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Bioorganic & Medicinal Chemistry Letters (v.17, #5)

Editorial board (pp. co2).
Graphical contents list (pp. 1131-1148).

Synthesis of O-prenylated and O-geranylated derivatives of 5-benzylidene2,4-thiazolidinediones and evaluation of their free radical scavenging activity as well as effect on some phase II antioxidant/detoxifying enzymes by Sk. Ugir Hossain; Sudin Bhattacharya (pp. 1149-1154).
Several 2,4-thiazolidinedione compounds were synthesized as free radical scavenger and phase II detoxifying/antioxidant enzymes inducer.A series of 5-arylidene-2,4-thiazolidinediones and its geranyloxy or prenyloxy derivative were synthesized and studied for their radical scavenging activity using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. Their comparable scavenging activities were expressed as IC50 value. Compounds2c,2d,4d, and6a showed appreciable radical scavenging activities. The vanillin based thiazolidinedione compound2c displayed highest activity comparable to that of α-tocopherol. But in vivo, compound6a showed better results in inducing phase II detoxifying/antioxidative enzyme.

Keywords: 2,4-Thiazolidinediones; Radical scavenger; Detoxifying enzyme; Mice


Synthesis and structure evaluation of a novel cantharimide and its cytotoxicity on SK-Hep-1 hepatoma cells by Stanton Hon Lung Kok; Chung Hin Chui; Wing Sze Lam; Jien Chen; Fung Yi Lau; Raymond Siu Ming Wong; Gregory Yin Ming Cheng; Paul Bo San Lai; Thomas Wai Tong Leung; Michael Wing Yiu Yu; Johnny Cheuk On Tang; Albert Sun Chi Chan (pp. 1155-1159).
A remarkable control of the potency of cantharimide is described based on the electronic properties of functional group and it exhibits a relatively less toxic effect to the non-malignant hematological disorder bone marrow cells.

Keywords: Cantharimide; 2-Aminobenzothiazole; Neoplasm


Opioids and efflux transporters. Part 1: P-Glycoprotein substrate activity of N-substituted analogs of meperidine by Susan L. Mercer; Hazem E. Hassan; Christopher W. Cunningham; Natalie D. Eddington; Andrew Coop (pp. 1160-1162).
P-Glycoprotein (P-gp) is an efflux transporter which is up-regulated at the blood–brain barrier in both morphine- and oxycodone-tolerant rats. Numerous studies have shown that many clinically employed opioid analgesics are substrates for P-gp, suggesting that up-regulation of P-gp may contribute to the development of central tolerance to opioids. The studies herein focus on the development of SAR for P-gp substrate activity in the meperidine series of compounds, and show that a meperidine analog of greater potency, N-phenylbutyl- N-normeperidine, has low activity as a P-gp substrate and has the potential to be utilized as a tool to study the contribution of P-gp to the development of central tolerance to opioids.

Keywords: Opioid; Tolerance


Synthesis of new xanthone analogues and their biological activity test—Cytotoxicity, topoisomerase II inhibition, and DNA cross-linking study by Sangwook Woo; Ji Jung; Chongsoon Lee; Youngjoo Kwon; Younghwa Na (pp. 1163-1166).
In this report, we prepared some 3-(2′,3′-epoxypropoxy)xanthones and their epoxide ring opened halohydrin analogues, and evaluated their cytotoxicity and topoisomerase II inhibition activity using doxorubicin and etoposide as references, respectively. Another xanthone compound9, 1,3-di(2′,3′-epoxypropoxy)xanthone, was also synthesized and its DNA cross-linking property including other two biological activities investigated. The biological test results showed compound9 possessed excellent cytotoxic and topoisomerase II inhibitory activity than other compounds tested. It also exhibited significant DNA cross-linking activities.

Keywords: Xanthones; Topoisomerase II inhibition; DNA cross-linking; Anti-cancer agents


Discovery of thienopyridines as Src-family selective Lck inhibitors by Lily Abbott; Patrick Betschmann; Andrew Burchat; David J. Calderwood; Heather Davis; Peter Hrnciar; Gavin C. Hirst; Biqin Li; Michael Morytko; Kelly Mullen; Bryant Yang (pp. 1167-1171).
We describe the identification, SAR, and in vivo pharmacology of a new series of Src-family selective Lck inhibitors. These thienopyridines were designed to access the unique residues in the extended hinge region of Lck.We describe the identification, SAR, and in vivo pharmacology of a new series of Src-family selective Lck inhibitors. These thienopyridines were designed based on a desire to access the unique residues in the extended hinge region of Lck.

Keywords: Lck inhibitors; Src-family; Kinase inhibitors; Thienopyridines


A new visual screening assay for catalytic antibodies with retro-aldol retro-Michael activity by Marina Shamis; Carlos F. Barbas III; Doron Shabat (pp. 1172-1175).
A black precipitate that is formed of three molecules of 3,4-cyclohexenoesculetin per ion of iron III is applied for visual detection of retro-aldol retro-Michael catalytic activity.Fast and convenient methods are required for the detection of novel catalysts. We have developed a new assay to allow direct visualization of retro-aldol retro-Michael catalytic activity and have demonstrated it with catalytic antibody 38C2. The assay is based on a catalytic cleavage of a physiologically stable substrate to release 3,4-cyclohexeneoesculetin. The latter then reacts with iron(III) to generate a non-soluble complex that precipitates in the form of a black dye. This assay may be used for screening new catalysts for retro-aldol retro-Michael activity with improved efficiency for specific prodrug activation.

