Bioorganic & Medicinal Chemistry

Editorial board ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3
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Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3
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Natural antitubulin agents: Importance of 3,4,5-trimethoxyphenyl fragment ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Arvind S. Negi , Yashveer Gautam , Sarfaraz Alam , Debabrata Chanda , Suaib Luqman , Jayanta Sarkar , Feroz Khan , Rituraj Konwar Microtubules are polar cytoskeletal filaments assembled from head-to-tail and comprised of lateral associations of α/β-tubulin heterodimers that play key role in various cellular processes. Because of their vital role in mitosis and various other cellular processes, microtubules have been attractive targets for several disease conditions and especially for cancer. Antitubulin is the most successful class of antimitotic agents in cancer chemotherapeutics. The target recognition of antimitotic agents as a ligand is not much explored so far. However, 3,4,5-trimethoxyphenyl fragment has been much highlighted and discussed in such type of interactions. In this review, some of the most important naturally occurring antimitotic agents and their interactions with microtubules are discussed with a special emphasis on the role of 3,4,5-trimethoxyphenyl unit. At last, some emerging naturally occurring antimitotic agents have also been tabulated. Graphical abstract image
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Evaluation of two novel antioxidants with differential effects on curcumin-induced apoptosis in C2 skeletal myoblasts; involvement of JNKs ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Maria Peleli , Ioanna-Katerina Aggeli , Alexios N. Matralis , Angeliki P. Kourounakis , Isidoros Beis , Catherine Gaitanaki Excessive levels of reactive oxygen species (ROS) result in numerous pathologies including muscle disorders. In essence, skeletal muscle performance of daily activities can be severely affected by the redox imbalances occurring after muscular injuries, surgery, atrophy due to immobilization, dystrophy or eccentric muscle contraction. Therefore, research on the potential beneficial impact of antioxidants is of outmost importance. In this context, aiming at further exploring the mechanisms of action of our newly synthesized antioxidant compounds (AK1 and AK2) in a skeletal muscle experimental setting, we initially investigated their scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH) and subsequently assessed their effect on the viability of C2 skeletal myoblasts in the presence of two pro-oxidants: H2O2 and curcumin (MTT assay). Interestingly, while both compounds reversed the detrimental effect of H2O2, only AK2 was cytoprotective in curcumin-treated C2 cells. We next confirmed the immediate activation of extracellular signal-regulated kinases (ERKs) and the more delayed activation profile of c-Jun NH2-terminal kinases (JNKs) in C2 skeletal myoblasts exposed to curcumin, by Western blotting. In correlation with the aforementioned results, only AK2 blocked the curcumin-induced activation of JNKs pathway. Furthermore, JNKs were revealed to mediate curcumin-induced apoptosis in C2 cells and only AK2 to effectively suppress it (by detecting its effect on poly(ADP-ribose) polymerase fragmentation). Overall, we have shown that two similar in structure novel antioxidants confer differential effects on C2 skeletal myoblasts viability under oxidative stress conditions. This result may be attributed to these antioxidants respective diverse mode of interaction with the signaling effectors involved in the observed responses. Future studies should further evaluate the mechanism of action of these compounds in order to support their potential application in therapeutic protocols against ROS-related muscle disorders. Graphical abstract image
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Synthesis and biological activities of some new isonicotinic acid 2-(2-hydroxy-8-substituted-tricyclo[7.3.1.02.7]tridec-13-ylidene)-hydrazides ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Lilia Matei , Coralia Bleotu , Ion Baciu , Carmen Cristina Diaconu , Anamaria Hanganu , Otilia Banu , Petre Ionita , Anca Paun , Arnaud Tatibouët , Irina Zarafu A series of several new isoniazid derivatives, isonicotinic acid 2-(2-hydroxy-8-substituted-tricyclo[7.3.1.02.7]tridec-13-ylidene)-hydrazides, were synthesized and fully characterized. These new isoniazid derivatives were studied regarding their antibacterial activity and cytotoxicity, as well as their influences on some metabolizing enzymes. The best anti-mycobacterial activity was observed in the case of compounds containing alkyl side chains in the 8 position of tricyclo[7.3.1.02.7]tridec-13-ylidene group. On contrary, the antimicrobial activity of these new compounds against various non-tuberculosis strains showed the best activity to be with the phenyl side chain of compound 6. It proved also to be the most toxic, inducing apoptosis and blocking the cell cycle in G0/G1 phase. The cell cycle was blocked in G0/G1 phase also by compound 3, but this compound did not show any toxicity. All compounds induced the expression of NAT1 and NAT2 genes in HT-29 cell line, and the expression of CYP1A1 in HT-29 and HCT-8 cell lines. The expression level of CYP3A4 was increased by compounds 1, 6 and 7 in HCT-8 cells. These results indicated that the activation of other metabolizing pathways, apart from those of isoniazid, take place. It might also point out the possibility of an increased isoniazid acetylation ratio by co-administration with new compounds in slow acetylators. Graphical abstract image
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Investigation of fatty acid conjugates of 3,5-bisarylmethylene-4-piperidone derivatives as antitumor agents and human topoisomerase-IIα inhibitors ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Elizabeth Potter , Mamta Jha , Khushwant S. Bhullar , H.P. Vasantha Rupasinghe , Jan Balzarini , Amitabh Jha A series of five 3,5-bisarylidene-4-piperidones designed as analogs of curcumin and their twenty five fatty acid conjugates were synthesized as candidate anticancer agents. The fatty acid conjugates were designed for efficient delivery of these compounds at the targeted cancer sites. The cytostatic potential of these compounds was evaluated against three representative cancer cell lines namely murine leukemic L1210 cells, and human T-lymphocyte CEM cells and cervical HeLa cells. Most compounds were found to exhibit significant anti-cancer activity in vitro. QSAR studies indicated electrophilicity of these compounds towards cellular nucleophiles may have a key role to play in their cytostatic activity. Representative compounds were also tested for topoisomerase IIα inhibitory potential, which indicated strong catalytic inhibition of the enzyme in vitro. The data showed that the fatty acid conjugates also possessed robust antioxidant activity in multiple analyses. This study also indicated that these compounds prompted significantly lower cellular damage in human fibroblasts than a currently used cancer drug sorafenib in vitro. The wide spectrum of anticancer action, supplemented with antioxidant potential along with non-toxic manifestations, certainly augment the anticancer candidacy of the novel fatty acid conjugates. Graphical abstract image
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Synthesis and evaluation of multi-functional NO-donor/insulin-secretagogue derivatives for the treatment of type II diabetes and its cardiovascular complications ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Maria Digiacomo , Alma Martelli , Lara Testai , Annalina Lapucci , Maria C. Breschi , Vincenzo Calderone , Simona Rapposelli Although there is a significant effort in the discovery of effective therapies to contrast both the pathological endocrine and metabolic aspects of diabetes and the endothelial dysfunction associated with this disease, no hypoglycemic drug has been proven to defeat the cardiovascular complications associated with type II diabetes. The aim of this research was to design new compounds exhibiting a double profile of hypoglycemic agents/NO-donors. The synthesis of molecules obtained by the conjunction of NO-donor moieties with two oral insulin-secretagogue drugs (repaglinide and nateglinide) was reported. NO-mediated vasorelaxing effects of the synthesized compounds were evaluated by functional tests on isolated endothelium-denuded rat aortic rings. The most potent molecule (4) was tested to evaluate the hypoglycemic and the anti-ischemic cardioprotective activities. This study indicates that 4 should represent a new insulin-secretagogue/NO-donor prodrug with an enhanced cardiovascular activity, which may contrast the pathological aspects of diabetes and endowed of cardioprotective activity. Graphical abstract image
