeptidase ()
Publication date: Available online 16 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Dmitrijs Zhulenkovs , Zhanna Rudevica , Kristaps Jaudzems , Maris Turks , Ainars Leonchiks Gram-positive bacteria, in general, and staphylococci, in particular, are the widespread cause of nosocomial and community-acquired infections. The rapid evolvement of strains resistant to antibiotics currently in use is a serious challenge. Novel antimicrobial compounds have to be developed to fight these resistant bacteria, and sortase A, a bacterial cell wall enzyme, is a promising target for novel therapies. As a transpeptidase that covalently attaches various virulence factors to the cell surface, this enzyme plays a crucial role in the ability of bacteria to invade the host’s tissues and to escape the immune response. In this study we have screened a small molecule library against recombinant Staphylococcus aureus sortase A using an in vitro FRET-based assay. The selected hits were validated by NMR methods in order to exclude false positives and to analyze the reversibility of inhibition. Further structural and functional analysis of the best hit allowed the identification of a novel class of benzisothiazolinone-based compounds as potent and promising sortase inhibitors. Graphical abstract image Highlights
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Synthesis of Triazole Derivatives of Schiff Bases: Novel Inhibitors of Nucleotide Pyrophosphatase / Phosphodiesterase-1 ()
Publication date: Available online 16 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Khalid Mohammed Khan , Salman Siddiqui , Muhammad Saleem , Muhammad Taha , Syed Muhammad Saad , Shahnaz Perveen , M. Iqbal Choudhary A series of Schiff base triazoles 1-25 was synthesized and evaluated for their nucleotide pyrophosphatase/phosphodiesterase-1 inhibitory activities. Among twenty-five compounds, three compounds 10 (IC50 = 132.20 ± 2.89 μM), 13 (IC50 = 152.83 ± 2.39 μM), and 22 (IC50 = 251.0 ± 6.64 μM) were identified as potent inhibitors with superior activities than the standard EDTA (IC50 = 277.69 ± 2.52 μM). The newly identified inhibitors can open a new avenue for the development of treatment of phosphodiesterase-I related disorders. These compounds were also evaluated for carbonic anhydrase, acetylcholinesterase and butyrylcholinesterase inhibitory potential and were found to be inactive. The compounds showed non-toxic effect towards PC3 cell lines. Graphical abstract image
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Synthesis and pharmacological evaluation of optically pure, novel carbonyl guanidine derivatives as dual 5-HT2B and 5-HT7 receptor antagonists ()
Publication date: Available online 16 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Ayako Moritomo , Hiroyoshi Yamada , Takaho Matsuzawa-Nomura , Toshihiro Watanabe , Hirotsune Itahana , Makoto Oku , Shinobu Akuzawa , Minoru Okada A series of 9-disubstituted N-(9H-fluorene-2-carbonyl)guanidine derivatives have been discovered as potent and orally active dual 5-HT2B and 5-HT7 receptor antagonists. Upon screening several compounds, N-(diaminomethylene)-4’,5’-dihydro-3’H-spiro[fluorene-9,2’-furan]-2-carboxamide (17) exhibited potent affinity for both 5-HT2B (K i = 5.1 nM) and 5-HT7 (K i = 1.7 nM) receptors with high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Optical resolution of the intermediate carboxylic acid 16 via the formation of diastereomeric salts using chiral alkaloids gave the optically pure compounds (R)-17 and (S)-17. Both enantiomers suppressed 5-HT-induced dural protein extravasation in guinea pigs in a dose-dependent manner and the amount of leaked protein was suppressed to near normal levels when orally administrated at 10 mg/kg. (R)-17 and (S)-17 were therefore selected as candidates for human clinical trials. Graphical abstract image
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Synthesis of chiral chloroquine and its analogues as antimalarial agents ()
Publication date: Available online 16 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Manish Sinha , Vasanth R. Dola , Awakash Soni , Pooja Agarwal , Kumkum Srivastava , Wahajul Haq , Sunil K. Puri , Seturam B. Katti In this investigation, we describe a new approach to chiral synthesis of chloroquine and its analogues. All tested compounds displayed potent activity against chloroquine sensitive as well as chloroquine resistant strains of Plasmodium falciparum in vitro and Plasmodium yoelli in vivo. Compounds S-13b, S-13c, S-13d and S-13i displayed excellent in vitro antimalarial activity with an IC50 value of 56.82, 60.41, 21.82 and 7.94 nM, respectively in the case of resistant strain. Furthermore, compounds S-13a, S-13c and S-13d showed in vivo suppression of 100% parasitaemia on day 4 in the mouse model against Plasmodium yoelii when administered orally. These results underscore the application of synthetic methodology and need for further lead optimization. Graphical abstract image
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Structure-guided design and development of novel benzimidazole class of compounds targeting DNA GyraseB enzyme of Staphylococcus aureus ()
Publication date: Available online 16 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Renuka Janupally , Variam Ullas Jeankumar , Karyakulam Andrews Bobesh , Vijay Soni , Parthiban Brindha Devi , Venkat Koushik Pulla , Priyanka Suryadevara , Keerthana Sharma Chennubhotla , Pushkar Kulkarni , Perumal Yogeeswari , Dharmarajan Sriram The gyraseB subunit of Staphylococcus aureus DNA gyrase is a well-established and validated target though less explored for the development of novel antimicrobial agents. Starting from the available structural information in PDB (3TTZ), we identified a novel series ofbenzimidazoleused as inhibitorsof DNA gyrase B with low micromolar inhibitory activity by employing structure-based drug design strategy. Subsequently, this chemical class of DNA gyrase inhibitors was extensively investigated biologically through in vitro assays, biofilm inhibition assays, cytotoxicity, and in vivo studies. The binding affinity of the most potent inhibitor 10 was further ascertained biophysically through differential scanning fluorimetry. Further, the most potent analogues did not show any signs of cardiotoxicity in Zebra fish ether-a-go-go-related gene (zERG), a major breakthrough among the previously reported cardiotoxic gyrase B inhibitors. Graphical abstract image
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Structure-Activity Relationship Study of Arbidol Derivatives as Inhibitors of Chikungunya Virus Replication ()
Publication date: Available online 16 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Antonia Di Mola , Antonella Peduto , Annalisa La Gatta , Leen Delang , Boris Pastorino , Johan Neyts , Pieter Leyssen , Mario de Rosa , Rosanna Filosa Chikungunya virus (CHIKV), a mosquito-borne arthrogenic Alphavirus, causes an acute febrile illness in humans that is accompanied by severe joint pains. In many cases, the infection leads to persistent arthralgia, which may last for weeks to several years. The re-emergence of this infection in the early 2000’s was exemplified by numerous outbreaks in the eastern hemisphere. Since then, the virus is rapidly spreading. Currently, no drugs have been approved or are in development for the treatment of CHIKV, which makes this viral infection particularly interesting for academic medicinal chemistry efforts. Several molecules have already been identified that inhibit CHIKV replication in phenotypic virus-cell-based assays. One of these is arbidol, a molecule that already has been licensed for the treatment of influenza A and B virus infections. For structural optimization, a dedicated libraries of 43 indole-based derivatives were evaluated leading to more potent analogues (IIIe and IIIf) with anti-Chikungunya virus (CHIKV) activities higher than those of the other derivatives, including the lead compound, and with a selective index of inhibition 13.2 and 14.6 respectively, higher than that of ARB (4.6). Graphical abstract image
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Synthesis and in vitro evaluation of radioiodinated indolequinones targeting NAD(P)H: quinone oxidoreductase 1 for internal radiation therapy ()