Keywords: Catalytic antibodies; Prodrug activation; Aldol reaction; Assay


Chiral tetrahydroquinoline derivatives as potent anti-hyperalgesic agents in animal models of sustained inflammation and chronic neuropathic pain by Romano Di Fabio; Giuseppe Alvaro; Barbara Bertani; Daniele Donati; Domenica Maria Pizzi; Gabriella Gentile; Giorgio Pentassuglia; Simone Giacobbe; Simone Spada; Emiliangelo Ratti; Mauro Corsi; Mauro Quartaroli; Robert J. Barnaby; Giovanni Vitulli (pp. 1176-1180).
Chiral tetrahydroquinolines have been prepared by an asymmetric Mannich- type condensation reaction as in vivo potent anti-hyperalgesic agents in different animal models of chronic pain.Chiral tetrahydroquinoline derivatives have been prepared by an asymmetric Mannich-type condensation reaction using commercially available vinyloxyethylsilane and a N-arylimino R-(+)- t-butyl lactate ester, in the presence of a catalytic amount of metal triflates as Lewis acids. This synthetic approach gave rise to the target aldehyde intermediate in moderate facial diastereoselectivity and in high chemical yield. This efficient route enabled to scale up the synthesis of an orally bioavailable glycine antagonist showing outstanding in vivo anti-hyperalgesic activity in different animal models of sustained inflammation and chronic neuropathic pain.

Keywords: Excitatory amino acids; Glycine antagonists; Pain


Synthesis and antibacterial evaluation of a novel series of rifabutin-like spirorifamycins by In Ho Kim; Keith D. Combrink; Zhenkun Ma; Katrina Chapo; Dalai Yan; Paul Renick; Timothy W. Morris; Mark Pulse; Jerry W. Simecka; Charles Z. Ding (pp. 1181-1184).
A novel series of spirorifamycins was synthesized and their antibacterial activity evaluated both in vitro and in vivo. This new series of rifamycins shows excellent activity against Staphylococcus aureus that is equivalent to rifabutin. However, some compounds of the series exhibit lower MICs than rifabutin against rifampin-resistant strains of S. aureus. Further, compound2e exhibits comparable efficacy in vivo in a murine model of S. aureus septicemia model following administration by either oral or parenteral dosing routes.

Keywords: Rifamycin; Rifabutin; Spirorifamycin; RNA polyerase inhibitors; Synthesis; Rifampin-resistant; Ansamycin; Staphylococcus aureus; Antibacterial


Synthesis and evaluation of aryl thioxothiazolidinone inhibitors of ADAMTS-5 (Aggrecanase-2) by Matthew G. Bursavich; Adam M. Gilbert; Sabrina Lombardi; Katy E. Georgiadis; Erica Reifenberg; Carl R. Flannery; Elisabeth A. Morris (pp. 1185-1188).
5-Benzylidene-2-thioxo-thiazolidin-4-one inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared via commercially available starting materials. The identified compounds show micromolar ADAMTS-5 potency and demonstrate SAR trends for both the aryl group and thioxothiazolidinone zinc chelator. This series of compounds represents steps toward a metalloprotease inhibitor as a disease-modifying osteoarthritis drug.

Keywords: Aggrecanase; ADAMTS-5; Thioxothiazolidinone; Metalloprotease inhibitor; Zinc chelator


5-((1 H-Pyrazol-4-yl)methylene)-2-thioxothiazolidin-4-one inhibitors of ADAMTS-5 by Adam M. Gilbert; Matthew G. Bursavich; Sabrina Lombardi; Katy E. Georgiadis; Erica Reifenberg; Carl R. Flannery; Elisabeth A. Morris (pp. 1189-1192).
A series of 5-((1 H-pyrazol-4-yl)methylene)-2-thioxothiazolidin-4-one inhibitors of ADAMTS-5 (aggrecanase-2) is described. These compounds show μM functional inhibition of ADAMTS-5, and represent a new class of agents with the potential of inhibiting degradation of aggrecan, a major component of cartilage which is lost in osteoporosis. Compound12 is noteworthy in that it has an ADAMTS-5 IC50: 1.1μM and shows >40-fold functional selectivity over ADAMTS-4 (aggrecanase-1).

Keywords: ADAMTS-5; Aggrecanase-2; Thioxothiazolidin-4-ones; Osteoporosis


Novel pyridinyl and pyrimidinylcarbazole sulfonamides as antiproliferative agents by Laixing Hu; Zhuo-rong Li; Yue-ming Wang; Yanbin Wu; Jian-Dong Jiang; David W. Boykin (pp. 1193-1196).
Carbazole sulfonamidesII showed potent antiproliferative activity.A series of azaheterocyclic carbazole sulfonamides was synthesized and evaluated for antiproliferative activity. The most potent compounds N-(2,6-dimethoxypyridine-3-yl)-9-ethyl and 9-methylcarbazole-3-sulfonamide (13 and14) gave significant cytotoxicity (IC50=122 and 101nM). Compound13 displayed submicromolar activities against seven human tumor cell lines. The SARs of this series of sulfonamides which includes the influence of azaheterocycle rings, sulfonamide linkage, and the carbazole ring are described.