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Design and synthesis of a novel series of histamine H3 receptor antagonists through a scaffold hopping strategy ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Zhongli Gao , William J. Hurst , Daniel Hall , Ryan Hartung , William Reynolds , Jiesheng Kang , Raisa Nagorny , James A. Hendrix , Pascal G. George Lead compounds 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-benzamide (1), tetrahydro-pyran-4-carboxylic acid [((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide (2), and 3,5-dimethyl-isoxazole-4-carboxylic acid [((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-amide (3) discovered in our laboratory, displayed high histamine H3 receptor (H3R) affinity, good selectivity and weak human Ether-à-go-go-Related Gene (hERG) channel affinity with desirable overall physico-chemical and pharmacokinetic (PK) profiles. Herein, we describe the design and synthesis of a novel series of H3R antagonists utilizing a scaffold hopping strategy. Further structure–activity relationship (SAR) studies of the series culminated in the identification of ((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-naphthalene-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide (4c) and -[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-N-(tetrahydro-pyran-4-yl)-acetamide (4d), which exhibited good H3R affinity in vitro, good selectivity, and desirable PK properties. Compounds 4c and 4d were also assessed in cardiac safety experiments. In particular, the effects of the compounds on action potentials recorded from ventricular myocytes isolated from guinea pigs were used to screen compounds that not only displayed a low affinity towards hERG channel, but also had lower interference with other cardiac ion channels. Compound 4c did not alter the major parameters in this model system at ⩽10μM, and no significant induction of any major haemodynamic effect when intravenously administered at 3mg/kg dose to anaesthetized mongrel dogs. Compound 4c is a new promising lead as orally potent and selective H3R antagonist belonging to a distinct structural class. Graphical abstract image
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Transformation of naltrexone into mesembrane and investigation of the binding properties of its intermediate derivatives to opioid receptors ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Kazuya Konoura , Hideaki Fujii , Satomi Imaide , Hiroaki Gouda , Shigeto Hirayama , Shuichi Hirono , Hiroshi Nagase We transformed naltrexone (5) with the morphinan skeleton into mesembrane (4) belonging to the Sceletium alkaloids via key intermediate 6, characterized by a cis-fused hydroindole skeleton with a suspended phenyl ring fixed by an epoxy bridge. We then investigated the binding affinities of 4 and the key intermediate 6 derivatives to the opioid receptors. Among the tested compounds, 15′, with a cis-fused hydroindole core, bound to the three opioid receptor types with strong to moderate affinities. The observed differences of binding affinities among the tested compounds were reasonably explained by the conformational analyses of the compounds. The structure–activity relationship (SAR) of the tested compounds like 15′ with the hydroindole structure was completely different from the reported SAR of morphinan derivatives with the hydroisoquinoline skeleton. Compound 15′ with a structure that differs from the morphinans represents a useful fundamental skeleton with a novel chemotype that may contribute to the development of new opioid ligands. Graphical abstract image
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Identification of the dioxygenase-generated intermediate formed during biosynthesis of the dihydropyrrole moiety common to anthramycin and sibiromycin ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Shalini Saha , Wei Li , Barbara Gerratana , Steven E. Rokita A description of pyrrolo[1,4]benzodiazepine (PBD) biosynthesis is a prerequisite for engineering production of analogs with enhanced antitumor activity. Predicted dioxygenases Orf12 and SibV associated with dihydropyrrole biosynthesis in PBDs anthramycin and sibiromycin, respectively, were expressed and purified for activity studies. UV–visible spectroscopy revealed that these enzymes catalyze the regiospecific 2,3-extradiol dioxygenation of l-3,4-dihydroxyphenylalanine (l-DOPA) to form l-2,3-secodopa (λ max =368nm). 1H NMR spectroscopy indicates that l-2,3-secodopa cyclizes into the α-keto acid tautomer of l-4-(2-oxo-3-butenoic-acid)-4,5-dihydropyrrole-2-carboxylic acid (λ max =414nm). Thus, the dioxygenases are key for establishing the scaffold of the dihydropyrrole moiety. Kinetic studies suggest the dioxygenase product is relatively labile and is likely consumed rapidly by subsequent biosynthetic steps. The enzymatic product and dimeric state of these dioxygenases are conserved in dioxygenases involved in dihydropyrrole and pyrrolidine biosynthesis within both PBD and non-PBD pathways. Graphical abstract image
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Discovery of triazolone derivatives as novel, potent stearoyl-CoA desaturase-1 (SCD1) inhibitors ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Shaoyi Sun , Zaihui Zhang , Natalia Pokrovskaia , Sultan Chowdhury , Qi Jia , Elaine Chang , Kuldip Khakh , Rainbow Kwan , David G. McLaren , Chris C. Radomski , Leslie G. Ratkay , Jianmin Fu , Natalie A. Dales , Michael D. Winther Stearoyl-CoA desaturase-1 (SCD1) plays an important role in lipid metabolism. Inhibition of SCD1 activity represents a potential novel approach for the treatment of metabolic diseases such as obesity, type 2 diabetes and dyslipidemia, as well as skin diseases, acne and cancer. Herein, we report the synthesis and structure–activity relationships (SAR) of a series of novel triazolone derivatives, culminating in the identification of pyrazolyltriazolone 17a, a potent SCD1 inhibitor, which reduced plasma C16:1/C16:0 triglycerides desaturation index (DI) in an acute Lewis rat model in a dose dependent manner, with an ED50 of 4.6mg/kg. In preliminary safety studies, compound 17a did not demonstrate adverse effects related to SCD1 inhibition after repeat dosing at 100mg/kg. Together, these data suggest that sufficient safety margins can be achieved with certain SCD1 inhibitors, thus allowing exploration of clinical utility in metabolic disease settings. Graphical abstract image
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Flavonoids as noncompetitive inhibitors of Dengue virus NS2B-NS3 protease: Inhibition kinetics and docking studies ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Lorena Ramos Freitas de Sousa , Hongmei Wu , Liliane Nebo , João Batista Fernandes , Maria Fátima das Graças Fernandes da Silva , Werner Kiefer , Manuel Kanitz , Jochen Bodem , Wibke E. Diederich , Tanja Schirmeister , Paulo Cezar Vieira NS2B-NS3 is a serine protease of the Dengue virus considered a key target in the search for new antiviral drugs. In this study flavonoids were found to be inhibitors of NS2B-NS3 proteases of the Dengue virus serotypes 2 and 3 with IC50 values ranging from 15 to 44μM. Agathisflavone (1) and myricetin (4) turned out to be noncompetitive inhibitors of dengue virus serotype 2 NS2B-NS3 protease with K i values of 11 and 4.7μM, respectively. Docking studies propose a binding mode of the flavonoids in a specific allosteric binding site of the enzyme. Analysis of biomolecular interactions of quercetin (5) with NT647-NHS-labeled Dengue virus serotype 3 NS2B-NS3 protease by microscale thermophoresis experiments, yielded a dissociation constant K D of 20μM. Our results help to understand the mechanism of inhibition of the Dengue virus serine protease by flavonoids, which is essential for the development of improved inhibitors. Graphical abstract image
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Ferrocenes as potential chemotherapeutic drugs: Synthesis, cytotoxic activity, reactive oxygen species production and micronucleus assay ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Wanda I. Pérez , Yarelys Soto , Carmen Ortíz , Jaime Matta , Enrique Meléndez Three new ferrocene complexes were synthesized with 4-(1H-pyrrol-1-yl)phenol group appended to one of the Cp ring. These are: 1,1′-4-(1H-pyrrol-1-yl)phenyl ferrocenedicarboxylate, (‘Fc-(CO2-Ph-4-Py)2’), 1,4-(1H-pyrrol-1-yl)phenyl, 1′-carboxyl ferrocenecarboxylate (‘Fc-(CO2-Ph-4-Py)CO2H’) and 4-(1H-pyrrol-1-yl)phenyl ferroceneacetylate (‘Fc-CH2CO2-Ph-4-Py’). The new species were characterized by standard analytical methods. Cyclic voltammetry experiments showed that Fc-CH2CO2-Ph-4-Py has redox potential very similar to the Fc/Fc+ redox couple whereas Fc-(CO2-Ph-4-Py)2 and Fc-(CO2-Ph-4-Py)CO2H have redox potentials of over 400mV higher than Fc/Fc+ redox couple. The in vitro studies on Fc-(CO2-Ph-4-Py)2 and Fc-(CO2-Ph-4-Py)CO2H revealed that these two compounds have moderate anti-proliferative activity on MCF-7 breast cancer cell line. In contrast Fc-CH2CO2-Ph-4-Py which displayed low anti-proliferative activity. In the HT-29 colon cancer cell line, the new species showed low anti-proliferative activity. Cytokinesis-block micronucleus assay (CBMN) was performed on these ferrocenes and it was determined they induce micronucleus formation on binucleated cells and moderate genotoxic effects on the MCF-7 breast cancer cell line. There is a correlation between the IC50 values of the ferrocenes and the amount of micronucleus formation activity on binucleated cells and the reactive oxygen species (ROS) production on MCF-7 cell line. Graphical abstract image
