Bioorganic & Medicinal Chemistry

Editorial board ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12
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Synthesis, anticancer activity, and SAR analyses of compounds containing the 5:7-fused 4,6,8-triaminoimidazo[4,5-e][1,3]diazepine ring system ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Min Xie, Rena G. Lapidus, Mariola Sadowska, Martin J. Edelman, Ramachandra S. Hosmane Described herein are our limited structure–activity relationship (SAR) studies on a 5:7-fused heterocycle (1), containing the 4,6,8-triaminoimidazo[4,5-e][1,3]diazepine ring system, whose synthesis and potent broad-spectrum anticancer activity we reported a few years ago. Our SAR efforts in this study are mainly focused on judicial attachment of substituents at N-1 and N6-positions of the heterocyclic ring. Our results suggest that there is some subtle correlation between the substituents attached at the N-1 position and those attached at the N6-position of the heterocycle. It is likely that there is a common hydrophobic binding pocket on the target protein that is occupied by the substituents attached at the N-1 and N6-positions of the heterocyclic ligand. This pocket appears to be large enough to hold either a C-18 alkyl chain of N6 and no attachment at N-1, or a combined C-10 at N6 and a CH2Ph at N-1. Any alkyl chain shorter or longer than C-10 at N6 with a CH2Ph attached at N-1, would result in decrease of biological activity. Graphical abstract image
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Discovery of pyrazinone based compounds that potently inhibit the drug-resistant enzyme variant R155K of the hepatitis C virus NS3 protease ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Anna Karin Belfrage, Eldar Abdurakhmanov, Eva Åkerblom, Peter Brandt, Anna Oshalim, Johan Gising, Anna Skogh, Johan Neyts, U. Helena Danielson, Anja Sandström Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors with variations in the C-terminus. Biochemical evaluation was performed using genotype 1a, both the wild-type and the drug resistant enzyme variant, R155K. Surprisingly, compounds without an acidic sulfonamide retained good inhibition, challenging our previous molecular docking model. Moreover, selected compounds in this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 protease inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance. Graphical abstract image
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Identification of 1,2,3-triazole derivatives that protect pancreatic β cells against endoplasmic reticulum stress-mediated dysfunction and death through the inhibition of C/EBP-homologous protein expression ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Hongliang Duan, Daleep Arora, Yu Li, Hendra Setiadi, Depeng Xu, Hui-Ying Lim, Weidong Wang The C/EBP-homologous protein (CHOP) acts as a mediator of endoplasmic reticulum (ER) stress-induced pancreatic insulin-producing β cell death, a key element in the pathogenesis of diabetes. Chemicals that inhibit the expression of CHOP might therefore protect β cells from ER stress-induced apoptosis and prevent or ameliorate diabetes. Here, we used high-throughput screening to identify a series of 1,2,3-triazole amide derivatives that inhibit ER stress-induced CHOP-luciferase reporter activity. Our SAR studies indicate that compounds with an N,1-diphenyl-5-methyl-1H-1,2,3-triazole-4-carboxamide backbone potently protect β cell against ER stress. Several representative compounds inhibit ER stress-induced up-regulation of CHOP mRNA and protein, without affecting the basal level of CHOP expression. We further show that a 1,2,3-triazole derivative 4e protects β cell function and survival against ER stress in a CHOP-dependent fashion, as it is inactive in CHOP-deficient β cells. Finally, we show that 4e significantly lowers blood glucose levels and increases concomitant β cell survival and number in a streptozotocin-induced diabetic mouse model. Identification of small molecule inhibitors of CHOP expression that prevent ER stress-induced β cell dysfunction and death may provide a new modality for the treatment of diabetes. Graphical abstract image
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Sulfone-stabilized carbanions for the reversible covalent capture of a posttranslationally-generated cysteine oxoform found in protein tyrosine phosphatase 1B (PTP1B) ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Zachary D. Parsons, Kasi Viswanatharaju Ruddraraju, Nicholas Santo, Kent S. Gates Redox regulation of protein tyrosine phosphatase 1B (PTP1B) involves oxidative conversion of the active site cysteine thiolate into an electrophilic sulfenyl amide residue. Reduction of the sulfenyl amide by biological thiols regenerates the native cysteine residue. Here we explored fundamental chemical reactions that may enable covalent capture of the sulfenyl amide residue in oxidized PTP1B. Various sulfone-containing carbon acids were found to react readily with a model peptide sulfenyl amide via attack of the sulfonyl carbanion on the electrophilic sulfur center in the sulfenyl amide. Both the products and the rates of these reactions were characterized. The results suggest that capture of a peptide sulfenyl amide residue by sulfone-stabilized carbanions can slow, but not completely prevent, thiol-mediated generation of the corresponding cysteine-containing peptide. Sulfone-containing carbon acids may be useful components in the construction of agents that knock down PTP1B activity in cells via transient covalent capture of the sulfenyl amide oxoform generated during insulin signaling processes. Graphical abstract image
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Structure-guided development of dual β2 adrenergic/dopamine D2 receptor agonists ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Dietmar Weichert, Markus Stanek, Harald Hübner, Peter Gmeiner Aiming to discover dual-acting β2 adrenergic/dopamine D2 receptor ligands, a structure-guided approach for the evolution of GPCR agonists that address multiple targets was elaborated. Starting from GPCR crystal structures, we describe the design, synthesis and biological investigation of a defined set of compounds leading to the identification of the benzoxazinone (R)-3, which shows agonist properties at the adrenergic β2 receptor and substantial G protein-promoted activation at the D2 receptor. This directed approach yielded molecular probes with tuned dual activity. The congener desOH-3 devoid of the benzylic hydroxyl function was shown to be a β2 adrenergic antagonist/D2 receptor agonist with K i values in the low nanomolar range. The compounds may serve as a promising starting point for the investigation and treatment of neurological disorders. Graphical abstract image
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Selectivity of 3-bromo-isoxazoline inhibitors between human and Plasmodium falciparum glyceraldehyde-3-phosphate dehydrogenases ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Stefano Bruno, Marilena Margiotta, Andrea Pinto, Gregorio Cullia, Paola Conti, Carlo De Micheli, Andrea Mozzarelli Compounds based on the 3-Br-isoxazoline scaffold fully inhibit glyceraldehyde 3-phosphate dehydrogenase from Plasmodium falciparum by selectively alkylating all four catalytic cysteines of the tetramer. Here, we show that, under the same experimental conditions that led to a fast and complete inhibition of the protozoan enzyme, the human ortholog was only 25% inhibited, with the alkylation of a single catalytic cysteine within the tetramer. The partial alkylation seems to produce a slow conformational rearrangement that severely limits the accessibility of the remaining active sites to bulky 3-Br-isoxazoline derivatives, but not to the substrate or smaller alkylating agents. Graphical abstract image