Keywords: Antiproliferative agents; Sulfonamides


Hydrolytic cleavage of DNA by quercetin zinc(II) complex by Tan Jun; Wang Bochu; Zhu Liancai (pp. 1197-1199).
Quercetin zinc(II) complex was investigated focusing on its hydrolytic activity toward DNA. The complex successfully promotes the cleavage of plasmid DNA, producing single and double DNA strand breaks. The amount of conversion of supercoiled form (SC) of plasmid to the nicked circular form (NC) depends on the concentration of the complex as well as the duration of incubation of the complex with DNA. The rate of conversion of SC to NC is 1.68×10−4s−1 at pH 7.2 in the presence of 100μM of the complex. The hydrolytic cleavage of DNA by the complex is supported by the evidence from free radical quenching, thiobarbituric acid-reactive substances (TBARS) assay, and T4 ligase ligation.

Keywords: Quercetin; Zinc(II) complex; DNA cleavage; Hydrolysis


Discovery of novel, non-acidic 1,5-biaryl pyrrole EP1 receptor antagonists by Adrian Hall; Stephen Atkinson; Susan H. Brown; Iain P. Chessell; Anita Chowdhury; Gerard M.P. Giblin; Paul Goldsmith; Mark P. Healy; Karamjit S. Jandu; Matthew R. Johnson; Anton D. Michel; Alan Naylor; Jennifer A. Sweeting (pp. 1200-1205).
The discovery and SAR of novel non-acidic 1,5-biaryl pyrrole derivatives is described. Several new motifs were discovered that were found to be effective replacements for the carboxylic acid in a series of EP1 receptor antagonists.Replacement of the carboxylic acid group in a series of previously described 1,5-biaryl pyrrole EP1 receptor antagonists led to the discovery of various novel non-acidic antagonists. Several analogues displayed high binding affinity and high binding efficiency indices.

Keywords: EP; 1; antagonist; Pyrrole; Carboxylic acid replacement


Synthesis and SAR of 3,5-diamino-piperidine derivatives: Novel antibacterial translation inhibitors as aminoglycoside mimetics by Yuefen Zhou; Vlad E. Gregor; Benjamin K. Ayida; Geoffrey C. Winters; Zhongxiang Sun; Douglas Murphy; Greg Haley; Dwight Bailey; Jamie M. Froelich; Sarah Fish; Stephen E. Webber; Thomas Hermann; Daniel Wall (pp. 1206-1210).
Aminoglycoside antibiotics target an internal RNA loop within the bacterial ribosomal decoding site. Here, we describe the synthesis and SAR of novel 3,5-diamino-piperidine derivatives as aminoglycoside mimetics, and show they act as inhibitors of bacterial translation and growth.

Keywords: Aminoglycosides; Antibiotics; Translation inhibitors; 2-Deoxy-streptamine; Ribosome; Decoding site; 3,5-Diamino-piperidine


Discovery and preliminary evaluation of 5-(4-phenylbenzyl)oxazole-4-carboxamides as prostacyclin receptor antagonists by Marc-Raleigh Brescia; Laura L. Rokosz; Andrew G. Cole; Tara M. Stauffer; John M. Lehrach; Douglas S. Auld; Ian Henderson; Maria L. Webb (pp. 1211-1215).
The synthesis and evaluation of 5-(4-phenylbenzyl)oxazole-4-carboxamides as prostacyclin receptor antagonists is reported.The discovery and evaluation of 5-(4-phenylbenzyl)oxazole-4-carboxamides as prostacyclin (IP) receptor antagonists is described. Analogs disclosed showed high affinity for the IP receptor in human platelet membranes with IC50 values of 0.05–0.50μM, demonstrated functional antagonism by inhibiting cAMP production in HEL cells with IC50 values of 0.016–0.070μM, and exhibited significant selectivity versus other prostanoid receptors.

Keywords: Prostacyclin; PGI; 2; Prostanoid receptors; Pain; Inflammation; ECLiPS™


In vitro selection of RNA aptamer against Escherichia coli release factor 1 by Shinsuke Sando; Atsushi Ogawa; Teruyuki Nishi; Masayoshi Hayami; Yasuhiro Aoyama (pp. 1216-1220).
We successfully selected RNA aptamers against Escherichia coli release factor 1, allowing an enhanced nonsense suppression at the amber (UAG) stop codon.A pool of 84-nt RNAs containing a randomized sequence of 50nt was selected against gel-immobilized Escherichia coli release factor 1 (RF-1) responsible for translation termination at amber (UAG) stop codon. The strongest aptamer (class II-1) obtained from 43 clones bound to RF-1, but not to UAA/UGA-targeting RF-2, with Kd=30±6nM (SPR). A couple of unpaired hairpin domains in the aptamer were suggested as the sites of attachment of RF-1. By binding to and hence inhibiting the action of RF-1 specifically or bio-orthogonally, aptamer class II-1 enhanced the amber suppression efficiency in the presence of an anticodon-adjusted (CUA) suppressor tRNA without practically damaging the protein translation machinery of the cell-free extract of E. coli, as confirmed by the translation of amber-mutated ( gfpamber141 or gfpamber178) and wild-type ( gfpwild) genes of GFP.