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Novel agonists of benzodiazepine receptors: Design, synthesis, binding assay and pharmacological evaluation of 1,2,4-triazolo[1,5-a]pyrimidinone and 3-amino-1,2,4-triazole derivatives ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Mehrdad Faizi , Sara Dabirian , Hamed Tajali , Fatemeh Ahmadi , Elham Rezaee Zavareh , Soraya Shahhosseini , Sayyed Abbas Tabatabai Agonists of benzodiazepine (BZD) binding site in GABA receptors are widely used in clinical practice. In spite of their benefits they have several side effects, so synthesis of new agonists of these receptors to get more specific effect and better profile of adverse drug reactions is still continued. Novel BZD agonists were designed based on the pharmacophore/receptor model of BZD binding site of GABAA receptor. Energy minima conformers of the designed compounds and estazolam, a known BZD receptor agonist, were well superimposed in conformational analysis. Docking studies revealed that the carbonyl group of the compound 4c, 3-(2-chlorobenzyl)-5-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one, was near the nitrogen moiety of triazole ring of estazolam providing the hydrogen bond acceptor in proper direction in the BDZ-binding site of GABAA receptor model (α1β2ϒ2). The designed compounds were synthesized and their in vitro affinity for the central BZD receptor was determined. Most of the novel compounds had better affinity for the BZD site of action on GABAA receptor complex than diazepam. Finally, the novel compound 4c with the best affinity in radioligand receptor binding assay (K i =0.42nM and IC50 =0.68nM) was selected as candidate for in vivo evaluation. This compound showed significant hypnotic activity and weak anticonvulsant effect with no impairment on learning and memory performance in mouse. The pharmacological effects of the compound 4c were antagonized by flumazenil, a BZD antagonist, which confirms the involvement of BZD receptors in the biological effects of the novel ligand. Graphical abstract image
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Synthesis and biological evaluation of isoindoloisoquinolinone, pyroloisoquinolinone and benzoquinazolinone derivatives as poly(ADP-ribose) polymerase-1 inhibitors ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Arumugam Suyavaran , Chitteti Ramamurthy , Ramachandran Mareeswaran , Yagna Viswa Shanthi , Jayaraman Selvakumar , Selvaraj Mangalaraj , Muthuvel Suresh Kumar , Chinnasamy Ramaraj Ramanathan , Chinnasamy Thirunavukkarasu A series of novel fused isoquinolinones with isoindoloisoquinolinone, pyroloisoquinolinone, and benzoquinalizinone skeletons were synthesized from corresponding phenethylimides. The isoquinolinone derivatives were evaluated for their protective effect on chicken erythrocytes subjected to oxidative damage. The effect of isoquinolinone derivatives were analysed by estimation of cell viability, antioxidant enzyme activities, DNA damage (comet assay), PARP-1 inhibition assay and molecular docking of the compounds with PARP-1 active site. The compounds CRR-271, CRR-288 and CRR-224+225 showed significant protective effect at 100μM concentration. The PARP-1 inhibition assay revealed the IC50 values of CRR-271, CRR-288 and CRR-224+225 as <200nM, further molecular docking studies shows higher binding energies with PARP-1 active site. Interesting findings in this study suggest that the novel isoquinolinone derivatives inhibit PARP-1 activity and protect cells against oxidative DNA damage, which could be implemented in the treatment of inflammatory diseases. Graphical abstract image
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Anthranilic acid derivatives as nuclear receptor modulators—Development of novel PPAR selective and dual PPAR/FXR ligands ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Daniel Merk , Christina Lamers , Julia Weber , Daniel Flesch , Matthias Gabler , Ewgenij Proschak , Manfred Schubert-Zsilavecz Nuclear receptors, especially the peroxisome proliferator activated receptors (PPARs) and the farnesoid X receptor (FXR) fulfill crucial roles in metabolic balance. Their activation offers valuable therapeutic potential which has high clinical relevance with the fibrates and glitazones as PPAR agonistic drugs. With growing knowledge about the various functions of nuclear receptors in many disorders, new selective or dual ligands of these pharmaceutical targets are however still required. Here we report the class of anthranilic acid derivatives as novel selective PPAR or dual FXR/PPAR ligands. We identified distinct molecular determinants that govern selectivity for each PPAR subtype or FXR as well as the amplitude of activation of the respective receptors. We thereby discovered several lead compounds for further optimization and developed a highly potent dual PPARα/FXR partial agonist that might have a beneficial synergistic effect on lipid homeostasis by simultaneous activation of two nuclear receptors involved in lipid metabolism. Graphical abstract image
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Design and synthesis of novel 2-pyrazoline-1-ethanone derivatives as selective MAO inhibitors ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Xu Tong , Rui Chen , Tong-Tian Zhang , Yan Han , Wen-Jian Tang , Xin-Hua Liu Thirty seven novel 2-pyrazoline-1-ethanone derivatives were designed, synthesized and evaluated as selective hMAO inhibitors. Among them, compounds 7h (IC50 =2.40μM) and 12c (IC50 =2.00μM) exhibited best inhibitory activity and selectivity against hMAO-A, surpassing that of the positive control Clorgyline (IC50 =2.76μM). Based on selective activity of hMAO-A, SAR analysis showed that the order of N1 substituent contribution was bromo (3)>piperidinyl (4)>morpholinyl (5)>imidazolyl (6), and compounds with electron-withdrawing substituents (-F, -Cl) at C3 or C5 phenyl ring of 2-pyrazoline nucleus dedicated stronger MAO-A inhibitory activity. Molecular docking showed that compounds 7h and 12c were nicely bound to hMAO-A via two hydrogen bonds (SER209, GLU216), one Pi–Pi interaction and three hydrogen bonds (SER209, GLU216, TYR69), one Sigma–Pi interaction, respectively. In addition, the substituent at C3 position of 2-pyrazoline with the N1 acetyl has little effect on MAO-A inhibitory activity. These data support further studies to assess rational design of more efficiently selective hMAO inhibitors in the future. Graphical abstract image
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Sulfonamide inhibition studies of the η-class carbonic anhydrase from the malaria pathogen Plasmodium falciparum ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Daniela Vullo , Sonia Del Prete , Gillian M. Fisher , Katherine T. Andrews , Sally-Ann Poulsen , Clemente Capasso , Claudiu T. Supuran The η-carbonic anhydrases (CAs, EC 4.2.1.1) were recently discovered as the sixth genetic class of this metalloenzyme superfamily, and are so far known only in protozoa, including various Plasmodium species, the causative agents of malaria. We report here an inhibition study of the η-CA from Plasmodium falciparum (PfCA) against a panel of sulfonamides and one sulfamate compound, some of which are clinically used. The strongest inhibitors identified were ethoxzolamide and sulthiame, with K Is of 131–132nM, followed by acetazolamide, methazolamide and hydrochlorothiazide (K Is of 153–198nM). Brinzolamide, topiramate, zonisamide, indisulam, valdecoxib and celecoxib also showed significant inhibitory action against PfCA, with K Is ranging from 217 to 308nM. An interesting observation was that the more efficient PfCA inhibitors are representative of several scaffolds and chemical classes, including benzene sulfonamides, monocyclic/bicyclic heterocyclic sulfonamides and compounds with a more complex scaffold (i.e., the sugar sulfamate derivative, topiramate, and the coxibs, celecoxib and valdecoxib). A comprehensive inhibition study of small molecules for η-CAs is needed as a first step towards assessing PfCA as a druggable target. The present work identifies the first known η-CA inhibitors and provides a platform for the development of next generation novel PfCA inhibitors. Graphical abstract image