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Design, synthesis and preliminary biological evaluation of 4-aminopyrazole derivatives as novel and potent JAKs inhibitors ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Xuewu Liang, Yongxue Huang, Jie Zang, Qianwen Gao, Binghe Wang, Wenfang Xu, Yingjie Zhang JAKs inhibitors were widely applied in the treatment of immunodeficiency diseases, inflammation and cancers. We designed and synthesized a novel series of 4-aminopyrazole derivatives, which showed inhibitory potency against various JAKs. The in vitro protein kinase inhibition experiment indicated that compounds 17k, 17l, 17m and 17n could inhibit JAKs effectively. Among them, compound 17m possessed the highest protein kinase inhibitory rates (%) at 10μM, which were 97, 96 and 100 to JAK1, JAK2 and JAK3, respectively. Further evaluation revealed that the IC50 values of 17m against JAK1, JAK2 and JAK3 were 0.67μM, 0.098μM and 0.039μM, respectively. Moreover, western blotting results showed compound 17m could inhibit the phosphorylation of JAK2 in Hela cells effectively. The data supports the further investigation of these compounds as novel JAKs inhibitors. Graphical abstract image
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Discovery of 5-(methylthio)pyrimidine derivatives as L858R/T790M mutant selective epidermal growth factor receptor (EGFR) inhibitors ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Qiang Xiao, Rong Qu, Dingding Gao, Qi Yan, Linjiang Tong, Wei Zhang, Jian Ding, Hua Xie, Yingxia Li To overcome the drug-resistance of first generation EGFR inhibitors and the nonselective toxicities of second generation inhibitors among NSCLC patients, a series of 5-(methylthio)pyrimidine derivatives were discovered as novel EGFR inhibitors, which harbored not only potent enzymatic and antiproliferative activities against EGFRL858R/T790M mutants, but good selectivity over wide-type form of the receptor. This goal was achieved by employing structure-based drug design and traditional optimization strategies, based on WZ4002 and CO1686. These derivatives inhibited the enzymatic activity of EGFRL858R/T790M mutants with IC50 values in subnanomolar ranges, while exhibiting hundreds of fold less potency on EGFRWT. These compounds also strongly inhibited the proliferation of H1975 non-small cell lung cancer cells bearing EGFRL858R/T790M, while being significantly less toxic to A431 human epithelial carcinoma cells with overexpressed EGFRWT. The EGFR kinase inhibitory and antiproliferative activities were further validated by Western blot analysis for activation of EGFR and the downstream signaling in cancer cells. Graphical abstract image
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Plasmid DNA delivery by arginine-rich cell-penetrating peptides containing unnatural amino acids ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Takuma Kato, Hiroko Yamashita, Takashi Misawa, Koyo Nishida, Masaaki Kurihara, Masakazu Tanaka, Yosuke Demizu, Makoto Oba Cell-penetrating peptides (CPPs) have been developed as drug, protein, and gene delivery tools. In the present study, arginine (Arg)-rich CPPs containing unnatural amino acids were designed to deliver plasmid DNA (pDNA). The transfection ability of one of the Arg-rich CPPs examined here was more effective than that of the Arg nonapeptide, which is the most frequently used CPP. The transfection efficiencies of Arg-rich CPPs increased with longer post-incubation times and were significantly higher at 48-h and 72-h post-incubation than that of the commercially available transfection reagent TurboFect. These Arg-rich CPPs were complexed with pDNA for a long time in cells and effectively escaped from the late endosomes/lysosomes into the cytoplasm. These results will be helpful for designing novel CPPs for pDNA delivery. Graphical abstract image
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Discovery, synthesis, and structure–activity relationships of 20S-dammar-24-en-2α,3β,12β,20-tetrol (GP) derivatives as a new class of AMPKα2β1γ1 activators ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Chenhuan Dong, Zhifu Xie, Yanyan Yu, Jia Li, Junhua Liu, Jingya Li, Lihong Hu As a follow-up discovery of AMPK activators from natural products, 20S-dammar-24-en-2α,3β,12β,20-tetrol (GP, 1), a dammarane-type triterpenoid, was found to have some favorable metabolic effects on dyslipidemia in Golden Syrian hamsters, and activate AMPKα2β1γ1 by around 2.4 fold with an EC50 of 5.1μM on molecular level. In order to enhance its potency at AMPK and structure–activity relationship study, GP derivatives were designed, synthesized, and evaluated in pharmacological AMPK activation assays. Structure–activity relationship analysis showed that amine at the 24-position (groups I–IV) effectively and significantly increased the potency and efficacy. GP derivatives 12 and 17–19 exhibited better potency (EC50: 0.3, 0.8, 0.8, and 1.0μM) and efficacy (fold: 3.2, 2.7, 3.0, and 2.8) in the activation of AMPK heterotrimer α2β1γ1 than positive control (AMP, EC50: 1.6μM, fold: 3.2). Furthermore, the most potent compounds 12 and 17 obviously inhibited glucose output through increasing the phosphorylation of AMPK, without affecting mitochondrial membrane potential or producing cytotoxicity. Graphical abstract image
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Design and synthesis of peptide conjugates of phosphoramide mustard as prodrugs activated by prostate-specific antigen ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Xinghua Wu, Longqin Hu A series of Glutaryl-Hyp-Ala-Ser-Chg-Gln-4-aminobenzyl phosphoramide mustard conjugates (1a–e) was designed and synthesized as potential prodrugs for site-specific activation by PSA in prostate cancer cells. All conjugates were found to be substrates of PSA with cleavage occurring between Gln and the para-aminobenzyl (PAB) linker. Structure–activity relationship studies on these conjugates indicated that introduction of electron-withdrawing fluorine(s) on the phenyl ring in the PAB linker uniformly improved the chemical stability of the conjugates while the position of substitution affected differently the self-immolative process of conjugates upon proteolysis. Introduction of a fluorine at ortho position to benzylic phosphoramide as in 1b results in better stability of the conjugate prior to activation while maintaining its antiproliferative activity upon activation by PSA. The conjugate 1b with 2-fluoro substitution was identified as a promising lead for further evaluation and optimization in the development of prostate cancer-targeted prodrugs. Graphical abstract image
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Design, synthesis, and biological evaluation of substrate-competitive inhibitors of C-terminal Binding Protein (CtBP) ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Sudha Korwar, Benjamin L. Morris, Hardik I. Parikh, Robert A. Coover, Tyler W. Doughty, Ian M. Love, Brendan J. Hilbert, William E. Royer, Glen E. Kellogg, Steven R. Grossman, Keith C. Ellis C-terminal Binding Protein (CtBP) is a transcriptional co-regulator that downregulates the expression of many tumor-suppressor genes. Utilizing a crystal structure of CtBP with its substrate 4-methylthio-2-oxobutyric acid (MTOB) and NAD+ as a guide, we have designed, synthesized, and tested a series of small molecule inhibitors of CtBP. From our first round of compounds, we identified 2-(hydroxyimino)-3-phenylpropanoic acid as a potent CtBP inhibitor (IC50 =0.24μM). A structure–activity relationship study of this compound further identified the 4-chloro- (IC50 =0.18μM) and 3-chloro- (IC50 =0.17μM) analogues as additional potent CtBP inhibitors. Evaluation of the hydroxyimine analogues in a short-term cell growth/viability assay showed that the 4-chloro- and 3-chloro-analogues are 2-fold and 4-fold more potent, respectively, than the MTOB control. A functional cellular assay using a CtBP-specific transcriptional readout revealed that the 4-chloro- and 3-chloro-hydroxyimine analogues were able to block CtBP transcriptional repression activity. This data suggests that substrate-competitive inhibition of CtBP dehydrogenase activity is a potential mechanism to reactivate tumor-suppressor gene expression as a therapeutic strategy for cancer. Graphical abstract image