Keywords: Aptamer; Amber suppression; Translation


Discovery of uracil-based histone deacetylase inhibitors able to reduce acquired antifungal resistance and trailing growth in Candida albicans by Antonello Mai; Dante Rotili; Silvio Massa; Gerald Brosch; Giovanna Simonetti; Claudio Passariello; Anna Teresa Palamara (pp. 1221-1225).
Among fungal pathogens such as Candida albicans, acquired drug resistance has not been associated with plasmids or other transferable elements, but it is thought to involve primarily mutations and genetic or epigenetic phenomena. This prompted us to test some histone deacetylase inhibitors (HDACi) from our library, in combination with fluconazole, against C. albicans strains in vitro. Among the tested compounds, the two chloro-containing uracil-hydroxamates1c and1d showed a strong reduction of the MIC values on Candida strains that show the trailing growth effect. In this assay,1c,d were more potent than SAHA, a well-known HDAC inhibitor, in reducing the Candida growth. More interestingly,1c,d as well as SAHA were able to inhibit the fluconazole-induced resistance induction in Candida cultures.

Keywords: Histone deacetylase inhibitors; Trailing; Antifungal resistance; Fluconazole


Simple criterion for selection of flavonoid compounds with anti-HIV activity by Veljko Veljkovic; Jean-François Mouscadet; Nevena Veljkovic; Sanja Glisic; Zeger Debyser (pp. 1226-1232).
Flavonoid compounds represent an important natural source of antiretrovirals for AIDS therapy due to their significant anti-HIV-1 activity and low toxicity. Here we propose a simple theoretical criterion to discriminate active from inactive flavonoids that is suitable for rapid in silico screening of flavonoid libraries, and selection and optimization of lead compounds with anti-HIV-1 activity.Flavonoid compounds represent an important natural source of antiretrovirals for AIDS therapy due to their significant anti-HIV-1 activity and low toxicity. Here we propose a simple theoretical criterion to discriminate active from inactive flavonoids that is suitable for rapid in silico screening of flavonoid libraries, and selection and optimization of lead compounds with anti-HIV-1 activity.

Keywords: Flavonoids; In silico screening; Anti-HIV compounds


Synthesis and biological evaluation of 4-amino derivatives of benzimidazoquinoxaline, benzimidazoquinoline, and benzopyrazoloquinazoline as potent IKK inhibitors by Francis Beaulieu; Carl Ouellet; Edward H. Ruediger; Makonen Belema; Yuping Qiu; Xuejie Yang; Jacques Banville; James R. Burke; Kurt R. Gregor; John F. MacMaster; Alain Martel; Kim W. McIntyre; Mark A. Pattoli; F. Christopher Zusi; Dolatrai Vyas (pp. 1233-1237).
We have recently identified BMS-345541 (1) as a highly selective and potent inhibitor of IKK-2 (IC50=0.30μM), which however was considerably less potent against IKK-1 (IC50=4.0μM). In order to further explore the SAR around the imidazoquinoxaline tricyclic structure of1, we prepared a series of tetracyclic analogues (7,13, and18). The synthesis and biological activities of these potent IKK inhibitors are described.

Keywords: NF-κB; IKK inhibitors; TNF-α; Quinoxaline


Synthesis, characterization, antibacterial activity, and interaction with DNA of the vanadyl-enrofloxacin complex by Eleni K. Efthimiadou; Nikos Katsaros; Alexandra Karaliota; George Psomas (pp. 1238-1242).
The synthesis, characterization, antimicrobial activity and interaction with calf-thymus DNA of the mononuclear vanadyl complex with the second-generation quinolone enrofloxacin are reported.The neutral mononuclear vanadyl complex with the quinolone antibacterial drug enrofloxacin has been prepared and characterized with physicochemical and spectroscopic techniques and molecular mechanics calculations. The interaction of the complex with calf-thymus DNA has also been investigated and the antimicrobial activity has been evaluated against three different microorganisms.

Keywords: Enrofloxacin; Quinolones; Vanadyl complex; Biological activity; Interaction with calf-thymus DNA; MIC


Synthesis of 3-(1 H-benzimidazol-2-yl)-5-isoquinolin-4-ylpyrazolo[1,2- b]pyridine, a potent cyclin dependent kinase 1 (CDK1) inhibitor by Shenlin Huang; Ronghui Lin; Yang Yu; Yanhua Lu; Peter J. Connolly; George Chiu; Shengjian Li; Stuart L. Emanuel; Steven A. Middleton (pp. 1243-1245).
A novel compound 3-(1 H-benzimidazol-2-yl)-5-isoquinolin-4-ylpyrazolo[1,2- b]pyridine was discovered to be a potent CDK1 inhibitor. An efficient chemistry was developed for the synthesis, with key steps including Pd(II) catalyzed Stille coupling reaction and sulfur(0) induced benzimidazole formation. The effects on VEGFR-2 kinase and tumour cell proliferation are also described.The novel compound 3-(1 H-benzimidazol-2-yl)-5-isoquinolin-4-ylpyrazolo[1,2- b]pyridine was discovered to be a potent CDK1 inhibitor. Described here is the chemistry for its synthesis, including Pd(II) catalyzed Stille coupling reaction and sulfur(0) induced benzimidazole formation. Its effects on VEGFR-2 kinase activity and tumour cell proliferation are also described.