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Design, synthesis, and biological evaluation of aminothiazole derivatives against the fungal pathogens Histoplasma capsulatum and Cryptococcus neoformans ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Ahmed Khalil , Jessica A. Edwards , Chad A. Rappleye , Werner Tjarks Invasive fungal disease constitutes a growing health burden and development of novel antifungal drugs with high potency and selectivity against new fungal molecular targets are urgently needed. Previously, an aminothiazole derivative, designated as 41F5, was identified in our laboratories as highly active against Histoplasma yeast (MIC50 0.4–0.8μM) through phenotypic high-throughput screening of a commercial library of 3600 purine mimicking compounds (Antimicrob. Agents Chemother. 2013, 57, 4349). Consequently, 68 analogues of 41F5 were designed and synthesized or obtained from commercial sources and their MIC50s of growth inhibition were evaluated in Histoplasma capsulatum to establish a basic structure–activity-relationship (SAR) for this potentially new class of antifungals. The growth inhibiting potentials of smaller subsets of this library were also evaluated in Cryptococcus neoformans and human hepatocyte HepG2 cells, the latter to obtain selectivity indices (SIs). The results indicate that a thiazole core structure with a naphth-1-ylmethyl group at the 5-position and cyclohexylamide-, cyclohexylmethylamide-, or cyclohexylethylamide substituents at the 2-position caused the highest growth inhibition of Histoplasma yeast with MIC50s of 0.4μM. For these analogues, SIs of 92 to >100 indicated generally low host toxicity. Substitution at the 3- and 4-position decreased antifungal activity. Similarities and differences were observed between Histoplasma and Cryptococcus SARs. For Cryptococcus, the naphth-1-ylmethyl substituent at the 5-position and smaller cyclopentylamide- or cyclohexylamide groups at the 2-position were important for activity. In contrast, slightly larger cyclohexylmethyl- and cyclohexylethyl substituents markedly decreased activity. Graphical abstract image Highlights
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Design, synthesis, and evaluation of hybrid vitamin D3 side chain analogues as hedgehog pathway inhibitors ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Upasana Banerjee , Albert M. DeBerardinis , M. Kyle Hadden Vitamin D3 (VD3) is a moderately potent and non-selective inhibitor of the Hedgehog (Hh) signaling cascade. Previous studies have established that the CD-ring region of VD3 serves as the Hh inhibitory pharmacophore. Subsequently, compound 3, an ester linked aromatic A-ring and CD-ring derivative was identified as an improved and selective Hh inhibitor. Herein, we report modifications of the CD-ring side chain that afford enhancement of selectivity for Hh modulation thereby diminishing the detrimental effects of concomitant vitamin D receptor activation. In general, linear or moderately branched alkyl chains of five or six carbons were optimal for potent and selective inhibition of Hh signaling. Moreover, hybrid VD3 side chain derivative 20 demonstrated 4-fold improvement in Hh antagonistic activity over VD3(IC50 =1.1–1.6μM) while gaining greater than a 1000-fold selectivity for Hh signaling over canonical activation of the vitamin D receptor pathway. Graphical abstract image
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4-Dechloro-14-deoxy-oxacyclododecindione and 14-deoxy-oxacylododecindione, two inhibitors of inducible connective tissue growth factor expression from the imperfect fungus Exserohilum rostratum ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Julia Richter , Louis P. Sandjo , Johannes C. Liermann , Till Opatz , Gerhard Erkel Connective tissue growth factor (CTGF/CCN2), a member of the CCN superfamily of secreted cysteine-rich glycoproteins, is a central mediator of tissue remodeling and fibrosis. CTGF is suggested to be an important down-stream effector of transforming growth factor-beta (TGF-β) signaling and has therefore reached considerable pathophysiological relevance because of its involvement in the pathogenesis of fibrotic diseases, atherosclerosis, skin scarring, and other conditions with excess production of connective tissue. In a search for inhibitors of inducible CTGF expression from fungi, two new macrocyclic lactones, namely 4-dechloro-14-deoxy-oxacyclododecindione (1) and 14-deoxy-oxacylododecindione, (2) along with the previously described congener oxacyclododecindione (3) were isolated from fermentations of the imperfect fungus Exserohilum rostratum. The structure of the compounds were elucidated by a combination of one- and two-dimensional NMR spectroscopy and mass spectrometry. Compounds 1 and 2 turned out to inhibit TGF-β induced CTGF promoter activity in transiently transfected HepG2 cells in a dose-dependent manner with IC50 values of 1.8μM and 336nM, respectively, and also antagonized TGF-β induced cellular effects including CTGF mRNA levels, CTGF protein expression and tube formation. Graphical abstract image
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Discovery and SAR study of c-Met kinase inhibitors bearing an 3-amino-benzo[d]isoxazole or 3-aminoindazole scaffold ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Xiaolong Jiang , Hongyan Liu , Zilan Song , Xia Peng , Yinchun Ji , Qizheng Yao , Meiyu Geng , Jing Ai , Ao Zhang A series of 3-amino-benzo[d]isoxazole-/3-aminoindazole-based compounds were designed, synthesized and pharmacologically evaluated as tyrosine kinase c-Met inhibitors. The SAR study was conducted leading to identification of nine compounds (8d, 8e, 12, 28a–d, 28h and 28i) with IC50s less than 10nM against c-Met. Compound 28a stood out as the most potent c-Met inhibitor displaying potent inhibitory effects both at enzymatic (IC50 =1.8nM) and cellular (IC50 =0.18μM on EBC-1 cells) levels. In addition, 28a had a relatively good selectivity compared to a panel of our in-house 14 RTKs. Graphical abstract image
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Fine tuning of 4,6-bisphenyl-2-(3-alkoxyanilino)pyrimidine focusing on the activity-sensitive aminoalkoxy moiety for a therapeutically useful inhibitor of receptor for advanced glycation end products (RAGE) ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Young Taek Han , Kyeojin Kim , Dohyun Son , Hongchan An , Hee Kim , Jeeyeon Lee , Hyun-Ju Park , Jeewoo Lee , Young-Ger Suh Through the fine tuning of the activity-sensitive aminoalkoxy moiety of 4,6-bisphenyl-2-(3-alkoxyanilino)pyrimidine as a novel inhibitor of the receptor for advanced glycation end products (RAGE), the tertiary amine was elucidated as an essential part associated with RAGE inhibition. On the basis of this finding, a 3-(N,N-dimethylamino)pyrrolidine analog 12o was identified as a therapeutically useful RAGE inhibitor with improved activity and solubility. Molecular modeling studies predicted that the improved inhibitory activity is induced by additional hydrogen bonds between the nitrogen atom of the pyrrolidine ring and Arg48 and by an interaction between the dimethylamino-substituent of the pyrrolidine moiety and a relatively hydrophobic groove in the RAGE binding site. Graphical abstract image
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Exploring the gyrase ATPase domain for tailoring newer anti-tubercular drugs: Hit to lead optimization of a novel class of thiazole inhibitors ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Variam Ullas Jeankumar , Sonali Kotagiri , Renuka Janupally , Priyanka Suryadevara , Jonnalagadda Padma Sridevi , Raghavender Medishetti , Pushkar Kulkarni , Perumal Yogeeswari , Dharmarajan Sriram Gyrase ATPase domain, the pharmaceutical underexploited segment of DNA gyrase, the sole Type II topoisomerase present in Mycobacterium tuberculosis represents an attractive target for anti-tubercular drug discovery. Here we report, the development of a novel series of MTB DNA gyraseB inhibitor identified through a medium throughput screening (MTS) of BITS in-house chemical library (3000 compounds). The MTS hit was further remodeled by chemical synthesis to identify the most potent analogue 27 exhibiting an in vitro gyrB inhibitory IC50 of 0.15μM. The series also demonstrated well correlating gyrase super coiling activity and in vitro anti-mycobacterial potency against MTB H37Rv strain. Furthermore the compounds displayed good safety profile in their subsequent cytotoxicity and hERG toxicity evaluations, to be worked out from a pharmaceutical point of view as potential anti-tubercular agents. Graphical abstract image
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IND-2, a pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinoline derivative, circumvents multi-drug resistance and causes apoptosis in colon cancer cells ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Chandrabose Karthikeyan , Crystal Lee , Joshua Moore , Roopali Mittal , Esther A. Suswam , Kodye L. Abbott , Satyanarayana R. Pondugula , Upender Manne , Narayanan K. Narayanan , Piyush Trivedi , Amit K. Tiwari Naturally occurring condensed quinolines have anticancer properties. In efforts to find active analogues, we designed and synthesized eight polycyclic heterocycles with a pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinoline framework (IND series). The compounds were evaluated for activity against colon (HCT-116 and S1-MI-80), prostate (PC3 and DU-145), breast (MCF-7 and MDAMB-231), ovarian (ov2008 and A2780), and hepatocellular (HepG2) cancer cells and against non-cancerous Madin Darby canine kidney (MDCK), mouse embryonic fibroblast (NIH/3T3), and human embryonic kidney cells (HEK293). IND-2, a 4-chloro-2-methyl pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinoline, exhibited more than ten-fold selectivity and potent cytotoxic activity against colon cancer cells relative to the other cancer and non-cancer cells. With five additional colon cancer cell lines (HT-29, HCT-15, LS-180, LS-174, and LoVo), IND-2 had similar cytotoxicity and selectivity, and sub-micromolar concentrations caused changes in the morphology of HCT-116 and HCT-15 cells. IND-2 did not activate the transactivating function of the pregnane X receptor (PXR), indicating that it does not induce PXR-regulated ABCB1 or ABCG2 transporters. Indeed, IND-2 was not a substrate of ABCB1 or ABCG2, and it induced cytotoxicity in HEK293 cells overexpressing ABCB1 or ABCG2 to the same extent as in normal HEK293 cells. IND-2 was cytotoxic to resistant colon carcinoma S1-MI-80 cells, approximately three- and five-fold more than SN-38 and topotecan, respectively. In HCT-116 colon cancer cells, IND-2 produced concentration-dependent changes in mitochondrial membrane potential, leading to apoptosis, and sub-micromolar concentrations caused chromosomal DNA fragmentation. These findings suggest that, by increasing apoptosis, IND-2 has potential therapeutic efficacy for colorectal cancer. Graphical abstract image