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Synthesis and in vitro growth inhibitory activity of novel silyl- and trityl-modified nucleosides ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Jenny-Lee Panayides, Véronique Mathieu, Laetitia Moreno Y. Banuls, Helen Apostolellis, Nurit Dahan-Farkas, Hajierah Davids, Leonie Harmse, M.E. Christine Rey, Ivan R. Green, Stephen C. Pelly, Robert Kiss, Alexander Kornienko, Willem A.L. van Otterlo Seventeen silyl- and trityl-modified (5′-O- and 3′,5′-di-O-) nucleosides were synthesized with the aim of investigating the in vitro antiproliferative activities of these nucleoside derivatives. A subset of the compounds was evaluated at a fixed concentration of 100μM against a small panel of tumor cell lines (HL-60, K-562, Jurkat, Caco-2 and HT-29). The entire set was also tested at varying concentrations against two human glioma lines (U373 and Hs683) to obtain GI50 values, with the best results being values of ∼25μM. Graphical abstract image
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Synthesis and inhibitory evaluation of 3-linked imipramines for the exploration of the S2 site of the human serotonin transporter ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Anne Brinkø, Maja T. Larsen, Heidi Koldsø, Louise Besenbacher, Anders Kolind, Birgit Schiøtt, Steffen Sinning, Henrik H. Jensen The human serotonin transporter is the primary target of several antidepressant drugs, and the importance of a primary, high affinity binding site (S1) for antidepressant binding is well documented. The existence of a lower affinity, secondary binding site (S2) has, however, been debated. Herein we report the synthesis of 3-position coupled imipramine ligands from clomipramine using a copper free Sonogashira reaction. Ligand design was inspired by results from docking and steered molecular dynamics simulations, and the ligands were utilized in a structure–activity relationship study of the positional relationship between the S1 and S2 sites. The computer simulations suggested that the S2 site does indeed exist although with lower affinity for imipramine than observed within the S1 site. Additionally, it was possible to dock the 3-linked imipramine analogs into positions which occupy the S1 and the S2 site simultaneously. The structure activity relationship study showed that the shortest ligands were the most potent, and mutations enlarging the proposed S2 site were found to affect the larger ligands positively, while the smaller ligands were mostly unaffected. Graphical abstract image
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Molecular design, synthesis and anticoagulant activity evaluation of fluorinated dabigatran analogues ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Fei Wang, Yu-Jie Ren, Ming-Hui Dong In the present study, a series of unreported fluorinated dabigatran analogues, which were based on the structural scaffold of dabigatran, were designed by computer-aided simulation. Fifteen fluorinated dabigatran analogues were screened and synthesized. All target compounds were characterized by 1H NMR, 13C NMR, 19F NMR and HRMS. According to the preliminary screening results of inhibition ratio, eleven analogues (inhibition ratio >90%) were evaluated for antithrombin activity in vitro (IC50). The test results expressed that all the analogues showed effective inhibitory activities against thrombin. Especially, compounds 8f, 8k and 8o, with IC50 values of 1.81, 3.21 and 2.16nM, respectively, showed remarkable anticoagulant activities which were in the range of reference drug dabigatran (IC50 =1.23nM). Moreover, compounds 8k and 8o were developed to investigate their anticoagulant activities in vivo. In those part, compound 8o exhibited a fairly strong inhibitory action for arteriovenous thrombosis with inhibition ratio of 84.66%, which was comparable with that of dabigatran (85.07%). Docking simulations demonstrated that these compounds could act as candidates for further development of novel anticoagulant drugs. Graphical abstract image
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Synthesis and characterization of a fluorescent probe for α-tocopherol suitable for fluorescence microscopy ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Mikel Ghelfi, Lynn Ulatowski, Danny Manor, Jeffrey Atkinson Previously prepared fluorescent derivatives of α-tocopherol have shown tremendous utility in both in vitro exploration of the mechanism of ligand transfer by the α-tocopherol transfer protein (α-TTP) and the intracellular transport of α-tocopherol in cells and tissues. We report here the synthesis of a 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) containing α-tocopherol analog having extended conjugation with an alkenyl thiophene group that extends the absorption and emission maxima to longer wavelengths (λ ex =571nm and λ em =583nm). The final fluorophore thienyl-ene-BODIPY-α-tocopherol, 2, binds to recombinant human α-TTP with a K d =8.7±1.1nM and is a suitable probe for monitoring the secretion of α-tocopherol from cultured Mcf7#189 cells. Graphical abstract image
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Design, synthesis, and biological evaluation of new arylamide derivatives possessing sulfonate or sulfamate moieties as steroid sulfatase enzyme inhibitors ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Mohammed I. El-Gamal, Mohammad H. Semreen, Paul A. Foster, Barry V.L. Potter A series of new arylamide derivatives possessing terminal sulfonate or sulfamate moieties was designed and synthesized. The target compounds were tested for in vitro inhibitory effects against the steroid sulfatase (STS) enzyme in a cell-free assay system. The free sulfamate derivative 1j was the most active. It inhibited the enzymatic activity by 72.0% and 55.7% at 20μM and 10μM, respectively. Compound 1j was further tested for STS inhibition in JEG-3 placental carcinoma cells with high STS enzyme activity. It inhibited 93.9% of the enzyme activity in JEG-3 placental carcinoma cells at 20μM with an efficacy near to that of the well-established drug STX64 as reference. At 10μM, 1j inhibited 86.1% of the STS activity of JEG-3. Its IC50 value against the STS enzyme in JEG-3 cells was 0.421μM. Thus, 1j represents an attractive new non-steroidal lead for further optimization. Graphical abstract image
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Synthesis and bioevaluation of substituted chalcones, coumaranones and other flavonoids as anti-HIV agents ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Amy L. Cole, Sandra Hossain, Alex M. Cole, Otto Phanstiel A series of chalcone, flavone, coumaranone and other flavonoid compounds were screened for their anti HIV-1 activity in two cell culture models using TZM-bl and PM1 cells. Within the systems evaluated, the most promising compounds contained either an α- or β-hydroxy-carbonyl motif within their structure (e.g., 8 and 9). Efficacious substituents were identified and used to design new HIV inhibitors with increased potency and lower cytotoxicity. Of the scaffolds evaluated, specific chalcones were found to provide the best balance between anti-HIV potency and low host cell toxicity. Chalcone 8l was shown to inhibit different clinical isolates of HIV in a dose-dependent manner (e.g., IC50 typically⩽5μM). Inhibition of HIV infection experiments using TZM-bl cells demonstrated that chalcone 8l and flavonol 9c had IC50 values of 4.7μM and 10.4μM, respectively. These insights were used to design new chalcones 8o and 8p. Rewardingly, chalcones 8o and 8p (at 10μM) each gave >92% inhibition of viral propagation without impacting PM1 host cell viability. Inhibition of viral propagation significantly increased (60–90%) when PM1 cells were pre-incubated with chalcone 8o, but not with the related flavonol 9c. These results suggested that chalcone 8o may be of value as both a HIV prophylactic and therapy. In summary, O-benzyl-substituted chalcones were identified as promising anti-HIV agents for future investigation. Graphical abstract image