Keywords: Pyrazolo[1,2-; b; ]pyridine; Cyclin dependent kinase 1 inhibitor


Thienopyridine urea inhibitors of KDR kinase by H. Robin Heyman; Robin R. Frey; Peter F. Bousquet; George A. Cunha; Maria D. Moskey; Asma A. Ahmed; Niru B. Soni; Patrick A. Marcotte; Lori J. Pease; Keith B. Glaser; Melinda Yates; Jennifer J. Bouska; Daniel H. Albert; Candace L. Black-Schaefer; Peter J. Dandliker; Kent D. Stewart; Paul Rafferty; Steven K. Davidsen; Michael R. Michaelides; Michael L. Curtin (pp. 1246-1249).
The evaluation of KDR kinase inhibitor2 (IC50=9nM) and related analogs is reported.A series of substituted thienopyridine ureas was prepared and evaluated for enzymatic and cellular inhibition of KDR kinase activity. Several of these analogs, such as2, are potent inhibitors of KDR (<10nM) in both enzymatic and cellular assays. Further characterization of inhibitor2 indicated that this analog possessed excellent in vivo potency (ED50 2.1mg/kg) as measured in an estradiol-induced mouse uterine edema model.

Keywords: KDR kinase; VEGF; Thienopyridine; Urea


Development of new pyrrolopyrimidine-based inhibitors of Janus kinase 3 (JAK3) by Michael P. Clark; Kelly M. George; Roger G. Bookland; Jack Chen; Steven K. Laughlin; Kumar D. Thakur; Wenlin Lee; Jan R. Davis; Ed J. Cabrera; Todd A. Brugel; John C. VanRens; Matthew J. Laufersweiler; Jennifer A. Maier; Mark P. Sabat; Adam Golebiowski; Vijay Easwaran; Mark E. Webster; Biswanath De; George Zhang (pp. 1250-1253).
A new class of bicyclic pyrrolopyrimidine-based Janus kinase 3 (JAK-3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK-3.

Keywords: JAK3; Janus Kinase; Tyrosine kinases; Cytokines; Pyrrolopyrimidine


Bicyclic carbamates as inhibitors of papain-like cathepsin proteases by Robert Epple; Hugo D. Urbina; Ross Russo; Hong Liu; Daniel Mason; Badry Bursulaya; Christine Tumanut; Jun Li; Jennifer L. Harris (pp. 1254-1259).
The discovery, SAR, and MoA investigation of a novel non-peptidic protease inhibitor scaffold are described.A 6-oxa-1-aza-bicyclo[3.2.1]octan-7-one system inhibits the proteolytic activity of several cysteine proteases belonging to the papain family. In vitro mechanistic studies and in silico calculations suggest that the minimal π-overlap between the bridgehead nitrogen and the carbonyl leads to a considerable weakening of the urethane system, making it susceptible to nucleophilic attack from the active site thiol group. The resulting covalent adduct is slowly hydrolyzed, releasing the hydroxypiperidine product of the inhibitor. Synthesis and testing of a set of analogs led to variable protease subtype selectivities ranging from micromolar to nanomolar potencies.

Keywords: Cathepsins; Protease inhibitors; Carbamates


Weak base dispiro-1,2,4-trioxolanes: Potent antimalarial ozonides by Yuanqing Tang; Yuxiang Dong; Sergio Wittlin; Susan A. Charman; Jacques Chollet; Francis C.K. Chiu; William N. Charman; Hugues Matile; Heinrich Urwyler; Arnulf Dorn; Saroj Bajpai; Xiaofang Wang; Maniyan Padmanilayam; Jean M. Karle; Reto Brun; Jonathan L. Vennerstrom (pp. 1260-1265).
Thirty weak base 1,2,4-dispiro trioxolanes (secondary ozonides) were synthesized. Amino amide trioxolanes had the best combination of antimalarial and biopharmaceutical properties. Guanidine, aminoxy, and amino acid trioxolanes had poor antimalarial activity. Lipophilic trioxolanes were less stable metabolically than their more polar counterparts.

Keywords: 1,2,4-Trioxolanes; Secondary ozonides; Antimalarial; Peroxide; Artemisinin


A novel diketo phosphonic acid that exhibits specific, strand-transfer inhibition of HIV integrase and anti-HIV activity by Guochen Chi; Vasu Nair; Elena Semenova; Yves Pommier (pp. 1266-1269).
We have synthesized novel phosphonic acid analogues of β-diketo acids. Interestingly, the phosphonic acid isostere,2, of our anti-HIV compound,1, was an inhibitor of only the strand transfer step, in stark contrast to1. Compound2 had lower anti-HIV activity than1, but was more active and less toxic than the phosphonic acid analogue ofL-708906. These isosteric compounds represent the first examples of β-diketo phosphonic acids of structural, synthetic, and antiviral interest.

Keywords: Synthesis; Phosphonates; HIV integrase inhibitors; Mechanism of inhibition; Anti-HIV activity


Identification of arylsulfonamides as Aquaporin 4 inhibitors by Vincent J. Huber; Mika Tsujita; Maya Yamazaki; Kenji Sakimura; Tsutomu Nakada (pp. 1270-1273).
A series of carbonic anhydrase inhibitors, including AZA, have been found to inhibit AQP4 mediated water transport in an in vitro functional assay. AZA has an apparent IC50=0.9μM against human AQP4-M23.Carbonic anhydrase inhibitors AZA, EZA, and 4-acetamidobenzsulfonamide were found to inhibit human AQP4-M23 mediated water transport by 80%, 68%, and 23%, respectively, at 20μM in an in vitro functional assay. AZA was found to have an IC50 against AQP4 of 0.9μM. Phloretin was inactive under the same conditions.