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Selective binding to monoamine oxidase A: In vitro and in vivo evaluation of 18F-labeled β-carboline derivatives ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Hanno Schieferstein , Markus Piel , Friderike Beyerlein , Hartmut Lüddens , Nicole Bausbacher , Hans-Georg Buchholz , Tobias L. Ross , Frank Rösch In this study we synthesized four different 18F-labeling precursors for the visualization of the monoamino oxidase A using harmol derivatives. Whereas two are for prosthetic group labeling using [18F]fluoro-d 2-methyl tosylate and 2-[18F]fluoroethyl-tosylate, the other three precursors are for direct nucleophilic 18F-labeling. Additionally the corresponding reference compounds were synthesized. The syntheses of [18F]fluoro-d 2-methyl-harmol and 2-[18F]fluoroethyl-harmol were carried out using harmol as starting material. For direct nucleophilic 18F-labeling of the tracers carrying oligoethyled spacers (PEG), a toluenesulfonyl leaving group was employed. The radiolabeling, purification and formulation for each tracer was optimized and evaluated in vitro and in vivo. Stability tests in human serum showed that all tracers were stable over the observation period of 60min. μPET studies using of the synthesized tracers revealed that the tracers carrying PEG spacers showed no sufficient brain uptake. Consequently, the 18F-fuoro alkylated tracers [18F]fluoro-d 2-methyl-harmol and 2-[18F]fluoroethyl-harmol were further evaluated showing SUVs in the brain of 1.0±0.2g/mL and 3.4±0.5g/mL after 45min, respectively. In blockade studies the selectivity and specificity of both tracers were demonstrated. However, for [18F]fluoro-d 2-methyl-harmol a rapid washout from the brain was also observed. In vitro binding assays revealed that 2-[18F]fluoroethyl-harmol (IC50 =0.54±0.06nM) has a higher affinity than the 18F-fluoro-d 2-methylated ligand (IC50 =12.2±0.6nM), making 2-[18F]fluoroethyl-harmol superior to the other evaluated compounds and a promising tracer for PET imaging of the MAO A. Graphical abstract image
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Synthesis and biological evaluation of DAPY–DPEs hybrids as non-nucleoside inhibitors of HIV-1 reverse transcriptase ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Hai-Qiu Wu , Jin Yao , Qiu-Qin He , Wen-Xue Chen , Fen-Er Chen , Christophe Pannecouque , Erik De Clercq , Dirk Daelemans A series of new DAPY–DPEs hybrids, combined the important pharmacophores of DAPYs and DPEs, has been synthesized and biologically evaluated for their anti-HIV activities against wild-type HIV-1 strain IIIB, double RT mutant (K103N+Y181C) strain RES056 and HIV-2 strain ROD in MT-4 cell cultures. Many promising candidates with potent inhibitory activity (wild-type) within the EC50 range from 0.16 to 0.013μM were obtained. In particular, 3c, 3p, 3r and 3s displayed low nM level EC50 values (35, 13, 50 and 17nM, respectively) and high selectivity (9342, 25131, 2890 and 11338, respectively), which were much more potent than NVP (EC50 =0.31μM, SI=48), 3TC (EC50 =2.24μM, SI>39), DDI (EC50 =23.20μM, SI>9) and DLV (EC50 =0.65μM, SI>67), and comparable to AZT (EC50 =0.0071μM, SI>13144) and EFV (EC50 =0.0062μM, SI>1014). The HIV-1 reverse transcriptase inhibitory assay confirmed that these DAPY–DPEs hybrids targeted HIV-1 RT. Molecular simulation was performed to investigate the potential binding mode of the newly synthesized compounds. And reasonable explanation for the activity results was discussed with docking method. Graphical abstract image
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Non-transpeptidase binding arylthioether β-lactams active against Mycobacterium tuberculosis and Moraxella catarrhalis ()
Publication date: 1 February 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 3 Author(s): Tim N. Beck , Dina Lloyd , Rostislav Kuskovsky , Jeanette Minah , Kriti Arora , Balbina J. Plotkin , Jacalyn M. Green , Helena I. Boshoff , Clifton Barry III , Jeffrey Deschamps , Monika I. Konaklieva The prevalence of drug resistance in both clinical and community settings as a consequence of alterations of biosynthetic pathways, enzymes or cell wall architecture is a persistent threat to human health. We have designed, synthesized, and tested a novel class of non-transpeptidase, β-lactamase resistant monocyclic β-lactams that carry an arylthio group at C4. These thioethers exhibit inhibitory and cidal activity against serine β-lactamase producing Mycobacterium tuberculosis wild type strain (Mtb) and multiple (n =8) β-lactamase producing Moraxella catarrhalis clinical isolates. Graphical abstract image
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The use of a conformational cathepsin D-derived epitope for vaccine development against Schistosoma mansoni ()
Publication date: Available online 30 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Abdullah A.H. Ahmad Fuaad , Romain Roubille , Mark S. Pearson , Darren A. Pickering , Alex C. Loukas , Mariusz Skwarczynski , Istvan Toth Schistosomiasis is caused by the infection from Schistosoma species. Among these, S. mansoni is one of the major species that infects millions of people worldwide. The use of praziquantel is effective in clearing the infestation but treatment of a large and widespread population in endemic areas is unsustainable. Thus, synergistic approach of using drug and vaccination can serve as an alternative to the current treatment. In this study, we have developed vaccine candidates that composed of three components: a B-cell epitope derived from S. mansoni cathepsin D protein (Sm-CatD) flanked by GCN4 helix promoting peptide; a promiscuous T-helper epitope (P25); and a lipid core peptide system, in attempt to develop self-adjuvanting vaccine candidates against the schistosome. Physicochemical properties of the vaccine candidates were analysed and antibodies to each construct were raised in BALB/c mice. The vaccine candidates were able to self-assemble into particles that induced high titres of IgG without the use of additional adjuvant. The antibody levels were comparable to that induced by peptide formulated with strong but toxic Freund’s adjuvant. The integration of a GCN4 sequence induced the helical conformation of the epitope, while the addition of the T helper peptide was very effective in inducing consistent IgG-specific antibodies response amongst mice. These findings are particularly encouraging for the development of efficient and immunogenic vaccine against schistosomiasis. Graphical abstract image
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Synthesis of dansyl-labeled probe of thiophene analogue of annonaceous acetogenins for visualization of cell distribution and growth inhibitory activity toward human cancer cell lines ()
Publication date: Available online 29 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Naoto Kojima , Yuki Suga , Takuya Matsumoto , Tetsuaki Tanaka , Akinobu Akatsuka , Takao Yamori , Shingo Dan , Hiroki Iwasaki , Masayuki Yamashita The convergent synthesis of the dansyl-labeled probe of the thiophene-3-carboxamide analogue of annonaceous acetogenins, which shows potent antitumor activity, was accomplished by two asymmetric alkynylations of the 2,5-diformyl THF equivalent with an alkyne having a thiophene moiety and another alkyne tagged with a dansyl group. The growth inhibitory profiles toward 39 human cancer cell lines revealed that the probe retained the biological function of its mother compound, and would be useful for studying cellular activity. Graphical abstract image
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Interrogating alkyl and arylalkylpolyamino (bis)urea and (bis)thiourea isosteres as potent antimalarial chemotypes against multiple lifecycle forms of Plasmodium falciparum parasites ()