Publication date: Available online 16 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Junichi Sasaki , Kohei Sano , Masayori Hagimori , Mai Yoshikawa , Minoru Maeda , Takahiro Mukai NAD(P)H: quinone oxidoreductase 1 (NQO1) is an obligate two-electron reductase and is highly expressed in many human solid cancers. Because NQO1 can be induced immediately after exposure to ionizing radiation, we aimed to develop an NQO1-targeted radiolabeled agent to establish a novel internal radiation therapy that amplifies the therapeutic effects when combined with external radiation therapy. We designed three NQO1-targeted radioiodinated compounds including two ether linkage compounds ([125I]1 and [125I]2) and a sulfide linkage compound ([125I]3) based on the selective binding of indolequinone analogs to the active site of NQO1 by the stacking effect. These compounds were successfully prepared using an oxidative iododestannylation reaction with high radiochemical yields and purity. In NQO1-expressing tumor cells, [125I]1 and [125I]2 were readily metabolized to p-[125I]iodophenol or m-[125I]iodophenol and [125I]I−, whereas over 85% of the initial radioactivity of [125I]3 was observed as an intact form at 1 h after incubation. The cellular uptake of [125I]3 was significantly higher than those of [125I]1 and [125I]2. The uptake of [125I]3 was specific and was dependent on the expression of NQO1. These data suggest that the novel NQO1-targeted radioiodinated compound [125I]3 could be used as a novel internal radiation agent for the treatment of cancer Graphical abstract image
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Piperazine and piperidine carboxamides and carbamates as inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) ()
Publication date: Available online 16 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Jani Korhonen , Anne Kuusisto , John van Bruchem , Jayendra Z. Patel , Tuomo Laitinen , Dina Navia-Paldanius , Jarmo T. Laitinen , Juha R. Savinainen , Teija Parkkari , Tapio J. Nevalainen The key hydrolytic enzymes of the endocannabinoid system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), are potential targets for various therapeutic applications. In this paper, we present more extensively the results of our previous work on piperazine and piperidine carboxamides and carbamates as FAAH and MAGL inhibitors. The best compounds of these series function as potent and selective MAGL/FAAH inhibitors or as dual FAAH/MAGL inhibitors at nanomolar concentrations. Graphical abstract image
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Editorial board ()
Publication date: 15 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 18
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Graphical contents list ()
Publication date: 15 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 18
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The cytoskeleton and its interactions with small molecules ()
Publication date: 15 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 18 Author(s): Karl-Heinz Altmann
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Microtubule-stabilizing agents as potential therapeutics for neurodegenerative disease ()
Publication date: 15 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 18 Author(s): Kurt R. Brunden , John Q. Trojanowski , Amos B. Smith III , Virginia M.-Y. Lee , Carlo Ballatore Microtubules (MTs), cytoskeletal elements found in all mammalian cells, play a significant role in cell structure and in cell division. They are especially critical in the proper functioning of post-mitotic central nervous system neurons, where MTs serve as the structures on which key cellular constituents are trafficked in axonal projections. MTs are stabilized in axons by the MT-associated protein tau, and in several neurodegenerative diseases, including Alzheimer’s disease, frontotemporal lobar degeneration, and Parkinson’s disease, tau function appears to be compromised due to the protein dissociating from MTs and depositing into insoluble inclusions referred to as neurofibrillary tangles. This loss of tau function is believed to result in alterations of MT structure and function, resulting in aberrant axonal transport that likely contributes to the neurodegenerative process. There is also evidence of axonal transport deficiencies in other neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington’s disease, which may result, at least in part, from MT alterations. Accordingly, a possible therapeutic strategy for such neurodegenerative conditions is to treat with MT-stabilizing agents, such as those that have been used in the treatment of cancer. Here, we review evidence of axonal transport and MT deficiencies in a number of neurodegenerative diseases, and summarize the various classes of known MT-stabilizing agents. Finally, we highlight the growing evidence that small molecule MT-stabilizing agents provide benefit in animal models of neurodegenerative disease and discuss the desired features of such molecules for the treatment of these central nervous system disorders. Graphical abstract image
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Microtubule-targeting agents are clinically successful due to both mitotic and interphase impairment of microtubule function ()
Publication date: 15 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 18 Author(s): Jessica J. Field , Arun Kanakkanthara , John H. Miller Microtubules undergo continual dynamic changes in mitotic cells as the mitotic spindle forms and is broken down and in interphase cells where they play a central role in intracellular trafficking, cell signaling, cell migration, and angiogenesis. Compounds that target the microtubule have been hugely successful in the clinic as chemotherapeutics, and this success is likely due to their ability to target cells regardless of their cell cycle stage. Additionally, new generation antibody-conjugated microtubule-targeting agents are improving the targeting of these drugs to tumors. Microtubule-targeting agents have been shown to have anti-angiogenic and vascular-disrupting properties as well as effects on cellular migration, intracellular trafficking, and cell secretion. There are a number of these compounds in development that target the vasculature, and different formulations of clinically used drugs are being developed to take advantage of these anti-angiogenic properties. Microtubule-targeting agents have also been shown to have the potential to treat neurodegenerative diseases, such as Alzheimer’s disease. Thus, drugs that target the microtubule will continue to have a major impact in oncology not only as anti-mitotics but also as potent inhibitors of interphase functions, and in future may also prove to be effective in reducing the consequences of neurodegenerative disease. Graphical abstract image
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Drug discovery targeting cell division proteins, microtubules and FtsZ ()
Publication date: 15 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 18 Author(s): Iwao Ojima , Kunal Kumar , Divya Awasthi , Jacob G. Vineberg Eukaryotic cell division or cytokinesis has been a major target for anticancer drug discovery. After the huge success of paclitaxel and docetaxel, microtubule-stabilizing agents (MSAs) appear to have gained a premier status in the discovery of next-generation anticancer agents. However, the drug resistance caused by MDR, point mutations, and overexpression of tubulin subtypes, etc., is a serious issue associated with these agents. Accordingly, the discovery and development of new-generation MSAs that can obviate various drug resistances has a significant meaning. In sharp contrast, prokaryotic cell division has been largely unexploited for the discovery and development of antibacterial drugs. However, recent studies on the mechanism of bacterial cytokinesis revealed that the most abundant and highly conserved cell division protein, FtsZ, would be an excellent new target for the drug discovery of next-generation antibacterial agents that can circumvent drug-resistances to the commonly used drugs for tuberculosis, MRSA and other infections. This review describes an account of our research on these two fronts in drug discovery, targeting eukaryotic as well as prokaryotic cell division. Graphical abstract image
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Taxanes with high potency inducing tubulin assembly overcome tumoural cell resistances ()