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Development of cyanopyridine–triazine hybrids as lead multitarget anti-Alzheimer agents ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Mudasir Maqbool, Apra Manral, Ehtesham Jameel, Jitendra Kumar, Vikas Saini, Ashutosh Shandilya, Manisha Tiwari, Nasimul Hoda, B. Jayaram A series of new cyanopyridine–triazine hybrids were designed, synthesized and screened as multitargeted anti-Alzheimer’s agents. These molecules were designed while using computational techniques and were synthesized via a feasible concurrent synthetic route. Inhibition potencies of synthetic compounds 4a–4h against cholinesterases, Aβ1–42 disaggregation, oxidative stress, cytotoxicity, and neuroprotection against Aβ1–42-induced toxicity of the synthesized compounds were evaluated. Compounds 4d and 4h showed promising inhibitory activity on acetylcholinesterase (AChE) with IC50 values 0.059 and 0.080μM, respectively, along with good inhibition selectivity against AChE over butyrylcholinesterase (BuChE). Molecular modelling studies revealed that these compounds interacted simultaneously with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The mixed type inhibition of compound 4d further confirmed their dual binding nature in kinetic studies. Furthermore, the results from neuroprotection studies of most potent compounds 4d and 4h indicate that these derivatives can reduce neuronal death induced by H2O2-mediated oxidative stress and Aβ1–42 induced cytotoxicity. In addition, in silico analysis of absorption, distribution, metabolism and excretion (ADME) profile of best compounds 4d and 4h revealed that they have drug like properties. Overall, these cyanopyridine–triazine hybrids can be considered as a candidate with potential impact for further pharmacological development in Alzheimer’s therapy. Graphical abstract image
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(7-Diethylaminocoumarin-4-yl)methyl ester of suberoylanilide hydroxamic acid as a caged inhibitor for photocontrol of histone deacetylase activity ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Naoya Ieda, Sota Yamada, Mitsuyasu Kawaguchi, Naoki Miyata, Hidehiko Nakagawa Histone deacetylases (HDACs) are involved in epigenetic control of the expression of various genes by catalyzing deacetylation of ε-acetylated lysine residues. Here, we report the design, synthesis and evaluation of the (7-diethylaminocoumarin-4-yl)methyl ester of suberoylanilide hydroxamic acid (AC-SAHA) as a caged HDAC inhibitor, which releases the known pan-HDAC inhibitor SAHA upon cleavage of the photolabile (7-diethylaminocoumarin-4-yl)methyl protecting group in response to photoirradiation. A key advantage of AC-SAHA is that the caged derivative itself shows essentially no HDAC-inhibitory activity. Upon photoirradiation, AC-SAHA decomposes to SAHA and a 7-diethylaminocoumarin derivative, together with some minor products. We confirmed that AC-SAHA inhibits HDAC in response to photoirradiation in vitro by means of chemiluminescence assay. AC-SAHA also showed photoinduced inhibition of proliferation of human colon cancer cell line HCT116, as determined by MTT assay. Thus, AC-SAHA should be a useful tool for spatiotemporally controlled inhibition of HDAC activity, as well as a candidate chemotherapeutic reagent for human colon cancer. Graphical abstract image
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Exploring the 2- and 5-positions of the pyrazolo[4,3-d]pyrimidin-7-amino scaffold to target human A1 and A2A adenosine receptors ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Lucia Squarcialupi, Matteo Falsini, Daniela Catarzi, Flavia Varano, Marco Betti, Katia Varani, Fabrizio Vincenzi, Diego Dal Ben, Catia Lambertucci, Rosaria Volpini, Vittoria Colotta A new series of 7-aminopyrazolo[4,3-d]pyrimidine derivatives (1–31) were synthesized to evaluate some structural modifications at the 2- and 5-positions aimed at shifting affinity towards the human (h) A2A adenosine receptor (AR) or both hA2A and hA1 ARs. The most active compounds were those featured by a 2-furyl or 5-methylfuran-2-yl moiety at position 5, combined with a benzyl or a substituted-benzyl group at position 2. Several of these derivatives (22–31) displayed nanomolar affinity for the hA2A AR (K i =3.62–57nM) and slightly lower for the hA1 ARs, thus showing different degrees (3–22 fold) of hA2A versus hA1 selectivity. In particular, the 2-(2-methoxybenzyl)-5-(5-methylfuran-2-yl) derivative 25 possessed the highest hA2A and hA1 AR affinities (K i =3.62nM and 18nM, respectively) and behaved as potent antagonist at both these receptors (cAMP assays). Its 2-(2-hydroxybenzyl) analog 26 also showed a high affinity for the hA2A AR (K i =5.26nM) and was 22-fold selective versus the hA1 subtype. Molecular docking investigations performed at the hA2A AR crystal structure and at a homology model of the hA1 AR allowed us to represent the hypothetical binding mode of our derivatives and to rationalize the observed SARs. Graphical abstract image
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Analysis of the aplyronine A-induced protein–protein interaction between actin and tubulin by surface plasmon resonance ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Yuichiro Hirayama, Kota Yamagishi, Tomohiro Suzuki, Hirokazu Kawagishi, Masaki Kita, Hideo Kigoshi The antitumor macrolide aplyronine A induces protein–protein interaction (PPI) between actin and tubulin to exert highly potent biological activities. The interactions and binding kinetics of these molecules were analyzed by the surface plasmon resonance with biotinylated aplyronines or tubulin as ligands. Strong binding was observed for tubulin and actin with immobilized aplyronine A. These PPIs were almost completely inhibited by one equivalent of either aplyronine A or C, or mycalolide B. In contrast, a non-competitive actin-depolymerizing agent, latrunculin A, highly accelerated their association. Significant binding was also observed for immobilized tubulin with an actin–aplyronine A complex, and the dissociation constant K D was 1.84μM. Our method could be used for the quantitative analysis of the PPIs between two polymerizing proteins stabilized with small agents. Graphical abstract image
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The 5-aromatic hydantoin-3-acetate derivatives as inhibitors of the tumour multidrug resistance efflux pump P-glycoprotein (ABCB1): Synthesis, crystallographic and biological studies ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Ewa Żesławska, Annamária Kincses, Gabriella Spengler, Wojciech Nitek, Karolina Wyrzuc, Katarzyna Kieć-Kononowicz, Jadwiga Handzlik A series of arylpiperazine derivatives of hydantoin-3-acetate, including previously obtained 5,5-diphenylhydantoin (1–7) and new-synthesized spirofluorene-hydantoin derivatives (8–12), were investigated in the search for new inhibitors of the tumour multidrug resistance (MDR) efflux pump P-glycoprotein (P-gp, ABCB1) overexpressed in mouse T-lymphoma cells. Synthesis of new compounds (8–12) was performed. Crystal structures of two compounds (8 and 11) were determined by X-ray diffraction method. The conformations of the investigated molecules (8 and 11) in the crystalline samples are different. The bent conformation seems to be more favourable for biological activity than the extended one. The efflux pump inhibitory properties of the compounds 1–12 were evaluated in the fluorescence uptake assay using rhodamine 123 dye in mouse T-lymphoma model in vitro. Their cytotoxic action was examined, too. All compounds with methyl acetate moiety displayed high potency to inhibit the MDR efflux pump. The most active compound, methyl 2-(1-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-5,5-diphenylhydantoin-3-yl)acetate (5), tested at 1/10 of verapamil concentration displayed the 9-fold higher P-gp inhibitory action. Graphical abstract image