Keywords: Aquaporin 4; AQP4; Inhibitors; Acetazolamide; AZA; 6-Ethoxybenzothiazole-2-sulfonamide; EZA; Phloretin


3-[2-((2 S)-2-Cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-3-methyl-butyramide analogues as selective DPP-IV inhibitors for the treatment of type-II diabetes by Mohane Selvaraj Coumar; Chung-Nien Chang; Chiung-Tong Chen; Xin Chen; Chia-Hui Chien; Ting-Yueh Tsai; Jai-Hong Cheng; Hsin-Yi Wu; Chia-Hung Han; Ssu-Hui Wu; Yu-Wen Huang; Tsu Hsu; Li-Jen Hsu; Yu-Sheng Chao; Hsing-Pang Hsieh; Weir-Torn Jiaang (pp. 1274-1279).
Based on the structures of NVP-DPP728 (1) and NVP-LAF237 (Vildagliptin,2), three series of DPP-IV inhibitors were synthesized by linking substituted anilines, benzylamines, and phenylethylamines to (2 S)-cyanopyrrolidine through a linker. More than 20 compounds were evaluated for their in vitro DPP-IV inhibition and selectivity profile over DPP-II, DPP8, and FAP enzymes. Selected compounds5f and7i showed in vivo plasma DPP-IV inhibition and inhibited glucose excursion in OGTT after oral administration in Wistar rats. Compound5f (DPP-IV IC50=116nM) has the potential for development as antidiabetic agent.

Keywords: DPP-IV; Type-II diabetes


High-throughput screening affords novel and selective trypanothione reductase inhibitors with anti-trypanosomal activity by Derek C. Martyn; Deuan C. Jones; Alan H. Fairlamb; Jon Clardy (pp. 1280-1283).
Trypanothione reductase (TR) was screened against 134,500 compounds. Four chemotypes were selective for TR over human glutathione reductase. The in vitro activity of 13 purchased compounds against TR and Trypanosoma brucei is summarized.Trypanothione reductase (TR), an enzyme that buffers oxidative stress in trypanosomatid parasites, was screened against commercial libraries containing approximately 134,500 compounds. After secondary screening, four chemotypes were identified as screening positives with selectivity for TR over human glutathione reductase. Thirteen compounds from these four chemotypes were purchased, and their in vitro activity against TR and Trypanosoma brucei is described.

Keywords: Trypanothione reductase; High-throughput screening; Trypanosomiasis


3-Hydroxychromones as cyclin-dependent kinase inhibitors: Synthesis and biological evaluation by Jinho Lee; Taesik Park; Shinwu Jeong; Kyoung-Hee Kim; Changyong Hong (pp. 1284-1287).
A novel series of 3-hydroxychromones were prepared and found to be CDK inhibitors. Isothiaszolidine 1,1-dioxide analogues showed potent CDK1 and CDK2 inhibitory activities and inhibited proliferation of EJ, HCT116, SW620, and MDA MB468 cancer cells.A novel series of 3-hydroxychromones were prepared and found to be CDK inhibitors. Isothiazolidine 1,1-dioxide analogues showed potent CDK1 and CDK2 inhibitory activities and inhibited proliferation of EJ, HCT116, SW620, and MDAMB468 cancer cells.

Keywords: 3-Hydroxychromone; Isothiazolidine 1,1-dioxide; CDK2


Synthesis, structural revision, and antioxidant activities of antimutagenic homoisoflavonoids from Hoffmanosseggia intricata by Vidavalur Siddaiah; Muchchintala Maheswara; Chunduri Venkata Rao; Somepalli Venkateswarlu; Gottumukkala V. Subbaraju (pp. 1288-1290).
Intricatin (2) has been revised into3 and antioxidant activity results are reported.Intricatinol and intricatin, the two homoisoflavonoids isolated from Hoffmanosseggia intricata, and two analogs have been synthesized from pyrogallol in three steps. The spectral data of synthetic intricatinol are in good agreement with those of natural metabolite, but the spectral data of intricatin are not corroborative with those of the natural product. The structure of intricatin has been thus revised to 8-methoxybonducellin, a compound isolated from Caesalpinia pulcherrima. The antioxidant activity of all the four homoisoflavonoids was determined by superoxide (NBT) and DPPH free radical scavenging methods. The synthetic analog 7,8-dihydroxy-3-[(3,4-dihydroxyphenyl)methylene]chroman-4-one displayed excellent activity in both methods.

Keywords: Homoisoflavonoids; Synthesis; Revised structure; Antioxidant activity


3-Substituted-(5-arylfuran-2-ylcarbonyl)guanidines as NHE-1 inhibitors by Sunkyung Lee; Taemi Kim; Byung Ho Lee; Sung-eun Yoo; Kyunghee Lee; Kyu Yang Yi (pp. 1291-1295).
The synthesis and evaluation as NHE-1 inhibitors of 3-substituted-(5-arylfuran-2-ylcarbonyl)guanidines is described.The C-3 substituents effect on NHE-1 inhibitory activity of (5-arylfuran-2-ylcarbonyl)guanidines, previously identified as potent NHE-1 inhibitors, was investigated. The introduction of amine or alkyl groups at the 3-position of the furan ring, next to the acylguanidine moiety, remarkably improves NHE-1 inhibitory potency. Especially the important finding is that 5-(2,5-dichloro)phenyl and 5-(2-methoxy-5-chloro)phenyl derivatives exhibit high NHE-1 inhibitory activities (IC50<0.02μM) that match those of 3-unsubstituted derivatives.