Publication date: 15 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 18 Author(s): Ruth Matesanz , Chiara Trigili , Javier Rodríguez-Salarichs , Ilaria Zanardi , Benet Pera , Aurora Nogales , Wei-Shuo Fang , Jesús Jímenez-Barbero , Ángeles Canales , Isabel Barasoain , Iwao Ojima , J. Fernando Díaz We have found that four taxanes with chemical modifications at positions C10 and C13 were active against all types of taxane resistant cell lines, resistant by P-gp overexpression, by mutations in the β-tubulin binding site or by overexpression of the highly dynamic βIII-tubulin isotype. We have characterized the interaction of taxanes with high activity on chemotherapy resistant tumoural cells with microtubules, and also studied their cellular effects. The biochemical property enhanced in comparison with other taxanes is their potency at inducing tubulin assembly, despite the fact that their interactions with the microtubule binding sites (pore and luminal) are similar as studied by NMR and SAXS. A differential interaction with the S7–S9 loop (M-loop) is responsible for their enhanced assembly induction properties. The chemical changes in the structure also induce changes in the thermodynamic properties of the interaction, indicating a higher hydrophilicity and also explaining their properties on P-gp and βIII overexpressing cells and on mutant cells. The effect of the compounds on the microtubular network is different from those observed with the classical (docetaxel and paclitaxel) taxanes, inducing different bundling in cells with microtubules being very short, indicating a very fast nucleation effect and reflecting their high assembly induction power. Graphical abstract image
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Taccalonolide microtubule stabilizers ()
Publication date: 15 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 18 Author(s): Jing Li , April L. Risinger , Susan L. Mooberry This review focuses on a relatively new class of microtubule stabilizers, the taccalonolides. The taccalonolides are highly oxygenated pentacyclic steroids isolated from plants of the genus Tacca. Originally identified in a cell-based phenotypic screen, the taccalonolides have many properties similar to other microtubule stabilizers. They increase the density of interphase microtubules, causing microtubule bundling, and form abnormal multi-polar mitotic spindles leading to mitotic arrest and, ultimately, apoptosis. However, the taccalonolides differ from other microtubule stabilizers in that they retain efficacy in taxane resistant cell lines and in vivo models. Binding studies with the newly identified, potent taccalonolide AJ demonstrated covalent binding to β-tubulin at or near the luminal and/or pore taxane binding site(s) which stabilizes microtubule protofilaments in a unique manner as compared to other microtubule stabilizers. The isolation and semi-synthesis of 21 taccalonolides helped to identify key structure activity relationships and the importance of multiple regions across the taccalonolide skeleton for optimal biological potency. Graphical abstract image
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Design, synthesis and biological evaluation of 3,5-disubstituted 2-amino thiophene derivatives as a novel class of antitumor agents ()
Publication date: 15 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 18 Author(s): Romeo Romagnoli , Pier Giovanni Baraldi , Carlota Lopez-Cara , Maria Kimatrai Salvador , Delia Preti , Mojgan Aghazadeh Tabrizi , Jan Balzarini , Peter Nussbaumer , Marcella Bassetto , Andrea Brancale , Xian-Hua Fu , Yang-Gao , Jun Li , Su-Zhan Zhang , Ernest Hamel , Roberta Bortolozzi , Giuseppe Basso , Giampietro Viola In search of new compounds with strong antiproliferative activity and simple molecular structure, we designed a novel series of agents based on the 2-amino-3-alkoxycarbonyl/cyano-5-arylethylthiophene scaffold. The presence of the ethyl spacer between the 2′,5′-dimethoxyphenyl and the 5-position of the thiophene ring, as well as the number and location of methoxy substitutents on the phenyl ring, played a profound role in affecting the antiproliferative activity. Among the synthesized compounds, we identified the 2-amino-3-cyano-[2-(2,5-dimethoxyphenyl)ethyl] thiophene 2c as the most promising derivative against a wide panel of cancer cell lines (IC50 =17–130nM). The antiproliferative activity of this compound appears to correlate well with its ability to inhibit tubulin assembly and the binding of colchicine to tubulin. Moreover 2c, as determined by flow cytometry, strongly induced arrest in the G2/M phase of the cell cycle, and annexin-V and propidium iodide staining indicate that cell death proceeds through an apoptotic mechanism that follows the intrinsic mitochondrial pathway. Graphical abstract image
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Podoverine A—a novel microtubule destabilizing natural product from the Podophyllum species ()
Publication date: 15 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 18 Author(s): Tuyen Thi Ngoc Tran , Claas Gerding-Reimers , Beate Schölermann , Bettina Stanitzki , Thomas Henkel , Herbert Waldmann , Slava Ziegler Natural products represent compound classes with high chemical and structural diversity and various biological activities. Libraries based on natural products are valuable starting point in the search for novel biologically active substances. Here we report on the identification of the natural product podoverine A from the plant Podophyllum versipelle Hance as a novel tubulin-acting agent. A natural product compound collection was subjected to a high-content screen that monitors changes in cytoskeleton and DNA and podoverine A was identified as inhibitor of mitosis. This natural product causes mitotic arrest and inhibits microtubule polymerization in vitro and in cells by targeting the vinca binding site on tubulin. Graphical abstract image
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Pharmacological characterization of actin-binding (−)-Doliculide ()
Publication date: 15 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 18 Author(s): Florian Foerster , Simone Braig , Tao Chen , Karl-Heinz Altmann , Angelika M. Vollmar Natural compounds offer a broad spectrum of potential drug candidates against human malignancies. Several cytostatic drugs, which are in clinical use for decades, derive directly from natural sources or are synthetically optimized derivatives of natural lead structures. An eukaryote target molecule to which many natural derived anti-cancer drugs bind to is the microtubule network. Of similar importance for the cell is the actin cytoskeleton, responsible for cell movements, migration of cells and cytokinesis. Nature provides also a broad range of compounds directed against actin as intracellular target, but none of these actin-targeting compounds has ever been brought to clinical trials. One reason why actin-binding compounds have not yet been considered for further clinical investigations is that little is known about their pharmacological properties in cancer cells. Herein, we focused on the closer characterization of doliculide, an actin binding natural compound of marine origin in the breast cancer cell lines MCF7 and MDA-MB-231. We used fluorescence-recovery-after-photobleaching (FRAP) analysis to determine doliculide’s early effects on the actin cytoskeleton and rhodamin–phalloidin staining for long-term effects on the actin CSK. After validating the disruption of the actin network, we further investigated the functional effects of doliculide. Doliculide treatment leads to inhibition of proliferation and impairs the migratory potential. Finally, we could also show that doliculide leads to the induction of apoptosis in both cell lines. Our data for the first time provide a closer characterization of doliculide in breast cancer cells and propagate doliculide for further investigations as lead structure and potential therapeutic option as actin-targeting compound. Graphical abstract image Highlights
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Design, synthesis and evaluation of novel tacrine-(β-carboline) hybrids as multifunctional agents for the treatment of Alzheimer’s disease ()