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Exploring new chemical functionalities to improve aromatase inhibition of steroids ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Carla L. Varela, Cristina Amaral, Georgina Correia-da-Silva, Saul C. Costa, Rui A. Carvalho, Giosuè Costa, Stefano Alcaro, Natércia A.A. Teixeira, Elisiário J. Tavares-da-Silva, Fernanda M.F. Roleira In this work, new potent steroidal aromatase inhibitors both in microsomes and in breast cancer cells have been found. The synthesis of the 3,4-(ethylenedioxy)androsta-3,5-dien-17-one (12), a new steroid containing a heterocycle dioxene fused in the A-ring, led to the discovery of a new reaction for which a mechanism is proposed. New structure–activity relationships were established. Some 5β-steroids, such as compound 4β,5β-epoxyandrostan-17-one (9), showed aromatase inhibitory activity, because they adopt a similar A-ring conformation as those of androstenedione, the natural substrate of aromatase. Moreover, new chemical features to increase planarity were disclosed, specifically the 3α,4α-cyclopropane ring, as in 3α,4α-methylen-5α-androstan-17-one (5) (IC50 =0.11μM), and the Δ9–11 double bond in the C-ring, as in androsta-4,9(11)-diene-3,17-dione (13) (IC50 =0.25μM). In addition, induced-fit docking (IFD) simulations and site of metabolism (SoM) predictions helped to explain the recognition of new potent steroidal aromatase inhibitors within the enzyme. These insights can be valuable tools for the understanding of the molecular recognition process by the aromatase and for the future design of new steroidal inhibitors. Graphical abstract image
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Evaluation of N-substituent structural variations in opioid receptor profile of LP1 ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Lorella Pasquinucci, Rita Turnaturi, Giuseppina Aricò, Carmela Parenti, Paschalina Pallaki, Zafiroula Georgoussi, Simone Ronsisvalle The benzomorphan scaffold has great potential as lead structure and the nature of the N-substituent is able to influence affinity, potency, and efficacy at all three opioid receptors. Building upon these considerations, we synthesized a new series of LP1 analogues by introducing naphthyl or heteroaromatic rings in propanamide side chain of its N-substituent (9–15). In vitro competition-binding assays in HEK293 cells stably expressing MOR, DOR or KOR showed that in compound 9 the 1-naphthyl ring led to the retention of MOR affinity (K i MOR =38±4nM) displaying good selectivity versus DOR and KOR. In the electrically stimulated GPI, compound 9 was inactive as agonist but produced an antagonist potency value (pA2) of 8.6 in presence of MOR agonist DAMGO. Moreover, subcutaneously administered it antagonized the antinociceptive effects of morphine with an AD50 =2.0mg/kg in mouse-tail flick test. Modeling studies on MOR revealed that compound 9 fit very well in the binding pocket but in a different way in respect to the agonist LP1. Probably the replacement of its N-substituent on the III, IV and V TM domains reflects an antagonist behavior. Therefore, compound 9 could represent a potential lead to further develop antagonists as valid therapeutic agents and useful pharmacological tools to study opioid receptor function. Graphical abstract image
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Synthesis and biological evaluation of 1,2-dithiol-3-thiones and pyrrolo[1,2-a]pyrazines as novel hypoxia inducible factor-1 (HIF-1) inhibitor ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Young Hun Lee, Jung Min Lee, Sang Geon Kim, Yong Sup Lee Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor which is strongly associated with tumor survival, progression, and therapeutic resistance. Accordingly, it has been suggested that the inhibition of the HIF-1 pathway can suppress tumor, and it has become an important therapeutic target. In present study, oltipraz, its metabolite M2, and their derivatives were synthesized and evaluated as HIF-1α inhibitors. Among the synthesized, benzyl-substituted pyrrolo[1,2-a]pyrazine 2g most potently inhibited HIF-1α protein accumulation (81% at 10μM) and VEGF, GLUT-1 transcription (77% and 92% at 10μM, respectively). Graphical abstract image
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Design, synthesis, structure–activity relationships, and docking studies of pyrazole-containing derivatives as a novel series of potent glucagon receptor antagonists ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Shuangjie Shu, Xiaoqing Cai, Jia Li, Yang Feng, Antao Dai, Jiang Wang, Dehua Yang, Ming-Wei Wang, Hong Liu Glucagon receptor antagonists possess a great potential for treatment of type 2 diabetes mellitus. A series of pyrazole-containing derivatives were designed, synthesized and evaluated by biological assays as glucagon receptor antagonists. Most of the compounds exhibited good in vitro efficacy. Two of them, compounds 17f and 17k, displayed relatively potent antagonist effects on glucagon receptors with IC50 values of 3.9 and 3.6μM, respectively. The possible binding modes of 17f and 17k with the cognate receptor were explored by molecular docking simulation. Graphical abstract image
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Hydraphiles enhance antimicrobial potency against Escherichia coli, Pseudomonas aeruginosa, and Bacillus subtilis ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Mohit B. Patel, Evan C. Garrad, Ariel Stavri, Michael R. Gokel, Saeedeh Negin, Joseph W. Meisel, Zachary Cusumano, George W. Gokel Hydraphiles are synthetic amphiphiles that form ion-conducting pores in liposomal membranes. These pores exhibit open-close behavior when studied by planar bilayer conductance techniques. In previous work, we showed that when co-administered with various antibiotics to the DH5α strain of Escherichia coli, they enhanced the drug’s potency. We report here potency enhancements at low concentrations of hydraphiles for the structurally and mechanistically unrelated antibiotics erythromycin, kanamycin, rifampicin, and tetracycline against Gram negative E. coli (DH5α and K-12) and Pseudomonas aeruginosa, as well as Gram positive Bacillus subtilis. Earlier work suggested that potency increases correlated to ion transport function. The data presented here comport with the function of hydraphiles to enhance membrane permeability in addition to, or instead of, their known function as ion conductors. Graphical abstract image
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Editorial board ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
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Quinazolines and quinazolinones as ubiquitous structural fragments in medicinal chemistry: An update on the development of synthetic methods and pharmacological diversification ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Imtiaz Khan, Sumera Zaib, Sadaf Batool, Naeem Abbas, Zaman Ashraf, Jamshed Iqbal, Aamer Saeed Nitrogen-rich heterocycles, particularly quinazolines and quinazolinones, represent a unique class of diversified frameworks displaying a broad spectrum of biological functions. Over the past several years, intensive medicinal chemistry efforts have generated numerous structurally functionalized quinazoline and quinazolinone derivatives. Interest in expanding the biological effects, demonstrated by these motifs, is growing exponentially, as indicated by the large number of publications reporting the easy accessibility of these skeletons in addition to the diverse nature of synthetic as well as biological applications. Therefore, the main focus of the present review is to provide an ample but condensed overview on various synthetic approaches providing access to quinazoline and quinazolinone compounds with multifaceted biological activities. Furthermore, mechanistic insights, synthetic utilization, structure–activity relationships and molecular modeling inputs for the potent derivatives have also been discussed. Graphical abstract image
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Cytoprotective small molecule modulators of endoplasmic reticulum stress ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Soumyabrata Munshi, Russell Dahl Cellular health depends on the normal function of the endoplasmic reticulum (ER) to fold, assemble, and modify critical proteins to maintain viability. When the ER cannot process proteins effectively, a condition known as ER stress ensues. When this stress is excessive or prolonged, cell death via apoptotic pathways is triggered. Interestingly, most major diseases have been shown to be intimately linked to ER stress, including diabetes, stroke, neurodegeneration, and many cancers. Thus, controlling ER stress presents a significant strategy for drug development for these diseases. The goal of this review is to present various small molecules that alleviate ER stress with the intention that they may serve as useful starting points for therapeutic agent development. Graphical abstract image