Publication date: Available online 28 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Bianca K. Verlinden , Marna de Beer , Boobalan Pachaiyappan , Ethan Besaans , Warren A. Andayi , Janette Reader , Jandeli Niemand , Riette van Biljon , Kiplin Guy , Timothy Egan , Patrick M. Woster , Lyn-Marie Birkholtz A new series of potent potent aryl/alkylated (bis)urea- and (bis)thiourea polyamine analogues were synthesized and evaluated in vitro for their antiplasmodial activity. Altering the carbon backbone and terminal substituents increased the potency of analogues in the compound library 3-fold, with the most active compounds, 15 and 16, showing half-maximal inhibitory concentrations (IC50 values) of 28 and 30 nM, respectively, against various Plasmodium falciparum parasite strains without any cross-resistance. In vitro evaluation of the cytotoxicity of these analogues revealed marked selectivity towards targeting malaria parasites compared to mammalian HepG2 cells (>5000-fold lower IC50 against the parasite). Preliminary biological evaluation of the polyamine analogue antiplasmodial phenotype revealed that (bis)urea compounds target parasite asexual proliferation, whereas (bis)thiourea compounds of the same series have the unique ability to block transmissible gametocyte forms of the parasite, indicating pluri-pharmacology against proliferative and non-proliferative forms of the parasite. In this manuscript, we describe these results and postulate a refined structure-activity relationship (SAR) model for antiplasmodial polyamine analogues. The terminally alkylated (bis)urea- and (bis)thiourea-polyamine analogues featuring a 3-5-3 or 3-6-3 carbon backbone represent a structurally novel and distinct class of potential antiplasmodials with activities in the low nanomolar range, and high selectivity against various lifecycle forms of P. falciparum parasites. Graphical abstract image
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Discovery and structure–activity relationship studies of N6-benzoyladenine derivatives as novel BRD4 inhibitors ()
Publication date: Available online 27 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Tomomi Noguchi-Yachide , Taki Sakai , Yuichi Hashimoto , Takao Yamaguchi Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that bind to acetylated lysines in histones. Among them, BRD4 is a candidate target molecule of therapeutic agents for diverse diseases, including cancer and inflammatory disease. As a part of our continuing structural development studies of thalidomide to obtain a broad spectrum of biological modifiers based on the “multi-template” approach, in this work we focused on BRD4-inhibitory activity, and discovered that N6-benzoyladenine derivatives exhibit this activity. Structure-activity relationship studies led to N6-(2,4,5-trimethoxybenzoyl)adenine (29), which exhibits potent BRD4 bromodomain1 inhibitory activity with an IC50 value of 0.427 μM. N6-Benzoyladenine appears to be a new chemical scaffold for development of BRD4 inhibitors. Graphical abstract image
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Synthesis and biological evaluation of 4-nitroindole derivatives as 5-HT2A receptor antagonists ()
Publication date: Available online 24 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Faisal Hayat , Ambily Nath Indu Viswanath , Ae Nim Pae , Hyewhon Rhim , Woo-Kyu Park , Hea-Young Park Choo A novel series of 4-nitroindole sulfonamides containing a methyleneamino-N,N-dimethylformamidine were prepared. The binding of these compounds to 5-HT2A and 5-HT2C was evaluated, and most of the compounds showed IC50 values of less than 1μM, and exhibited high selectivity for the 5-HT2C receptor. However, little selectivity was observed in the functional assay for 5-HT6 receptors. The computational modeling studies further validated the biological results and also demonstrated a reasonable correlation between the activity of compounds and the mode of superimposition with specified pharmacophoric features. Graphical abstract image
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Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal-antiplasmodial activity ()
Publication date: Available online 24 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Irene Sola , Sílvia Castellà , Elisabet Viayna , Carles Galdeano , Martin C. Taylor , Stephen Y. Gbedema , Belén Pérez , M. Victòria Clos , Deuan C. Jones , Alan H. Fairlamb , Colin W. Wright , John M. Kelly , Diego Muñoz-Torrero Dual submicromolar trypanocidal-antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity. Graphical abstract image
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Synthesis and biological activity evaluation of hydrazone derivatives based on a Tröger’s base skeleton ()
Publication date: Available online 23 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Robert Kaplánek , Martin Havlík , Bohumil Dolenský , Jakub Rak , Petr Džubák , Petr Konečný , Marián Hajdúch , Jarmila Králová , Vladimír Král We report the design and synthesis of novel anticancer agents based on bis-hydrazones separated by a rigid Tröger’s base skeleton. This novel approach combines a biologically active moiety (hydrazone) with this scaffold (Tröger’s base) to construct DNA intercalators. Evaluation of the anticancer activity of these agents using seven cancer cell lines and two healthy cell lines found that several derivatives had potent anticancer activity and excellent selectivity indexes toward cancer cells. The antimicrobial activities were tested on a set of thirteen bacterial stains, but the prepared compounds were not active. Complexation studies using biologically important metal ions demonstrated that these compounds are able to bind Cu2+, Fe3+, Co2+, Ni2+ and Zn2+. DNA intercalation studies showed that the compounds themselves do not interact with DNA, but their metallocomplexes do interact, most likely via intercalation into DNA. Graphical abstract image
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Spectral and Biological Evaluation of a Synthetic Antimicrobial Peptide derived from 1-aminocyclohexane carboxylic acid ()
Publication date: Available online 22 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): J.J. Abercrombie , Kia P. Leung , Hanbo Chai , Rickey P. Hicks Ac-GF(A6c)G(A6c)K(A6c)G(A6c)F(A6c)G(A6c)GK(A6c)KKKK-amide (A6c = 1-aminocyclohexane carboxylic acid) is a synthetic antimicrobial peptide (AMP) that exhibits in vitro inhibitory activity against drug resistant strains of S. aureus, A. baumannii, K. pneumoniae, P. aeruginosa, Enterobacter aerogenes, and Enterococcus faecium at concentrations ranging from 10.9 to 43 μM. Spectroscopic investigations were conducted to determine how this AMP interacts with simple membrane model systems in order to provide insight into possible mechanisms of action. CD and 2D-1H NMR experiments indicated this AMP on binding to SDS and DPC micelles adopts conformations with varying percentages of helical and random coil conformers. CD investigations in the presence of three phospholipid SUVs consisting of POPC, 4:1 POPC/POPG, and 60% POPE/21%POPG/19%POPC revealed: 1) The interactions occurring with POPC SUVs have minimal effect on the conformational diversity of the AMP yielding conformations similar to those observed in buffer. 2) The interactions with 4:1 POPC/POPG, and 60% POPE/21%POPG/19%POPC SUVs exhibited a greater influence on the percentage of different conformers contributing to the CD spectra. 3) The presence of a high of percentage of helical conformers was not observed in the presence of SUVs as was the case with micelles. This data indicates that the diversity of surface bound conformations adopted by this AMP are very different from the diversity of conformations adopted by this AMP on insertion into the lipid bilayer. CD spectra of this AMP in the presence of SUVs consisting of LPS isolated from P. aeruginosa, K. pneumoniae and E. Coli exhibited characteristics associated with various helical conformations. Graphical abstract image
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Rat hormone sensitive lipase inhibition by cyclipostins and their analogs ()
Publication date: Available online 22 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Elena Vasilieva , Supratik Dutta , Raj K. Malla , Benjamin P. Martin , Christopher D. Spilling , Cynthia M. Dupureur Cyclipostins are bicyclic lipophilic phosphate natural products. We report here that synthesized individual diastereomers of cyclipostins P and R have nanomolar IC50s toward hormone sensitive lipase (HSL). The less potent diastereomers of these compounds have 10-fold weaker IC50s. The monocyclic phosphate analog of cyclipostin P is nearly as potent as the bicyclic natural product. Bicyclic phosphonate analogs of both cyclipostins exhibit IC50s similar to those of the weaker diastereomer phosphates (about 400 nM). The monocyclic phosphonate analog of cyclipostin P has similar potency. A series of monocyclic phosphonate analogs in which a hydrophobic tail extends from the lactone side of the ring are considerably poorer inhibitors, with IC50s around 50 μM. Finally cyclophostin, a related natural product inhibitor of acetylcholinesterase (AChE) that lacks the hydrocarbon tail of cyclipostins, is not active against HSL. These results indicate a critical SAR for these compounds, the hydrophobic tail. The smaller lactone ring is not critical to activity, a similarity shared with cyclophostin and AChE. The HSL kinetics of inhibition for the cyclipostin P trans diastereomer were examined in detail. The reaction is irreversible with a KI of 40 nM and a rate constant for inactivation of 0.2 min-1. These results are similar to those observed for cyclophostin and AChE. Graphical abstract image