Publication date: Available online 15 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Jin-Shuai Lan , Sai-Sai Xie , Su-Yi Li , Long-Fei Pan , Xiao-Bing Wang , Ling-Yi Kong A series of tacrine-(β-carboline) hybrids (11a-q) were designed, synthesized and evaluated as multifunctional cholinesterase inhibitors against Alzheimer’s disease (AD). In vitro studies showed that most of them exhibited significant potency to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (BuChE) and self-induced β-amyloid (Aβ) aggregation, Cu2+-induced Aβ (1-42) aggregation, and to chelate metal ions. Especially, 11l presented the greatest ability to inhibit cholinesterase (IC50, 21.6 nM for eeAChE, 63.2 nM for hAChE and 39.8 nM for BuChE), good inhibition of Aβ aggregation (65.8% at 20 μM) and good antioxidant activity (1.57 trolox equivalents). Kinetic and molecular modeling studies indicated that 11l was a mixed-type inhibitor, binding simultaneously to the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 11l could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). These results suggested that 11l might be an excellent multifunctional agent for AD treatment. Graphical abstract image
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Celastrol inhibits Plasmodium falciparum enoyl-acyl carrier protein reductase ()
Publication date: Available online 15 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Lorillee C. Tallorin , Jacob D. Durrant , Quynh G. Nguyen , J. Andrew McCammon , Michael D. Burkart Enoyl-acyl carrier protein reductase (ENR), a critical enzyme in type II fatty acid biosynthesis, is a promising target for drug discovery against hepatocyte-stage Plasmodium falciparum. In order to identify PfENR-specific inhibitors, we docked 70 FDA-approved, bioactive, and/or natural product small molecules known to inhibit the growth of whole-cell blood-stage P. falciparum into several PfENR crystallographic structures. Subsequent in vitro activity assays identified a noncompetitive low-micromolar PfENR inhibitor, celastrol, from this set of compounds. Graphical abstract image
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Synthesis of iboga-like isoquinuclidines: Dual opioid receptors agonists having antinociceptive properties ()
Publication date: Available online 15 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Tuhin Suvro Banerjee , Sibasish Paul , Surajit Sinha , Sumantra Das Some novel iboga-analogues consisting of benzofuran moiety and dehydroisoquinuclidine ring connected by –CH2-, (CH2)2 and (CH2)3 linkers have been synthesized with the view to develop potential antinociceptive drugs. The compounds 14 and 21 showed binding at the μ-opioid receptor (MOR), while the compound 11a exhibited dual affinities at both MOR and κ-opioid receptor (KOR). MAP kinase activation indicated all three compounds have opioid agonistic properties. The presence of a double bond and endo-methylcarboxylate group in the dehydroisoquinuclidine ring and the benzofuran and methylene spacer appeared to be essential for opioid receptor binding. Further studies demonstrated 11a caused significant antinociception in mice in the hot-plate test which was comparable to that produced by morphine. The compound 11a was also found to be nontremorigenic unlike various iboga congeners. This study identifies a new pharmacophore which may lead to the development of suitable substitute of morphine in the treatment of pain. Graphical abstract image
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Neuraminidase inhibitory activities of quaternary isoquinoline alkaloids from Corydalis turtschaninovii rhizome ()
Publication date: Available online 15 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Jang Hoon Kim , Young Bae Ryu , Woo Song Lee , Young Ho Kim Clostridium perfringens is a Gram-positive spore-forming bacterium that causes food poisoning. The neuraminidase (NA) protein of C. perfringens plays a pivotal role in bacterial proliferation and is considered a novel antibacterial drug target. Based on screens for novel NA inhibitors, a 95% EtOH extract of Corydalis turtschaninovii rhizome showed NA inhibitory activity (68% at 30 μg/ml), which resulted in the isolation of 10 isoquinoline alkaloids; namely, palmatine (1), berberine (2), coptisine (3), pseudodehydrocorydaline (4), jatrorrhizine (5), dehydrocorybulbine (6), pseudocoptisine (7), glaucine (8), corydaline (9) and tetrahydrocoptisine (10). Interestingly, seven quaternary isoquinoline alkaloids 1-7 (IC50 = 12.8±1.5 - 65.2±4.5 μM) showed stronger NA inhibitory activity than the tertiary alkaloids 8-10. In addition, highly active compounds 1 and 2 showed reversible non-competitive behavior based on a kinetic study. Molecular docking simulations using the Autodock 4.2 software increased our understanding of receptor–ligand binding of these compounds. In addition, we demonstrated that compounds 1 and 2 suppressed bacterial growth. Graphical abstract image
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Synthesis of IB-01212 by Multiple N-Methylations of Peptide Bonds ()
Publication date: Available online 8 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Ryota Nabika , Shinya Oishi , Ryosuke Misu , Hiroaki Ohno , Nobutaka Fujii There are many natural peptides with multiple N-methylamino acids that exhibit potent attractive biological activities. N-Methylation of a peptide bond(s) is also one of the standard approaches in medicinal chemistry of bioactive peptides, to improve the potency and physicochemical properties, especially membrane permeability. In this study, we investigated a facile synthesis process of N-methylated peptides via simultaneous N-methylation of several peptide bonds in the presence of peptide bonds that were not to be methylated. As a model study, we investigated the synthesis of the antiproliferative depsipeptide, IB-01212. We used a pseudoproline to protect the non-methylated peptide bond during a simultaneous N-methylation with MeI-Ag2O. Using further manipulations including a dimerization/cyclization process, IB-01212 and its derivatives were successfully synthesized. A preliminary structure-activity relationship study demonstrated that the symmetric structure contributed to the potent cytotoxic activity of IB-01212. Graphical abstract image
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Altertoxins with potent anti-HIV activity from Alternaria tenuissima QUE1Se, a fungal endophyte of Quercus emoryi ()
Publication date: Available online 8 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Bharat P. Bashyal , Brian P. Wellensiek , Rajesh Ramakrishnan , Stanley H. Faeth , Nafees Ahmad , A.A. Leslie Gunatilaka Screening of a small library of natural product extracts derived from endophytic fungi of the Sonoran desert plants in a cell-based anti-HIV assay involving T-cells infected with the HIV-1 virus identified the EtOAc extract of a fermentation broth of Alternaria tenuissima QUE1Se inhabiting the stem tissue of Quercus emoryi as a promising candidate for further investigation. Bioactivity-guided fractionation of this extract led to the isolation and identification of two new metabolites, altertoxins V (1) and VI (2) together with the known compounds, altertoxins I (3), II (4), and III (5). The structures of 1 and 2 were determined by detailed spectroscopic analysis and those of 3–5 were established by comparison with reported data. When tested in our cell-based assay at concentrations insignificantly toxic to T-cells, altertoxins V (1), I (3), II (4), and III (5) completely inhibited replication of the HIV-1 virus at concentrations of 0.50, 2.20, 0.30, and 1.50 μM respectively. Our findings suggest that the epoxyperylene structural scaffold in altertoxins may be manipulated to produce potent anti-HIV therapeutics. Graphical abstract image
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Design, Synthesis and Biological Activity of Flavonoid Derivatives as Selective Agonists for Neuromedin U 2 Receptor ()
Publication date: Available online 8 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Ming-Liang Ma , Ming Li , Jiao-Jiao Gou , Tian-Yu Ruan , Hai-Shan Jin , Ling-Hong Zhang , Liang-Chun Wu , Xiao-Yan Li , Ying-He Hu , Ke Wen , Zheng Zhao Central neuromedin U 2 receptor (NMU2R) plays important roles in the regulation of food intake and body weight. Identification of NMU2R agonists may lead to the development of pharmaceutical agents to treat obesity. Based on the structure of rutin, a typical flavonoid and one of the NMU2R agonists we previously identified from an in-house made natural product library, 30 flavonoid derivatives have been synthesized and screened on a cell-based reporter gene assay. A number of compounds were found to be selective and highly potent to NMU2R. For example, the EC50 value of compound NRA 4 is very close to that of NMU, the endogenous peptide ligand of NMU2R. Structure-activity relationship analysis revealed that a 3-hydroxyl group in ring C and a 2’-fluoride group in ring B were essential for this class of compounds to be active against NMU2R. Graphical abstract image