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Exploration of 3-methylisoquinoline-4-carbonitriles as protein kinase A inhibitors of Plasmodium falciparum ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Melissa J. Buskes, Katherine L. Harvey, Boris Prinz, Brendan S. Crabb, Paul R. Gilson, David J.D. Wilson, Belinda M. Abbott A series of isoquinolines have been evaluated in a homology model of Plasmodium falciparum Protein Kinase A (PfPKA) using molecular dynamics. Synthesis of these compounds was then undertaken to investigate their structure–activity relationships. One compound was found to inhibit parasite growth in an in vitro assay and provides a lead to further develop 3-methylisoquinoline-4-carbonitriles as antimalarial compounds. Development of a potent and selective PfPKA inhibitor would provide a useful tool to shed further insight into the mechanisms enabling malaria parasites to establish infection. Graphical abstract image
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Synthesis and biological evaluation of sialyl-oligonucleotide conjugates targeting leukocyte B trans-membranal receptor CD22 as delivery agents for nucleic acid drugs ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Gabrielle St-Pierre, Sudip Pal, Michael E. Østergaard, Tianyuan Zhou, Jinghua Yu, Michael Tanowitz, Punit P. Seth, Stephen Hanessian Antisense oligonucleotides (ASOs) modified with ligands which target cell surface receptors have the potential to significantly improve potency in the target tissue. This has recently been demonstrated using triantennary N-acetyl d-galactosamine conjugated ASOs. CD22 is a cell surface receptor expressed exclusively on B cells thus presenting an attractive target for B cell specific delivery of drugs. Herein, we reported the synthesis of monovalent and trivalent ASO conjugates with biphenylcarbonyl (BPC) modified sialic acids and their study as ASO delivery agents into B cells. CD22 positive cells exhibited reduced potency when treated with ligand modified ASOs and mechanistic examination suggested reduced uptake into cells potentially as a result of sequestration of ASO by other cell-surface proteins. Graphical abstract image
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Synergistic reduction of HIV-1 infectivity by 5-azacytidine and inhibitors of ribonucleotide reductase ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Jonathan M.O. Rawson, Megan E. Roth, Jiashu Xie, Michele B. Daly, Christine L. Clouser, Sean R. Landman, Cavan S. Reilly, Laurent Bonnac, Baek Kim, Steven E. Patterson, Louis M. Mansky Although many compounds have been approved for the treatment of human immunodeficiency type-1 (HIV-1) infection, additional anti-HIV-1 drugs (particularly those belonging to new drug classes) are still needed due to issues such as long-term drug-associated toxicities, transmission of drug-resistant variants, and development of multi-class resistance. Lethal mutagenesis represents an antiviral strategy that has not yet been clinically translated for HIV-1 and is based on the use of small molecules to induce excessive levels of deleterious mutations within the viral genome. Here, we show that 5-azacytidine (5-aza-C), a ribonucleoside analog that induces the lethal mutagenesis of HIV-1, and multiple inhibitors of the enzyme ribonucleotide reductase (RNR) interact in a synergistic fashion to more effectively reduce the infectivity of HIV-1. In these drug combinations, RNR inhibitors failed to significantly inhibit the conversion of 5-aza-C to 5-aza-2′-deoxycytidine, suggesting that 5-aza-C acts primarily as a deoxyribonucleoside even in the presence of RNR inhibitors. The mechanism of antiviral synergy was further investigated for the combination of 5-aza-C and one specific RNR inhibitor, resveratrol, as this combination improved the selectivity index of 5-aza-C to the greatest extent. Antiviral synergy was found to be primarily due to the reduced accumulation of reverse transcription products rather than the enhancement of viral mutagenesis. To our knowledge, these observations represent the first demonstration of antiretroviral synergy between a ribonucleoside analog and RNR inhibitors, and encourage the development of additional ribonucleoside analogs and RNR inhibitors with improved antiretroviral activity. Graphical abstract image
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Synthesis and evaluation of 4-(2-hydroxypropyl)piperazin-1-yl) derivatives as Hsp90 inhibitors ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Bahidja Cherfaoui, Tian-kun Guo, Hao-Peng Sun, Wei-Lin Cheng, Fang Liu, Fen Jiang, Xiao-Li Xu, Qi-Dong You We previously reported 4-(3-((6-bromonaphthalen-2-yl)oxy)-2-hydroxypropyl)-N,N-dimethylpiperazine-1-sulfonamide (1) as a novel heat shock protein 90 inhibitor with moderate activity. In our ongoing efforts for the discovery of Hsp90 modulators we undertake structural investigations on 1. Series of the titled compound were designed, synthesized and evaluated. We have found that compounds with a hydroxyl group at C-4 of the aryl ring on the piperazine moiety possess Hsp90 inhibition properties. Compound 6f with improved activity could be further developed and optimized as Hsp90 inhibitor. Graphical abstract image
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New imidazoquinoxaline derivatives: Synthesis, biological evaluation on melanoma, effect on tubulin polymerization and structure–activity relationships ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Zahraa Zghaib, Jean-François Guichou, Johanna Vappiani, Nicole Bec, Kamel Hadj-Kaddour, Laure-Anaïs Vincent, Stéphanie Paniagua-Gayraud, Christian Larroque, Georges Moarbess, Pierre Cuq, Issam Kassab, Carine Deleuze-Masquéfa, Mona Diab-Assaf, Pierre-Antoine Bonnet Microtubules are considered as important targets of anticancer therapy. EAPB0503 and its structural imidazo[1,2-a]quinoxaline derivatives are major microtubule-interfering agents with potent anticancer activity. In this study, the synthesis of several new derivatives of EAPB0503 is described, and the anticancer efficacy of 13 novel derivatives on A375 human melanoma cell line is reported. All new compounds show significant antiproliferative activity with IC50 in the range of 0.077–122μM against human melanoma cell line (A375). Direct inhibition of tubulin polymerization assay in vitro is also assessed. Results show that compounds 6b, 6e, 6g, and EAPB0503 highly inhibit tubulin polymerization with percentages of inhibition of 99%, 98%, 90%, and 84% respectively. Structure–activity relationship studies within the series are also discussed in line with molecular docking studies into the colchicine-binding site of tubulin. Graphical abstract image
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Substituted quinolines as noncovalent proteasome inhibitors ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Tanner J. McDaniel, Theresa A. Lansdell, Amila A. Dissanayake, Lauren M. Azevedo, Jacob Claes, Aaron L. Odom, Jetze J. Tepe Screening of a library of diverse heterocyclic scaffolds identified substituted quinolines as inhibitors of the human proteasome. The heterocyclic library was prepared via a novel titanium-catalyzed multicomponent coupling reaction, which rendered a diverse set of isoxazoles, pyrimidines, pyrroles, pyrazoles and quinolines. SAR of the parent lead compound indicated that hydrophobic residues on the benzo-moiety significantly improved potency. Lead compound 25 inhibits the chymotryptic-like proteolytic activity of the proteasome (IC50 5.4μM), representing a new class of nonpeptidic, noncovalent proteasome inhibitors. Graphical abstract image