Keywords: Sodium hydrogen exchanger; 3-Substituted-(5-arylfuran-2-ylcarbonyl)guanidine; Cardioprotective


N-(3-Cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amides as potent, selective, inhibitors of JNK2 and JNK3 by Richard M. Angell; Francis L. Atkinson; Murray J. Brown; Tsu Tshen Chuang; John A. Christopher; Maria Cichy-Knight; Allison K. Dunn; Kendra E. Hightower; Susanna Malkakorpi; James R. Musgrave; Margarete Neu; Paul Rowland; Robyn L. Shea; Jeffery L. Smith; Donald O. Somers; Sonia A. Thomas; Gladstone Thompson; Ruolan Wang (pp. 1296-1301).
The identification and exploration of a novel, potent and selective series of N-(3-cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amide inhibitors of JNK2 and JNK3 kinases is described. Compounds5a and11a were identified as potent inhibitors of JNK3 (pIC50 6.7 and 6.6, respectively), with essentially equal potency against JNK2 (pIC50 6.5). Selectivity within the mitogen-activated protein kinase (MAPK) family, against JNK1, p38α and ERK2, was observed for the series. X-ray crystallography of5e and8a in JNK3 revealed a unique binding mode, with the 3-cyano substituent forming an H-bond acceptor interaction with the hinge region of the ATP-binding site.The identification and exploration of a novel, potent and selective series of N-(3-cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amide inhibitors of JNK2 and JNK3 kinases is described. Compounds5a and11a were identified as potent inhibitors of JNK3 (pIC50 6.7 and 6.6, respectively), with essentially equal potency against JNK2 (pIC50 6.5). Selectivity within the mitogen-activated protein kinase (MAPK) family, against JNK1, p38α and ERK2, was observed for the series. X-ray crystallography of5e and8a in JNK3 revealed a unique binding mode, with the 3-cyano substituent forming an H-bond acceptor interaction with the hinge region of the ATP-binding site.

Keywords: Kinase; Inhibitor; JNK; JNK3; MAPK; Selective


Rational design, synthesis, and structure–activity relationship of benzoxazolones: New potent mglu5 receptor antagonists based on the fenobam structure by Simona M. Ceccarelli; Georg Jaeschke; Bernd Buettelmann; Jörg Huwyler; Sabine Kolczewski; Jens-Uwe Peters; Eric Prinssen; Richard Porter; Will Spooren; Eric Vieira (pp. 1302-1306).
A novel class of potent and stable mGlu5 receptor antagonists was developed by combining information from a high-throughput screening campaign with the structure of the known anxiolytic fenobam.A novel class of potent and stable mGlu5 receptor antagonists was developed by combining information from a high-throughput screening campaign with the structure of the known anxiolytic fenobam. Representative compounds from this class show favorable pharmacokinetic properties and are active in an in vivo model of anxiety.

Keywords: mGluR5; Fenobam; Anxiety; MPEP; Benzoxazolone


Synthesis and biological evaluation of fenobam analogs as mGlu5 receptor antagonists by Georg Jaeschke; Richard Porter; Bernd Büttelmann; Simona M. Ceccarelli; Wolfgang Guba; Bernd Kuhn; Sabine Kolczewski; Jörg Huwyler; Vincent Mutel; Jens-Uwe Peters; Theresa Ballard; Eric Prinssen; Eric Vieira; Jürgen Wichmann; Will Spooren (pp. 1307-1311).
Optimization of affinity and microsomal stability led to identification of the potent, metabolically stable fenobam analog4l. Robust in vivo efficacy of4l was demonstrated in four different models of anxiety. Additionally, a ligand based pharmacophore alignment of fenobam and MPEP is proposed.Optimization of affinity and microsomal stability led to identification of the potent, metabolically stable fenobam analog4l. Robust in vivo efficacy of4l was demonstrated in four different models of anxiety. Additionally, a ligand based pharmacophore alignment of fenobam and MPEP is proposed.

Keywords: mGluR5; Fenobam; Anxiety; MPEP; Pharmacophore


Structure–activity relationships of 3-aminoquinazolinediones, a new class of bacterial type-2 topoisomerase (DNA gyrase and topo IV) inhibitors by Tuan P. Tran; Edmund L. Ellsworth; Joseph P. Sanchez; Brian M. Watson; Michael A. Stier; H.D. Hollis Showalter; John M. Domagala; Martin A. Shapiro; E. Themis Joannides; Stephen J. Gracheck; Dai Q. Nguyen; Paul Bird; Judy Yip; Anurag Sharadendu; Chan Ha; Saeed Ramezani; Xiujuan Wu; Rajeshwar Singh (pp. 1312-1320).
The syntheses and antibacterial SAR of the 3-aminoquinazolinediones are reported.A series of 3-aminoquinazolinediones was synthesized and evaluated for its antibacterial and DNA gyrase activity. The SAR around the quinazolinedione core was explored and the optimal substitutions were combined to give two compounds,2r and2s, with exceptional enzyme potency (IC50= 0.2μM) and activity against Gram-positive organisms (MIC’s= 0.015–0.06μ g/mL).