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2-(2-bromophenyl)-formononetin and 2-heptyl-formononetin are PPARγ partial agonists and reduce lipid accumulation in 3T3-L1 adipocytes ()
Publication date: Available online 8 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Charlotte Andersen , Dorota Kotowska , Christian G. Tortzen , Karsten Kristiansen , John Nielsen , Rasmus Koefoed Petersen Isoflavones are bioactive compounds that have been shown to decrease lipid accumulation in vitro. However, the knowledge of the isoflavone formononetin is limited. The aim of the study was to assess the effects of formononetin and its two synthetic analogues, 2-(2-bromophenyl)-formononetin and 2-heptyl-formononetin, on lipid accumulation in 3T3-L1 adipocytes and investigate possible mechanisms. Formononetin and the two analogues were added day 0-8 or day 8-10 of the differentiation period, and lipid accumulation, glycerol release and gene expression were measured. Additionally, competitive peroxisome proliferator-activated receptor (PPAR)- binding assay, PPARγ transactivation assay and Western blot for phosphorylated AMP-activated protein kinase (AMPK) were performed. Chronic treatment (day 0-8) with formononetin increased lipid accumulation, whereas the two analogues decreased lipid accumulation partly due to decreased differentiation. The two analogues, but not formononetin, also decreased lipid content in mature adipocytes. 2-heptyl-formononetin increased glycerol release and lipolytic gene expression and decreased lipogenic gene expression. Formononetin did not bind to or activate PPARγ whereas both analogues bound to the receptor and behaved as PPARγ partial agonists in the transactivation assay. Neither of the compounds affected phosphorylation of AMPK. In conclusion, the analogues of formononetin decreased lipid accumulation possibly in part by acting as PPARγ partial agonists. Graphical abstract image
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Design, synthesis, and structure–activity relationships of a series of novel N-aryl-2-phenylcyclopropanecarboxamide that are potent and orally active orexin receptor antagonists ()
Publication date: Available online 8 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Yu Yoshida , Taro Terauchi , Yoshimitsu Naoe , Yuji Kazuta , Fumihiro Ozaki , Carsten T. Beuckmann , Makoto Nakagawa , Michiyuki Suzuki , Ikuo Kushida , Osamu Takenaka , Takashi Ueno , Masahiro Yonaga Herein we describe the design, synthesis, and structure-activity relationships (SARs) of a novel phenylcyclopropane series represented by 7 and 33b as antagonists of orexin 1 and orexin 2 receptors. With 4 serving as the initial lead for the development of orexin antagonists, exploration of SAR resulted in improved binding affinity for orexin 1 and orexin 2 receptors. Among the synthesized compounds, 33b ((-)-N-(5-cyanopyridin-2-yl)-2-[(3,4-dimethoxyphenyl)oxymethyl]-2-phenylcyclopropanecarboxamide) exhibited potent in vitro activity and oral efficacy in animal sleep measurement experiments. The results of our study suggest that compound 33b may serve as a valuable template for the development of new orexin receptor antagonists. Graphical abstract image
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SAR analysis and biological studies of synthesized podophyllum derivates obtained by N linkage modification at C-4 position ()
Publication date: Available online 7 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Huai Wang , Lijun Tang , Yajie Tang , Zhanpeng Yuan A series of C4-N-substituted podophyllum derivatives were synthesized and tested for cytotoxicity in HeLa, BGC-823, A549, Huh7 and MCF-7 cells by MTT assay. Pharmacologically, most derivatives displayed potent cytotoxicity against at least one of the tested tumor cell lines. Structure activity relationship (SAR) analysis suggests that compounds with imidogen exposed on the pyridine, rather than pyrimidine, exhibited significantly elevated potency. Moreover, the presence of a chlorine atom in the heterocyclic ring enhanced cytotoxicity, with the order 3-position > 4-position > 5-position > 6-position. Specifically, two compounds, 3g and 3h, with 2-amino-3-chloropyridine substituted into the podophyllotoxin (PPT) and 4′-O-demethyl-epipodophyllotoxin (DMEP) scaffolds were shown to have the most potent HeLa cells cytotoxicity compared to other synthesized derivatives or reference compounds PPT, DMEP and etoposide (VP-16). The compound 3g was shown to inhibit microtubule polymerization and compound 3h affected topoisomerase II catalytic activity. Both compounds resulted in G2/M phase arrest and apoptosis, purportedly by increasing the expression of P53, followed by Bax up-regulation, Bcl-2 down-regulation, and caspase-3 activation. As a result of this work, we conclude that compounds 3g and 3h are more potent anticancer agents than VP-16, and that they work by different antitumor mechanisms. Graphical abstract image
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Active compounds from a diverse library of triazolothiadiazole and triazolothiadiazine scaffolds: Synthesis, crystal structure determination, cytotoxicity, cholinesterase inhibitory activity, and binding mode analysis ()
Publication date: Available online 6 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Imtiaz Khan , Aliya Ibrar , Sumera Zaib , Sarfraz Ahmad , Norbert Furtmann , Shahid Hameed , Jim Simpson , Jürgen Bajorath , Jamshed Iqbal In an effort to identify novel cholinesterase candidates for the treatment of Alzheimer’s disease (AD), a diverse array of potentially bioactive compounds including triazolothiadiazoles (4a-h and 5a-f) and triazolothiadiazines (6a-h) was obtained in good yields through the cyclocondensation reaction of 4-amino-5-(pyridin-3-yl)-4H-1,2,4-triazole-3-thiol (3) with various substituted aryl/heteroaryl/aryloxy acids and phenacyl bromides, respectively. The structures of newly prepared compounds were confirmed by IR, 1H and 13C NMR spectroscopy and, in case of 4a, by single crystal X-ray diffraction analysis. The purity of the synthesized compounds was ascertained by elemental analysis. The newly synthesized conjugated heterocycles were screened for cholinesterase inhibitory activity against electric eel acetylcholinesterase (EeAChE) and horse serum butyrylcholinesterase (hBChE). Among the evaluated hybrids, several compounds were identified as potent inhibitors. Compounds 5b and 5d were most active with an IC50 value of 3.09 ± 0.154 and 11.3 ± 0.267 μM, respectively, against acetylcholinesterase, whereas 5b, 6a and 6g were most potent against butyrylcholinesterase, with an IC50 of 0.585 ± 0.154, 0.781 ± 0.213, and 1.09 ± 0.156 μM, respectively, compared to neostigmine and donepezil as standard drugs. The synthesized heteroaromatic compounds were also tested for their cytotoxic potential against lung carcinoma (H157) and vero cell lines. Among them, compound 6h exhibited highest antiproliferative activity against H157 cell lines, with IC50 value of 0.96 ± 0.43 μM at 1mM concentration as compared to vincristine (IC50 = 1.03 ± 0.04 μM), standard drug used in this study. Graphical abstract image
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New derivatives of lupane triterpenoids disturb breast cancer mitochondria and induce cell death ()
Publication date: Available online 6 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Teresa L. Serafim , Filipa S. Carvalho , Telma C. Bernardo , Gonçalo C. Pereira , Edward Perkins , Jon Holy , Dmytro A. Krasutsky , Oksana N. Kolomitsyna , Pavel A. Krasutsky , Paulo J. Oliveira Novel cationic dimethylaminopyridine derivatives of pentacyclic triterpenes were previously described to promote mitochondrial depolarization and cell death in breast and melanoma cell lines. The objective of this work was to further investigate in detail the mechanism of mitochondrial perturbations, correlating those effects with breast cancer cell responses to those same agents. Initially, a panel of tumor and non-tumor cell lines was grown in high-glucose or glucose-free glutamine-containing media, the later forcing cells to synthesize ATP by oxidative phosphorylation only. Cell proliferation, cell cycle, cell death and mitochondrial membrane polarization were evaluated. Inhibition of cell proliferation was observed, accompanied by an arrest in the G1- cell cycle phase, and importantly, by loss of mitochondrial membrane potential. On a later time-point, caspase-9 and 3 activation were observed, resulting in cell death. For the majority of test compounds, we determined that cell toxicity was augmented in the galactose media. To investigate direct evidences on mitochondria isolated rat liver mitochondria were used. The results showed that the compounds were strong inducers of the permeability transition pore. Confirming our previous results, this work shows that the novel DMAP derivatives strongly interact with mitochondria, resulting in pro-apoptotic signaling and cell death. Graphical abstract image Highlights