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Synthesis of novel amide and urea derivatives of thiazol-2-ethylamines and their activity against Trypanosoma brucei rhodesiense ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Donald A. Patrick, Tanja Wenzler, Sihyung Yang, Patrick T. Weiser, Michael Zhuo Wang, Reto Brun, Richard R. Tidwell 2-(2-Benzamido)ethyl-4-phenylthiazole (1) was one of 1035 molecules (grouped into 115 distinct scaffolds) found to be inhibitory to Trypanosoma brucei, the pathogen causing human African trypanosomiasis, at concentrations below 3.6μM and non-toxic to mammalian (Huh7) cells in a phenotypic high-throughput screen of a 700,000 compound library performed by the Genomics Institute of the Novartis Research Foundation (GNF). Compound 1 and 72 analogues were synthesized in this lab by one of two general pathways. These plus 10 commercially available analogues were tested against T. brucei rhodesiense STIB900 and L6 rat myoblast cells (for cytotoxicity) in vitro. Forty-four derivatives were more potent than 1, including eight with IC50 values below 100nM. The most potent and most selective for the parasite was the urea analogue 2-(2-piperidin-1-ylamido)ethyl-4-(3-fluorophenyl)thiazole (70, IC50 =9nM, SI>18,000). None of 33 compounds tested were able to cure mice infected with the parasite; however, seven compounds caused temporary reductions of parasitemia (⩾97%) but with subsequent relapses. The lack of in vivo efficacy was at least partially due to their poor metabolic stability, as demonstrated by the short half-lives of 15 analogues against mouse and human liver microsomes. Graphical abstract image
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Discovery and optimization of 1,7-disubstituted-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-ones as potent and selective PKCθ inhibitors ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Taisuke Katoh, Takafumi Takai, Takafumi Yukawa, Tetsuya Tsukamoto, Etsurou Watanabe, Hideyuki Mototani, Takeo Arita, Hiroki Hayashi, Hideyuki Nakagawa, Michael G. Klein, Hua Zou, Bi-Ching Sang, Gyorgy Snell, Yoshihisa Nakada A high-throughput screening campaign helped us to identify an initial lead compound (1) as a protein kinase C-θ (PKCθ) inhibitor. Using the docking model of compound 1 bound to PKCθ as a model, structure-based drug design was employed and two regions were identified that could be explored for further optimization, i.e., (a) a hydrophilic region around Thr442, unique to PKC family, in the inner part of the hinge region, and (b) a lipophilic region at the forefront of the ethyl moiety. Optimization of the hinge binder led us to find 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one as a potent and selective hinge binder, which resulted in the discovery of compound 5. Filling the lipophilic region with a suitable lipophilic substituent boosted PKCθ inhibitory activity and led to the identification of compound 10. The co-crystal structure of compound 10 bound to PKCθ confirmed that both the hydrophilic and lipophilic regions were fully utilized. Further optimization of compound 10 led us to compound 14, which demonstrated an improved pharmacokinetic profile and inhibition of IL-2 production in a mouse. Graphical abstract image
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1,6-Bis[(benzyloxy)methyl]uracil derivatives—Novel antivirals with activity against HIV-1 and influenza H1N1 virus ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Alexander N. Geisman, Vladimir T. Valuev-Elliston, Alexander A. Ozerov, Anastasia L. Khandazhinskaya, Alexander O. Chizhov, Sergey N. Kochetkov, Christophe Pannecouque, Lieve Naesens, Katherine L. Seley-Radtke, Mikhail S. Novikov A series of 1,6-bis[(benzyloxy)methyl]uracil derivatives combining structural features of both diphenyl ether and pyridone types of NNRTIs were synthesized. Target compounds were found to inhibit HIV-1 reverse transcriptase at micro- and submicromolar levels of concentrations and exhibited anti-HIV-1 activity in MT-4 cell culture, demonstrating resistance profile similar to first generation NNRTIs. The synthesized compounds also showed profound activity against influenza virus (H1N1) in MDCK cell culture without detectable cytotoxicity. The lead compound of this assay appeared to exceed rimantadine, amantadine, ribavirin and oseltamivir carboxylate in activity. The mechanism of action of 1,6-bis[(benzyloxy)methyl]uracils against influenza virus is currently under investigation. Graphical abstract image
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Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel 1-(1H-benzimidazol-6-yl)pyridin-2(1H)-one derivatives and design to avoid CYP3A4 time-dependent inhibition ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Hideyuki Igawa, Masashi Takahashi, Mikio Shirasaki, Keiko Kakegawa, Asato Kina, Minoru Ikoma, Jumpei Aida, Tsuneo Yasuma, Shoki Okuda, Yayoi Kawata, Toshihiro Noguchi, Syunsuke Yamamoto, Yasushi Fujioka, Mrinalkanti Kundu, Uttam Khamrai, Masaharu Nakayama, Yasutaka Nagisa, Shizuo Kasai, Tsuyoshi Maekawa Melanin-concentrating hormone (MCH) is an attractive target for antiobesity agents, and numerous drug discovery programs are dedicated to finding small-molecule MCH receptor 1 (MCHR1) antagonists. We recently reported novel pyridine-2(1H)-ones as aliphatic amine-free MCHR1 antagonists that structurally featured an imidazo[1,2-a]pyridine-based bicyclic motif. To investigate imidazopyridine variants with lower basicity and less potential to inhibit cytochrome P450 3A4 (CYP3A4), we designed pyridine-2(1H)-ones bearing various less basic bicyclic motifs. Among these, a lead compound 6a bearing a 1H-benzimidazole motif showed comparable binding affinity to MCHR1 to the corresponding imidazopyridine derivative 1. Optimization of 6a afforded a series of potent thiophene derivatives (6q–u); however, most of these were found to cause time-dependent inhibition (TDI) of CYP3A4. As bioactivation of thiophenes to form sulfoxide or epoxide species was considered to be a major cause of CYP3A4 TDI, we introduced electron withdrawing groups on the thiophene and found that a CF3 group on the ring or a Cl adjacent to the sulfur atom helped prevent CYP3A4 TDI. Consequently, 4-[(5-chlorothiophen-2-yl)methoxy]-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (6s) was identified as a potent MCHR1 antagonist without the risk of CYP3A4 TDI, which exhibited a promising safety profile including low CYP3A4 inhibition and exerted significant antiobesity effects in diet-induced obese F344 rats. Graphical abstract image
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Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel non-basic 1-(2H-indazole-5-yl)pyridin-2(1H)-one derivatives and mitigation of mutagenicity in Ames test ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Hideyuki Igawa, Masashi Takahashi, Minoru Ikoma, Hiromi Kaku, Keiko Kakegawa, Asato Kina, Jumpei Aida, Shoki Okuda, Yayoi Kawata, Toshihiro Noguchi, Natsu Hotta, Syunsuke Yamamoto, Masaharu Nakayama, Yasutaka Nagisa, Shizuo Kasai, Tsuyoshi Maekawa To develop non-basic melanin-concentrating hormone receptor 1 (MCHR1) antagonists with a high probability of target selectivity and therapeutic window, we explored neutral bicyclic motifs that could replace the previously reported imidazo[1,2-a]pyridine or 1H-benzimidazole motif. The results indicated that the binding affinity of a chemically neutral 2H-indazole derivative 8a with MCHR1 (hMCHR1: IC50 =35nM) was comparable to that of the imidazopyridine and benzimidazole derivatives (1 and 2, respectively) reported so far. However, 8a was positive in the Ames test using TA1537 in S9− condition. Based on a putative intercalation of 8a with DNA, we introduced a sterically-hindering cyclopropyl group on the indazole ring to decrease planarity, which led to the discovery of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-{[5-(trifluoromethyl)thiophen-3-yl]methoxy}pyridin-2(1H)-one 8l without mutagenicity in TA1537. Compound 8l exerted significant antiobesity effects in diet-induced obese F344 rats and exhibited promising safety profile. Graphical abstract image