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3-Oxoisoxazole-2(3H)-carboxamides and isoxazol-3-yl carbamates: Resistance-breaking acetylcholinesterase inhibitors targeting the malaria mosquito, Anopheles gambiae ()
Publication date: Available online 22 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Astha Verma , Dawn M. Wong , Rafique Islam , Fan Tong , Maryam Ghavami , James M. Mutunga , Carla Slebodnick , Jianyong Li , Elisabet Viayna , Polo C.-H. Lam , Maxim M. Totrov , Jeffrey R. Bloomquist , Paul R. Carlier To identify potential selective and resistance-breaking mosquitocides against the African malaria vector Anopheles gambiae, we investigated the acetylcholinesterase (AChE) inhibitory and mosquitocidal properties of isoxazol-3-yl dimethylcarbamates (15), and the corresponding 3-oxoisoxazole-2(3H)-dimethylcarboxamide isomers (14). In both series, compounds were found with excellent contact toxicity to wild-type susceptible (G3) strain and multiply resistant (Akron) strain mosquitoes that carry the G119S resistance mutation of AChE. Compounds possessing good to excellent toxicity to Akron strain mosquitoes inhibit the G119S mutant of An. gambiae AChE (AgAChE) with k i values at least 10- to 600-fold higher than that of propoxur, a compound that does not kill Akron mosquitoes at the highest concentration tested. On average, inactivation of WT AgAChE by dimethylcarboxamides 14 was 10-20 fold faster than that of the corresponding isoxazol-3-yl dimethylcarbamates 15. X-ray crystallography of dimethylcarboxamide 14d provided insight into that reactivity, a finding that may explain the inhibitory power of structurally-related inhibitors of hormone-sensitive lipase. Finally, human/An. gambiae AChE inhibition selectivities of these compounds were low, suggesting the need for additional structural modification. Graphical abstract image
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Design, synthesis and evaluation of XZH-5 analogues as STAT3 inhibitors ()
Publication date: Available online 22 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Philias Daka , Aiguo Liu , Chamini Karunaratne , Erika Csatary , Cameron Williams , Hui Xiao , Jiayuh Lin , Zhenghu Xu , Rick Page , Hong Wang Inhibition of the signaling pathways of signal transducer and activator of transcription 3 (STAT 3) has shown to be a promising strategy to combat cancer. In this paper we report the design, synthesis and evaluation of a novel class of small molecule inhibitors, i.e., XZH-5 and its analogues, as promising leads for further development of STAT3 inhibitors. Preliminary SARs was established for XZH-5 and its derivatives; and the binding modes were predicted by molecular docking. Lead compounds with IC50 as low as 6.5μM in breast cancer cell lines and 7.6μM in pancreatic cancer cell lines were identified. Graphical abstract image
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Design, Synthesis, and Biological Evaluation of Air-Stable Nafuredin-γ Analogs as Complex I Inhibitors ()
Publication date: Available online 22 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Masaki Ohtawa , Mari Matsunaga , Keiko Fukunaga , Risa Shimizu , Eri Shimizu , Shiho Arima , Junko Ohmori , Kiyoshi Kita , Kazuro Shiomi , Satoshi Omura , Tohru Nagamitsu Nafuredin-γ (2), converted from nafuredin (1) under mild basic conditions, demonstrates potent and selective inhibitory activity against helminth complex I. However, 2 is unstable in air because the conjugated dienes are oxygen-labile. To address this, we designed and synthesized air-stable nafuredin-γ analogs. Although the complex I inhibitory activities of all the new nafuredin-γ analogs were lower than that of 2, all were in the high nM range (IC50: 300-820 nM). Graphical abstract image
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A peptide affinity reagent for isolating an intact and catalytically active multi-protein complex from mammalian cells ()
Publication date: Available online 22 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Hinnerk Saathoff , Mattias Brofelth , Anne Trinh , Benjamin L. Parker , Daniel P. Ryan , Jason K.K. Low , Sarah R. Webb , Ana P.G. Silva , Joel P. Mackay , Nicholas E. Shepherd We have developed an approach for directly isolating an intact multi-protein chromatin remodeling complex from mammalian cell extracts using synthetic peptide affinity reagent 4. FOG1(1-15), a short peptide sequence known to target subunits of the nucleosome remodeling and deacetylase (NuRD) complex, was joined via a 35-atom hydrophilic linker to the StreptagII peptide. Loading this peptide onto Streptactin beads enabled capture of the intact NuRD complex from MEL cell nuclear extract. Gentle biotin elution yielded the desired intact complex free of significant contaminants and in a form that was catalytically competent in a nucleosome remodeling assay. The efficiency of 4 in isolating the NuRD complex was comparable to other reported methods utilising recombinantly produced GST-FOG1(1-45). Graphical abstract image
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Rational design, synthesis and structure–activity relationships of 4-alkoxy- and 4-acyloxy-phenylethylenethiosemicarbazone analogues as novel tyrosinase inhibitors ()
Publication date: Available online 22 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Ao You , jie Zhou , Senchuan Song , Guoxun Zhu , Huacan Song , Wei Yi In continuing our program aimed to search for potent compounds as highly efficient tyrosinase inhibitors, here a series of novel 4-alkoxy- and 4-acyloxy-phenylethylenethiosemicarbazone analogues were designed, synthesized and their biological activities on mushroom tyrosinase were evaluated. Notably, most of compounds displayed remarkable tyrosinase inhibitory activities with IC50 value of lower than 1.0μM. Furthermore, the structure–activity relationships (SARs) were discussed and the inhibition mechanism and the inhibitory kinetics of selected compounds 7k and 8d were also investigated. Taken together, these results suggested that such compounds could serve as the promising candidates for the treatment of tyrosinase-related disorders and further development of such compounds might be of great interest. Graphical abstract image
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Synthesis and Biological Evaluation of 3-phenyl-3-aryl carboxamido propanoic acid Derivatives as Small Molecule Inhibitors of Retinoic Acid 4-Hydroxylase (CYP26A1) ()
Publication date: Available online 21 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Dongmei Zhao , Bin Sun , Jinhong Ren , Fengrong Li , Shuai Song , Xuejiao Lv , Chenzhou Hao , Maosheng Cheng All-trans-retinoic acid (ATRA), the biologically active metabolite of vitamin A, is used medicinally for the treatment of hyperproliferative diseases and cancers. However, it is easily metabolized. In this study, the leading compound S8 was found based on virtual screening. To improve the activity of the leading compound S8, a series of novel S8 derivatives were designed, synthesized and evaluated for their in vitro biological activities. All of the prepared compounds showed that substituting the 5-chloro-3-methyl-1-phenyl-1H-pyrazole group for the 2-tertbutyl-5-methylfuran scaffold led to a clear increase in the biological activity. The most promising compound 32, with a CYP26A1 IC50 value of 1.36μM (compared to liarozole (IC50 = 2.45μM) and S8 (IC50 =3.21μM)) displayed strong inhibitory and differentiation activity against HL60 cells. In addition, the study focused on the effect of β-phenylalanine, which forms the coordination bond with the heme of CYP26A1. These studies suggest that the compound 32 can be used as an appropriate candidate for future development. Graphical abstract image
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Enantioselective synthesis of dictyoceratin-A (smenospondiol) and -C, hypoxia-selective growth inhibitors from marine sponge ()
Publication date: Available online 19 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Yuji Sumii , Naoyuki Kotoku , Akinori Fukuda , Takashi Kawachi , Yuta Sumii , Masayoshi Arai , Motomasa Kobayashi Total syntheses of (+)-dictyoceratin-C (1) and (+)-dictyoceratin-A (smenospondiol) (2), hypoxia-selective growth inhibitors isolated from marine sponge, were executed. The absolute stereochemistry of the each compound was determined through the enantioselective total syntheses of them. It revealed that the unnatural enantiomers of them also exhibited the hypoxia-selective growth inhibitory activity against human prostate cancer DU-145 cells. Graphical abstract image
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Design and synthesis of a novel candidate compound NTI-007 targeting sodium taurocholate cotransporting polypeptide [NTCP]-APOA1-HBx- Beclin1-mediated autophagic pathway in HBV therapy ()