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Thymol and eugenol derivatives as potential antileishmanial agents ()
Publication date: Available online 6 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Selene Maia de Morais , Nadja Soares Vila-Nova , Claudia Maria Leal Bevilaqua , Fernanda Cristina Rondon , Carlos Henrique Lobo , Arlindo de Alencar Araripe Moura , Antônia Débora Sales , Ana Paula Ribeiro Rodrigues , José Ricardo de Figuereido , Claudio Cabral Campello , Mary E. Wilson , Heitor Franco de Andrade Jr. In Northeastern Brazil visceral leishmaniasis is endemic with lethal cases among humans and dogs. Treatment is toxic and 5-10% of humans die despite treatment. The aim of this work was to survey natural active compounds to find new molecules with high activity and low toxicity against Leishmania infantum chagasi. The compounds thymol and eugenol were chosen to be starting compounds to synthesize acetyl and benzoyl derivatives and to test their antileishmanial activity in vitro and in vivo against L. i. chagasi. A screening assay using luciferase-expressing promastigotes was used to measure the growth inhibition of promastigotes, and an ELISA in situ was performed to evaluate the growth inhibition of amastigote. For the in vivo assay, thymol and eugenol derivatives were given IP to BALB/c mice at 100 mg/Kg/day for 30 days. The thymol derivatives demonstrated the greater activity than the eugenol derivatives, and benzoyl-thymol was the best inhibitor (8.67 ± 0.28 μg/mL). All compounds demonstrated similar activity against amastigotes, and acetyl-thymol was more active than thymol and the positive control drug Amphotericin B. Immunohistochemistry demonstrated the presence of Leishmania amastigote only in the spleen but not the liver of mice treated with acetyl-thymol. Thus, these synthesized derivatives demonstrated anti-leishmanial activity both in vitro and in vivo. These may constitute useful compounds to generate new agents for treatment of Leishmaniasis. Graphical abstract image
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Pyrazole derivatives as potent inhibitors of c-Jun N-terminal kinase: synthesis and SAR studies ()
Publication date: Available online 6 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Anuradha Doma , Ravindra Kulkarni , Radhakrishna Palakodety , G. Narahari Sastry , Janardhan Sridhara , Achaiah Garlapati Mitogen activated protein kinases including c-Jun N-terminal kinase play an indispensible role in inflammatory diseases. Investigation of reported JNK-1 inhibitors indicated that diverse heterocyclic compounds bearing an amide group rendered potent JNK-1 inhibitory activity which prompted us to synthesize new JNK-1 inhibitors containing a pyrazole heterocyclic group. A DABCO mediated 1, 3-dipolar cycloaddition reaction in neat resulted in pyrazole carboxylic acid which was converted to desired amides. Upon confirmation of the structures, all the compounds were screened for JNK-1 inhibitory activity and in vivo anti-inflammatory activity. Several synthesized analogues have exhibited JNK-1 inhibitory activity less than 10 μM, in particular compounds 9c, 10a and 10d were found to be potent among all the compounds. Graphical abstract image Highlights A series of pyrazole amides was synthesized and screened for JNK-1 inhibitory and anti-inflammatory activity. Docking study was also performed.
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Design, synthesis and biological evaluation of novel 5-phenyl-1H-pyrazol derivatives as potential BRAFV600E inhibitors ()
Publication date: Available online 6 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Shu-Fu Wang , Yin-Ling Zhu , Ping-Ting Zhu , Jigar A. Makawana , Ya-Liang Zhang , Meng-Yue Zhao , Peng-Cheng Lv , Hai-Liang Zhu A series of novel 5-phenyl-1H-pyrazol derivatives (5a-5u) containing niacinamide moiety were synthesized and evaluated for biological activity as potential BRAFV600E inhibitors. Among them, compound 5h exhibited the most potent inhibitory activity with an IC50 value of 0.33 μM for BRAFV600E. Antiproliferative assay results indicated that compound 5h has better antiproliferative activity against WM266.4 and A375 in vitro with IC50 value of 2.63 and 3.16 μM respectively, being comparable with the positive control vemurafenib. Molecular docking of 5h into the BRAFV600E active site was performed to determine the probable binding mode. Furthermore, molecular docking and 3D QSAR study by means of DS 3.5 (Discovery Studio 3.5, Accelrys, Co. Ltd) explored the binding modes and the structure and activity relationship (SAR) of these derivatives. Graphical abstract image
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Design, synthesis and pharmacological evaluation of chalcone derivatives as acetylcholinesterase inhibitors ()
Publication date: Available online 4 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Hao-ran Liu , Xian-jun Liu , Hao-qun Fan , Jing-jing Tang , Xiao-hui Gao , Wu-Kun Liu A novel series of chalcone derivatives (4a∼8d) were designed, synthesized, and evaluated for the inhibition activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The log P values of the compounds were shown to range from1.49 to 2.19, which suggested that they were possible to pass blood brain barriers in vivo. The most promising compound 4a (IC50: 4.68 μmol/L) was 2-fold more potent than Rivastigmine against AChE (IC50: 10.54 μmol/L) and showed a high selectivity for AChE over BuChE (Ratio: 4.35). Enzyme kinetic study suggested that the inhibition mechanism of compound 4a was a mixed-type inhibition. Meanwhile, the result of molecular docking showed its potent inhibition of AChE and high selectivity for AChE over BuChE. Graphical abstract image Highlights
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Development of benzo[d]oxazol-2(3H)-ones derivatives as novel inhibitors of Mycobacterium tuberculosis InhA ()
Publication date: Available online 4 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Ganesh S. Pedgaonkar , Jonnalagadda Padma Sridevi , Variam Ullas Jean Kumar , Shalini Saxena , Parthiban Brindha Devi , Janupally Renuka , Perumal Yogeeswari , Dharmarajan Sriram A series of twenty seven substituted 2-(2-oxobenzo[d]oxazol-3(2H)-yl)acetamide derivatives were designed based on our earlier reported Mycobacterium tuberculosis (MTB) enoyl-acyl carrier protein reductase (InhA) lead. Compounds were evaluated for MTB InhA inhibition study, in vitro activity against drug-sensitive and -resistant MTB strains, and cytotoxicity against RAW 264.7 cell line. Among the compounds tested, 2-(6-nitro-2-oxobenzo[d]oxazol-3(2H)-yl)-N-(5-nitrothiazol-2-yl)acetamide (30) was found to be the most promising compound with IC50 of 5.12±0.44 μM against MTB InhA, inhibited drug sensitive MTB with MIC 17.11 μM and was non-cytotoxic at 100 μM. The interaction with protein and enhancement of protein stability in complex with compound 30 was further confirmed biophysically by differential scanning fluorimetry. Graphical abstract image
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Design, synthesis and biological evaluation of 4-anilinothieno[2,3-d]pyrimidine-based hydroxamic acid derivatives as novel histone deacetylase inhibitors ()
Publication date: Available online 4 September 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Wei Yang , Lixuan Li , Xun Ji , Xiaowei Wu , Mingbo Su , Li Sheng , Yi Zang , Jia Li , Hong Liu A series of 4-anilinothieno[2,3-d]pyrimidine-based hydroxamic acid derivatives as novel HDACs inhibitors were designed, synthesized and evaluated. Most of these compounds displayed good to excellent inhibitory activities against HDAC1, 3, 6. The IC50 values of compound 10r against HDAC1,HDAC3,HDAC6 was 1.14 ± 0.03 nM, 3.56 ± 0.08 nM,11.43 ± 0.12 nM. Compound 10r noticeably up-regulated the level of histone H3 acetylation compared to the SAHA. Most of the compounds showed the strong anti-proliferative activity against human cancer cell lines including RMPI8226 and HCT-116. The IC50 values of Compounds 10r and 10t against RPMI8226 was 2.39 ± 0.20 μM, 1.41 ± 0.44 μM respectively, and the HCT-116 was sensitive to the compounds 10h, 10m, 10r, 10w with the IC50 values < 1.9 μM. Graphical abstract image