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Design, discovery, modelling, synthesis, and biological evaluation of novel and small, low toxicity s-triazine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Birgit Viira, Anastasia Selyutina, Alfonso T. García-Sosa, Maarit Karonen, Jari Sinkkonen, Andres Merits, Uko Maran A set of top-ranked compounds from a multi-objective in silico screen was experimentally tested for toxicity and the ability to inhibit the activity of HIV-1 reverse transcriptase (RT) in cell-free assay and in cell-based assay using HIV-1 based virus-like particles. Detailed analysis of a commercial sample that indicated specific inhibition of HIV-1 reverse transcription revealed that a minor component that was structurally similar to that of the main compound was responsible for the strongest inhibition. As a result, novel s-triazine derivatives were proposed, modelled, discovered, and synthesised, and their antiviral activity and cellular toxicity were tested. Compounds 18a and 18b were found to be efficient HIV-1 RT inhibitors, with an IC50 of 5.6±1.1μM and 0.16±0.05μM in a cell-based assay using infectious HIV-1, respectively. Compound 18b also had no detectable toxicity for different human cell lines. Their binding mode and interactions with the RT suggest that there was strong and adaptable binding in a tight (NNRTI) hydrophobic pocket. In summary, this iterative study produced structural clues and led to a group of non-toxic, novel compounds to inhibit HIV-RT with up to nanomolar potency. Graphical abstract image
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2-Arylacetamido-4-phenylamino-5-substituted pyridazinones as formyl peptide receptors agonists ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Claudia Vergelli, Igor A. Schepetkin, Giovanna Ciciani, Agostino Cilibrizzi, Letizia Crocetti, Maria Paola Giovannoni, Gabriella Guerrini, Antonella Iacovone, Liliya N. Kirpotina, Andrei I. Khlebnikov, Richard D. Ye, Mark T. Quinn N-Formyl peptide receptors (FPRs: FPR1, FPR2, and FPR3) are G protein-coupled receptors that play key roles in modulating immune cells. FPRs represent potentially important therapeutic targets for the development of drugs that could enhance endogenous anti-inflammation systems associated with various pathologies, thereby reducing the progression of inflammatory conditions. Previously, we identified 2-arylacetamide pyridazin-3(2H)-ones as FPR1- or FPR2-selective agonists, as well as a large number of FPR1/FPR2-dual agonists and several mixed-agonists for the three FPR isoforms. Here, we report a new series of 2-arylacetamido-4-aniline pyridazin-3(2H)-ones substituted in position 5 as a further development of these FPR agonists. Chemical manipulation presented in this work resulted in mixed FPR agonists 8a, 13a and 27b, which had EC50 values in nanomolar range. In particular, compound 8a showed a preference for FPR1 (EC50 =45nM), while 13a and 27b showed a moderate preference for FPR2 (EC50 =35 and 61nM, respectively). Thus, these compounds may represent valuable tools for studying FPR activation and signaling. Graphical abstract image
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Antiplasmodial phloroglucinol derivatives from Syncarpia glomulifera ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Qingxi Su, Seema Dalal, Michael Goetz, Maria B. Cassera, David G.I. Kingston Bioassay guided fractionation of a MeOH extract of the stem bark of Syncarpia glomulifera (Myrtaceae) led to the isolation of the two new phloroglucinol derivatives (±)-rhodomyrtosone F (1) and (±)-calliviminone C (2), the three known triterpenes, betulinic acid (3), ursolic acid-3-acetate (4), and ursolic acid (5), and 1-(2,4,6-trihydroxyphenyl)-1-hexanone (6). Compound 1 exhibited strong antiplasmodial activity, while compounds 2–4 were moderately active and 5 and 6 were inactive in this assay. The structures of 1 and 2 were elucidated based on analyses of their mass spectrometric data, 1D and 2D NMR spectra, and comparison with related compounds. Graphical abstract image
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Design, synthesis and biological evaluation of benzyloxyphenyl-methylaminophenol derivatives as STAT3 signaling pathway inhibitors ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Dingding Gao, Qiang Xiao, Mingming Zhang, Yingxia Li STAT3 signaling pathway has been validated as a vital therapeutic target for cancer therapy. Based on the novel STAT3 inhibitor of a benzyloxyphenyl-methylaminophenol scaffold hit (1) discovered through virtual screening, a series of analogues had been designed and synthesized for more potent inhibitors. The preliminary SAR had been discussed and the unique binding site in SH2 domain was predicted by molecular docking. Among them, compounds 4a and 4b exhibited superior activities than hit compound (1) against IL-6/STAT3 signaling pathway with IC50 values as low as 7.71μM and 1.38μM, respectively. Compound 4a also displayed potent antiproliferative activity against MDA-MB-468 cell line with an IC50 value of 9.61μM. We believe that these benzyloxyphenyl-methylaminophenol derivatives represent a unique mechanism for interrogating STAT3 as well as a potential structure type for further exploration. Graphical abstract image
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Synthesis of 24(S)-hydroxycholesterol esters responsible for the induction of neuronal cell death ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Kimiyuki Shibuya, Toshiaki Watanabe, Yasuomi Urano, Wakako Takabe, Noriko Noguchi, Hiroaki Kitagishi We synthesized several candidates of 24(S)-hydroxycholesterol (24S-OHC) esters, which are involved in neuronal cell death, through catalysis with acyl-CoA:cholesterol acyltransferase-1 (ACAT-1). We studied the regioselectivity of the acylation of the secondary alcohol at the 3- or 24-position of 24S-OHC. The appropriate saturated and unsaturated long-chain fatty acids were esterified with the protected 24S-OHC and then de-protected to afford the desired esters at a satisfactory yield. We then confirmed by HPLC monitoring that the retention times of four esters of 24S-OHC, namely 3-oleate, 3-linoleate, 3-arachidonoate and 3-docosahexaenoate, were consistent with those of 24S-OHC esters observed in 24S-OHC-treated SH-SY5Y cells. Graphical abstract image
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Design, synthesis and in vitro evaluation studies of sulfonyl-amino-acetamides as small molecule BACE-1 inhibitors ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Priti Jain, Pankaj K. Wadhwa, Sinduri Gunapati, Hemant R. Jadhav The identification of a series of sulfonyl-amino-acetamides as BACE-1 (β-secretase) inhibitors for the treatment of Alzheimer’s disease is reported. The derivatives were designed based on the docking simulation study, synthesized and assessed for BACE-1 inhibition in vitro. The designed ligands revealed desired binding interactions with the catalytic aspartate dyad and occupance of S1 and S2′ active site regions. These in silico results correlated well with in vitro activity. Out of 33 compounds synthesized, 12 compounds showed significant inhibition at 10μM concentration. The most active compound 2.17S had IC50 of 7.90μM against BACE-1, which was concomitant with results of in silico docking study. Graphical abstract image
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3D-QSAR-aided design, synthesis, in vitro and in vivo evaluation of dipeptidyl boronic acid proteasome inhibitors and mechanism studies ()
Publication date: 1 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11 Author(s): Meng Lei, Huayun Feng, Cheng Wang, Hailing Li, Jingmiao Shi, Jia Wang, Zhaogang Liu, Shanshan Chen, Shihe Hu, Yongqiang Zhu Proteasome had been clinically validated as an effective target for the treatment of cancers. Up to now, many structurally diverse proteasome inhibitors were discovered. And two of them were launched to treat multiple myeloma (MM) and mantle cell lymphoma (MCL). Based on our previous biological results of dipeptidyl boronic acid proteasome inhibitors, robust 3D-QSAR models were developed and structure–activity relationship (SAR) was summarized. Several structurally novel compounds were designed based on the theoretical models and finally synthesized. Biological results showed that compound 12e was as active as the standard bortezomib in enzymatic and cellular activities. In vivo pharmacokinetic profiles suggested compound 12e showed a long half-life, which indicated that it could be administered intravenously. Cell cycle analysis indicated that compound 12e inhibited cell cycle progression at the G2M stage. Graphical abstract image
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