Publication date: Available online 19 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Jin Zhang , Lei-lei Fu , Mao Tian , Hao-qiu Liu , Jing-jing Li , Yan Li , Jun He , Jian Huang , Liang Ouyang , Hui-yuan Gao , Jin-hui Wang Sodium taurocholate cotransporting polypeptide (NTCP) is a multiple transmembrane transporter predominantly expressed in the liver, functioning as a functional receptor for HBV. Through our continuous efforts to identify NTCP as a novel HBV target, we designed and synthesized a series of new compounds based on the structure of our previous compound NT-5. Molecular docking and MD simulation validated that a new compound named NTI-007 can tightly bind to NTCP, whose efficacy was also measured in vitro virological examination and cytotoxicity studies. Furthermore, autophagy was observed in NTI-007 incubated HepG 2.2.15 cells, and results of q-PCR and western blotting revealed that NTI-007 induced autophagy through NTCP-APOA1-HBx-Beclin1-mediated pathway. Taken together, considering crucial role of NTCP in HBV infection, NTCP-mediated autophagic pathway may provide a promising strategy of HBV therapy and given efficacy of NTI-007 triggering autophagy. Our study suggests pre-clinical potential of this compound as a novel anti-HBV drug candidate. Graphical abstract image
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Dibenzosuberyl substituted polyamines and analogs of clomipramine as effective inhibitors of trypanothione reductase; molecular docking, and assessment of trypanocidal activities ()
Publication date: Available online 17 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Mary C. O’Sullivan , Timothy B. Durham , Hannah E. Valdes , Kelly L. Dauer , Nicholas J. Karney , Andrew C. Forrestel , Cyrus J. Bacchi , Jerome F. Baker Trypanothione reductase (TR) is an enzyme critical to the maintenance of the thiol redox balance in trypanosomatids, including the genera Trypanosoma and Leishmania that are parasites responsible for several serious diseases. Analogs of clomipramine were prepared since clomipramine is reported to inhibit TR and cure mice infected with trypanosomes, however its psychotropic activity precludes its use as an anti-trypanosomal therapeutic. The clomipramine analogs contained a tricyclic dibenzosuberyl moiety. Additionally a series of polyamines with N-dibenzosuberyl substituents were prepared. All compounds studied were competitive inhibitors of TR and showed trypanocidal activities against T. brucei in vitro. The analogs of clomipramine were poor inhibitors of TR, whereas the polyamine derivatives were effective TR inhibitors with the most potent compound, N 4,N 8-bis(dibenzosuberyl)spermine (7), having a K i value of 0.26 μM. However, compound (7) did not prolong the lives of mice infected with trypanosomes. Analysis of docking studies indicated: the tricyclic groups of inhibitors bind at four distinct hydrophobic regions in the active site of TR; the importance of the chlorine substituent of clomipramine in binding to TR; and binding of the dibenzosuberyl groups of (7) occur at separate and distinct hydrophobic regions within the active site of TR. Graphical abstract image
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Stereoselective synthesis of a natural product inspired tetrahydroindolo[2,3-a]-quinolizine compound library ()
Publication date: Available online 17 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Muthukumar G. Sankar , Luca Mantilli , James Bull , Fabrizio Giordanetto , Jonathan O. Bauer , Carsten Strohmann , Herbert Waldmann , Kamal Kumar A natural product-inspired synthesis of a compound collection embodying the tetrahydroindolo[2,3-a]quinolizine scaffold was established with a five step synthesis route. An imino-Diels-Alder reaction between Danishefsky’s diene and the iminoesters derived from tryptamines was used as a key reaction. Reductive amination of the ketone function and amide synthesis with the carboxylic acid derived from the ethyl ester, were used to decorate the core scaffold. Thus a compound library of 530 tetrahydroindolo[2,3-a]quinolizines was generated and submitted to European Lead Factory consortium for various biological screenings. Graphical abstract image
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Naturally occurring polyphenol, morin hydrate, inhibits enzymatic activity of N-methylpurine DNA glycosylase, a DNA repair enzyme with various roles in human disease ()
Publication date: Available online 16 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Monica Dixon , Jordan Woodrick , Suhani Gupta , Soumendra Krishna Karmahapatra , Stephen Devito , Sona Vasudevan , Sivanesan Dakshanamurthy , Sanjay Adhikari , Venkata M. Yenugonda , Rabindra Roy Interest in the mechanisms of DNA repair pathways, including the base excision repair (BER) pathway specifically, has heightened since these pathways have been shown to modulate important aspects of human disease. Modulation of the expression or activity of a particular BER enzyme, N-methylpurine DNA glycosylase (MPG), has been demonstrated to play a role in carcinogenesis and resistance to chemotherapy as well as neurodegenerative diseases, which has intensified the focus on studying MPG-related mechanisms of repair. A specific small molecule inhibitor for MPG activity would be a valuable biochemical tool for understanding these repair mechanisms. By screening several small molecule chemical libraries, we identified a natural polyphenolic compound, morin hydrate, which inhibits MPG activity specifically (IC50 = 2.6 μM). Detailed mechanism analysis showed that morin hydrate inhibited substrate DNA binding of MPG, and eventually the enzymatic activity of MPG. Computational docking studies with an x-ray derived MPG structure as well as comparison studies with other structurally-related flavanoids offer a rationale for the inhibitory activity of morin hydrate observed. The results of this study suggest that the morin hydrate could be an effective tool for studying MPG function and it is possible that morin hydrate and its derivatives could be utilized in future studies focused on the role of MPG in human disease. Graphical abstract image
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Synthesis of New Ligands for Targeting the S1P1 Receptor ()
Publication date: Available online 16 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Stefanie S. Schilson , Petra Keul , Rizwan S. Shaikh , Michael Schäfers , Bodo Levkau , Günter Haufe Sphingosine-1-phosphate (S1P) influences various fundamental biological processes by interacting with a family of five G protein-coupled receptors (S1P1-5). FTY720, a sphingosine analogue, which was approved for treatment of relapsing forms of multiple sclerosis, is phosphorylated in vivo and acts as an agonist of four of the five S1P receptor subtypes. Starting from these lead structures we developed new agonists for the S1P1 receptor. The biological activity was tested in vivo and promising ligands were fluorinated at different positions to identify candidates for positron emission tomography (PET) imaging after [ 18 F]-labelling. The radioligands shall enable the imaging of S1P1 receptor expression in vivo and thus may serve as novel imaging markers of S1P-related diseases. Graphical abstract image
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Synthesis and pharmacological characterization of 2-aminobenzaldehyde oxime analogs as dual inhibitors of neutrophil elastase and proteinase 3 ()
Publication date: Available online 16 January 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Tsong-Long Hwang , Wen-Hui Wang , Ting-Yi Wang , Huang-Ping Yu , Pei-Wen Hsieh Proteinase 3 (Pr3), and human neutrophil elastase (HNE) are two major neutrophilic serine proteases (NsPs) expressed in neutrophil azurophil granules. Emerging data suggest that excessive release of proteases mediates tissue damage, and therefore prolonged neutrophil accumulation has an important role in the pathogenesis of many diseases. Thus, HNE and Pr3 inhibitors may prove to be targets for the generation of agents in the treatment of neutrophilic inflammatory disease. Sivelestat is the only commercially available selective HNE inhibitor. Therefore, sivelestat was chosen as the model structure in an attempt to obtain more potent anti-NsPs agents. In the present study, a series 2-aminobenzaldehyde oxime and 2-aminobenzoate analogs were synthesized and their inhibitory effects on NsPs (CatG, Pr3, and HNE) were determined, respectively. The results of structure-activity relationships studies concluded that a hydroxyl oxime moiety plays an important role in ligand-enzyme affinity through hydrogen bonding. As compound 6 had more potency and showed dual inhibitory effects on NE and Pr3, both in vitro and in vivo experiments were carried out to evaluate its selectivity, effects in cell-based assays, and efficacy in models of inflammation and damage. Compound 6 had the potential to reduce paw edema induced by LPS and HNE, as well as acute lung injury, and may be approved as a candidate for the development of new agents in the treatment of neutrophilic inflammatory diseases. Graphical abstract image
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