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Editorial board ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17
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Graphical contents list ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17
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Sulfonamide inhibition study of the carbonic anhydrases from the bacterial pathogen Porphyromonas gingivalis: The β-class (PgiCAb) versus the γ-class (PgiCA) enzymes ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Sonia Del Prete , Daniela Vullo , Sameh M. Osman , Andrea Scozzafava , Zeid AlOthman , Clemente Capasso , Claudiu T. Supuran The oral pathogenic bacterium Porphyromonas gingivalis, encodes for two carbonic anhydrases (CAs, EC 4.2.1.1) one belonging to the γ-class (PgiCA) and another one to the β-class (PgiCAb). This last enzyme has been cloned and characterized here for its inhibition profile with the main class of CA inhibitors, the sulfonamides. Many of the clinically used sulfonamides as well as simple aromatic/heterocyclic sulfonamides were ineffective as PgiCAb inhibitors whereas better inhibition was observed with simple derivatives such as sulfanilamide, metanilamide, 4-aminoalkylbenzenesulfonamides (K Is of 364–475nM). The halogenosulfanilamides incorporating heavy halogens, 4-hydroxy- and 4-hydroxyalkyl-benzenesulfonamides, were also micromolar, ineffective PgiCAb inhibitors. The best inhibitors of the β-class enzyme were acetazolamide and ethoxzolamide, with K Is of 214–280nM. Interestingly, the γ-class enzyme was much more sensitive to sulfonamide inhibitors compared to the β-class one, PgiCAb. Identification of potent and possibly selective inhibitors of PgiCAb/PgiCA may lead to pharmacological tools useful for understanding the physiological role(s) of these enzymes, since this bacterium is the main causative agent of periodontitis and few treatment options are presently available. Graphical abstract image
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Development of novel membrane active lipidated peptidomimetics active against drug resistant clinical isolates ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Sandeep Lohan , Arneesh Kalanta , Praveen Sonkusre , Swaranjit Singh Cameotra , Gopal Singh Bisht A new series of small cationic lipidated peptidomimetics have been synthesized and found to be highly active against several susceptible as well as drug resistant clinical isolates of bacteria and fungi. All lipidated peptidomimetics do not cause significant lysis of human erythrocytes (HC50 >200μg/mL). Calcein dye leakage experiment revealed membranolytic effect of LPEP08 which was further confirmed by scanning electron microscopy (SEM). The involvement of intracellular targets as an alternate mode of action was precluded by DNA retardation assay. Additionally, LPEP08 exhibit high proteolytic stability and dose not elicit resistance against drug resistant clinical isolate of Staphylococcus aureus, even after 16 rounds of passaging. These results demonstrate the potential of lipidated peptidomimetics as biocompatible anti-infective therapeutics. Graphical abstract image
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Ethyl 2-(benzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate analogues as a new scaffold for protein kinase casein kinase 2 inhibitor ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Cheng-Hao Jin , Kyu-Yeon Jun , Eunjung Lee , Seongrak Kim , Youngjoo Kwon , Kunhong Kim , Younghwa Na Protein kinase casein kinase 2 (PKCK2) is a constitutively active, growth factor-independent serine/threonine kinase, and changes in PKCK2 expression or its activity are reported in many cancer cells. To develop a novel PKCK2 inhibitor(s), we first performed cell-based phenotypic screening using 4000 chemicals purchased from ChemDiv chemical libraries (2000: randomly selected; 2000: kinase-biased) and performed in vitro kinase assay-based screening using hits found from the first screening. We identified compound 24 (C24)[(Z)-ethyl 5-(4-chlorophenyl)-2-(3,4-dihydroxybenzylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a] pyrimidine-6-carboxylate] as a novel inhibitor of PKCK2 that is more potent and selective than 4,5,6,7-tetrabromobenzotriazole (TBB). In particular, compound 24 [half maximal inhibitory concentration (IC50)=0.56μM] inhibited PKCK2 2.2-fold more efficiently than did TBB (IC50 =1.24μM), which is quite specific toward PKCK2 with respect to ATP binding, in a panel of 31 human protein kinases. The K i values of compound 24 and TBB for PKCK2 were 0.78μM and 2.70μM, respectively. Treatment of cells with compound 24 inhibited endogenous PKCK2 activity and showed anti-proliferative and pro-apoptotic effects against stomach and hepatocellular cancer cell lines more efficiently than did TBB. As expected, compound 24 also enabled tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-resistant cancer cells to be sensitive toward TRAIL. In comparing the molecular docking of compound 24 bound to PKCK2α versus previously reported complexes of PKCK2 with other inhibitors, our findings suggest a new scaffold for specific PKCK2α inhibitors. Thus, compound 24 appears to be a selective, cell-permeable, potent, and novel PKCK2 inhibitor worthy of further characterization. Graphical abstract image
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Identification of novel inhibitors of phospho-MurNAc-pentapeptide translocase MraY from library screening: Isoquinoline alkaloid michellamine B and xanthene dye phloxine B ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Agnes Mihalyi , Shirin Jamshidi , Justinas Slikas , Timothy D.H. Bugg The National Cancer Institute (NCI) Diversity Set was screened for potential inhibitors of phospho-MurNAc-pentapeptide translocase MraY from Escherichia coli using a primary fluorescence enhancement assay, followed by a secondary radiochemical assay. One new MraY inhibitor was identified from this screen, a naphthylisoquinoline alkaloid michellamine B, which inhibited E. coli MraY (IC50 456μM) and Bacillus subtilis MraY (IC50 386μM), and which showed antimicrobial activity against B. subtilis (MIC 16μg/mL). Following an earlier report of halogenated fluoresceins identified from a combined MraY/MurG screen, three halogenated fluoresceins were tested as inhibitors of E. coli MraY and E. coli MurG, and phloxine B was identified as an inhibitor of E. coli MraY (IC50 32μM). Molecular docking of inhibitor structures against the structure of Aquifex aeolicus MraY indicates that phloxine B appears to bind to the Mg2+ cofactor in the enzyme active site, while michellamine B binds to a hydrophobic groove formed between transmembrane helices 5 and 9. Graphical abstract image
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Endoperoxide polyketides from a Chinese Plakortis simplex: Further evidence of the impact of stereochemistry on antimalarial activity of simple 1,2-dioxanes ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Giuseppina Chianese , Marco Persico , Fan Yang , Hou-Wen Lin , Yue-Wei Guo , Nicoletta Basilico , Silvia Parapini , Donatella Taramelli , Orazio Taglialatela-Scafati , Caterina Fattorusso Chemical investigation of the organic extract obtained from the sponge Plakortis simplex collected in the South China Sea afforded five new polyketide endoperoxides (2 and 4–7), along with two known analogues (1 and 3). The stereostructures of these metabolites have been deduced on the basis of spectroscopic analysis and chemical conversion. The isolated endoperoxide derivatives have been tested for their in vitro antimalarial activity against Plasmodium falciparum strains, showing IC50 values in the low micromolar range. The structure–activity relationships were analyzed by means of a detailed computational investigation and rationalized in the light of the mechanism of action proposed for this class of simple antimalarials. The relative orientation of the atoms involved in the putative radical generation and transfer reaction was demonstrated to have a great impact on the antimalarial activity. The resulting 3D pharmacophoric model can be a useful guide to design simple and effective antimalarial lead compounds belonging to the class of 1,2-dioxanes. Graphical abstract image
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‘Carba’-carfentanil (trans isomer): A μ opioid receptor (MOR) partial agonist with a distinct binding mode ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Grazyna Weltrowska , Carole Lemieux , Nga N. Chung , Jason J. Guo , Brian C. Wilkes , Peter W. Schiller There is strong evidence to indicate that a positively charged nitrogen of endogenous and exogenous opioid ligands forms a salt bridge with the Asp residue in the third transmembrane helix of opioid receptors. To further examine the role of this electrostatic interaction in opioid receptor binding and activation, we synthesized ‘carba’-analogues of the highly potent μ opioid analgesic carfentanil (3), in which the piperidine nitrogen was replaced with a carbon. The resulting trans isomer (8b) showed reduced, but still significant MOR binding affinity (K i μ =95.2nM) with no MOR versus DOR binding selectivity and was a MOR partial agonist. The cis isomer (8a) was essentially inactive. A MOR docking study indicated that 8b bound to the same binding pocket as parent 3, but its binding mode was somewhat different. A re-evaluation of the uncharged morphine derivative N-formylnormorphine (9) indicated that it was a weak MOR antagonist showing no preference for MOR over KOR. Taken together, the results indicate that deletion of the positively charged nitrogen in μ opioid analgesics reduces MOR binding affinity by 2–3 orders of magnitude and may have pronounced effects on the intrinsic efficacy and on the opioid receptor selectivity profile. Graphical abstract image
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Novel N-biphenyl-2-ylmethyl 2-methoxyphenylpiperazinylalkanamides as 5-HT7R antagonists for the treatment of depression ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Youngjae Kim , Jinsung Tae , Kangho Lee , Hyewhon Rhim , Il Han Choo , Heeyeong Cho , Woo-Kyu Park , Gyochang Keum , Hyunah Choo 5-HT7 receptor (5-HT7R) is a promising target for the treatment of depression and neuropathic pain. 5-HT7R antagonists exhibited antidepressant effects, while the agonists produced strong anti-hyperalgesic effects. In our efforts to discover selective 5-HT7R antagonists or agonists, N-biphenylylmethyl 2-methoxyphenylpiperazinylalkanamides 1 were designed, synthesized, and biologically evaluated against 5-HT7R. Among the synthesized compounds, N-2′-chlorobiphenylylmethyl 2-methoxyphenylpiperazinylpentanamide 1–8 showed the best binding affinity with a K i value of 8.69nM and it was verified as a novel antagonist according to functional assays. The compound 1–8 was very selective over 5-HT1DR, 5-HT2AR, 5-HT3R, 5-HT5AR and 5-HT6R and moderately selective over 5-HT1AR, 5-HT1BR and 5-HT2CR. The novel 5-HT7R antagonist 1–8 exhibited an antidepressant effect at a dose of 25mg/kg in the forced swimming test in mice and showed a U-shaped dose–response curve which typically appears in 5-HT7R antagonists such as SB-269970 and lurasidone. Graphical abstract image
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Ricinine: A pyridone alkaloid from Ricinus communis that activates the Wnt signaling pathway through casein kinase 1α ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Kensuke Ohishi , Kazufumi Toume , Midori A. Arai , Samir K. Sadhu , Firoj Ahmed , Takamasa Mizoguchi , Motoyuki Itoh , Masami Ishibashi Wnt signaling plays important roles in proliferation, differentiation, development of cells, and various diseases. Activity-guided fractionation of the MeOH extract of the Ricinus communis stem led to the isolation of four compounds (1–4). The TCF/β-catenin transcription activities of 1 and 3 were 2.2 and 2.5 fold higher at 20 and 30μM, respectively. Cells treated with ricinine (1) had higher β-catenin and lower of p-β-catenin (ser 33, 37, 45, Thr 41) protein levels, whereas glycogen synthase kinase 3β (GSK3β) and casein kinase 1α (CK1α) protein levels remained unchanged. Cells treated with pyrvinium, an activator of CK1α, had lower β-catenin levels. However, the combined treatment of pyrvinium and 1 led to higher β-catenin levels than those in cells treated with pyrvinium alone, which suggested that 1 inhibited CK1α activity. Furthermore, 1 increased β-catenin protein levels in zebrafish embryos. These results indicated that 1 activated the Wnt signaling pathway by inhibiting CK1α. Graphical abstract image
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Design, synthesis, and in vitro evaluation of an activity-based protein profiling (ABPP) probe targeting agmatine deiminases ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Andrew Thomson , Sean O’Connor , Bryan Knuckley , Corey P. Causey Agmatine deiminases (AgDs) belong to a family of enzymes known as guanidinium group modifying enzymes (GMEs). Many pathogenic bacteria encode an AgD that participates in the catabolism of agmatine (decarboxylated arginine). This catabolism may confer a competitive survival advantage, by virtue of energy production and increased acid tolerance, making this sub-family of enzymes a potential therapeutic target that warrants further study. Herein we report the development of an activity-based protein profiling (ABPP) probe that selectively targets the AgD from Streptococcus mutans. Due to the selectivity and covalent nature of the modification, this probe could prove to be a valuable tool for the study of other AgD family members. Graphical abstract image
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2-Phenylaminonaphthoquinones and related compounds: Synthesis, trypanocidal and cytotoxic activities ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Ivan Sieveking , Pablo Thomas , Juan C. Estévez , Natalia Quiñones , Mauricio A. Cuéllar , Juan Villena , Christian Espinosa-Bustos , Angélica Fierro , Ricardo A. Tapia , Juan D. Maya , Rodrigo López-Muñoz , Bruce K. Cassels , Ramon J. Estévez , Cristian O. Salas A series of new 2-aminonaphthoquinones and related compounds were synthesized and evaluated in vitro as trypanocidal and cytotoxic agents. Some tested compounds inhibited epimastigote growth and trypomastigote viability. Several compounds showed similar or higher activity and selectivity as compared with current trypanocidal drug, nifurtimox. Compound 4l exhibit higher selectivity than nifurtimox against Trypanosoma cruzi in comparison with Vero cells. Some of the synthesized quinones were tested against cancer cells and normal fibroblasts, showing that certain chemical modifications on the naphthoquinone moiety induce and excellent increase the selectivity index of the cytotoxicity (4g and 10). The results presented here show that the anti-T. cruzi activity of 2-aminonaphthoquinones derivatives can be improved by the replacement of the benzene ring by a pyridine moiety. Interestingly, the presence of a chlorine atom at C-3 and a highly lipophilic alkyl group or aromatic ring are newly observed elements that should lead to the discovery of more selective cytotoxic and trypanocidal compounds. Graphical abstract image
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Stereoselective synthesis of lanthionine derivatives in aqueous solution and their incorporation into the peptidoglycan of Escherichia coli ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Thibaut Denoël , Astrid Zervosen , Thomas Gerards , Christian Lemaire , Bernard Joris , Didier Blanot , André Luxen The three diastereoisomers—(R,R), (S,S) and meso—of lanthionine were synthesized in aqueous solution with high diastereoselectivity (>99%). The (S) and (R) enantiomers of two differently protected sulfamidates were opened by nucleophilic attack of (R) or (S)-cysteine. Acidification and controlled heating liberated the free lanthionines. Using the same chemistry, an α-benzyl lanthionine was also prepared. The proposed method, which avoids the need of enrichment by recrystallization, opens the way to the labelling of these compounds with 35S. Furthermore, in vivo bioincorporation into Escherichia coli W7 was studied. No incorporation of α-benzyl lanthionine was observed. In contrast, meso-lanthionine can effectively replace meso-diaminopimelic acid in vivo, while in the presence of (R,R)-lanthionine the initial increase of bacterial growth was followed by cell lysis. In the future, meso-[35S]lanthionine could be used to study the biosynthesis of peptidoglycan and its turnover in relation to cell growth and division. Graphical abstract image
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