Keywords: 3-Aminoquinazolinediones; Antibacterial agents; DNA gyrase inhibitors; Topoisomerase inhibitors; Antibacterial activity


Diastereoselective synthesis of glycosylated prolines as α-glucosidase inhibitors and organocatalyst in asymmetric aldol reaction by Jyoti Pandey; Namrata Dwivedi; Nimisha Singh; A.K. Srivastava; A. Tamarkar; R.P. Tripathi (pp. 1321-1325).
1,3-Dipolar cycloaddition of azomethine ylides and glycosyl E-olefins in presence of LDA led to diastereoselective formation of C-glycosylated proline esters. The selected esters on regioselective hydrolysis with LiOH gave C-glycosyl prolines. Few of the proline esters exhibited very good α-glucosidase inhibitory activity. The organocatalytic activity of the proline derivatives in a prototype Aldol reaction has also been investigated.

Keywords: Glycosyl prolines; 1,3-Dipolar cycloaddition; α-Glucosidase; Tetrasubstituted pyrrolidines


Amino acid-based enantiomerically pure 3-substituted 1,4-benzodiazepin-2-ones: A new class of anti-ischemic agents by Jitendra Kumar Mishra; Puja Garg; Preeti Dohare; Ashutosh Kumar; Mohammad Imran Siddiqi; Madhur Ray; Gautam Panda (pp. 1326-1331).
A series of 3-substituted 1, 4-benzodiazepin-2-ones derived from S and R amino acids were evaluated for their anti-ischemic activity in vitro. Treatment with compounds7h,16,9d, and17 decreased the apoptotic neuronal number, however increased the neuronal viability. The compounds decreasing apoptosis could protect neurons from the ischemic injury. The difference in the activities of 1,4-benzodiazepin-2-ones derived from S- and R-amino acids is discussed and explained on the basis of molecular modeling studies.

Keywords: Anti-ischemic agents; 1,4-Benzodiazepin-2-ones; Amino acids


Novel antiproliferative analogs of the Taq DNA polymerase inhibitor catalpol by Carlos R. Pungitore; Leticia G. León; Celina García; Víctor S. Martín; Carlos E. Tonn; José M. Padrón (pp. 1332-1335).
A series of new silylated catalpol analogs inhibit in a dose-dependent manner the proliferation of a panel of diverse human cancer cell lines through G0/G1 phase arrest.The naturally occurring iridoid catalpol (1) is a Taq DNA polymerase inhibitor. However, its poor lipophilicity might account for the lack of biological activity against human solid tumor cell lines. The traditional prodrug approach by means of peracetylation of the free hydroxyl groups led to a compound, which showed a marginal growth inhibition against the most sensitive cell line A2780 (ovarian cancer). However, the formation of analogs bearing one to three silyl ether groups led to antiproliferative compounds against a panel of six human solid tumor cell lines, with GI50 values in the range 1.8–4.8μM. Cell cycle studies revealed arrest in G0/G1 phase that is consistent with DNA polymerase inhibition.

Keywords: Iridoids; Silyl ethers; Anticancer drugs; Solid tumors; DNA polymerase inhibitors


Carbonic anhydrase activators: An activation study of the human mitochondrial isoforms VA and VB with amino acids and amines by Daniela Vullo; Isao Nishimori; Alessio Innocenti; Andrea Scozzafava; Claudiu T. Supuran (pp. 1336-1340).
The mitochondrial isozymes of human carbonic anhydrase (hCA, EC 4.2.1.1), hCA VA and hCA VB, were investigated for activation with a series of amino acids and amines.d-His,l-DOPA, histamine, dopamine, and 4-(2-aminoethyl)morpholine were excellent hCA VA activators, with KAs in the range of 10–130nM. Good hCA VB activating effects were identified forl-His,d-Phe,d-DOPA,l-Trp,l-Tyr, serotonin, and 2-(2-aminoethyl)-pyridine, with KAs in the range of 44–110nM. All these activators enhanced kcat, having no effect on KM, favoring thus the rate-determining step in the catalytic cycle, the proton transfer reactions between the active site and environment. The activation pattern of the two mitochondrial isoforms is very different from each other and as compared to those of the cytosolic isoforms hCA I and II.

Keywords: Carbonic anhydrase; Isoform VA; VB; Activation; Amine; Amino acid; Histamine; Mitochondria


Synthesis and biological evaluation of new conformationally biased integrin ligands based on a tetrahydroazoninone scaffold by Luca Banfi; Andrea Basso; Gianluca Damonte; Federico De Pellegrini; Andrea Galatini; Giuseppe Guanti; Ilaria Monfardini; Renata Riva; Carlo Scapolla (pp. 1341-1345).
The synthesis of new conformationally biased cyclic pentapeptides, incorporating the RGD sequence, and built around a tetrahydroazoninone scaffold, is reported. They exhibit interesting activity towards integrin αVβ3 and a remarkable selectivity in comparison with integrin αVβ5.

Keywords: Integrin ligands; Azoninones; Angiogenesis; Peptidomimetics


Synthesis and antitubercular activity of quaternized promazine and promethazine derivatives by Aaron B. Bate; Jay H. Kalin; Eric M. Fooksman; Erica L. Amorose; Cristofer M. Price; Heather M. Williams; Michael J. Rodig; Miguel O. Mitchell; Sang Hyun Cho; Yuehong Wang; Scott G. Franzblau (pp. 1346-1348).
Quaternized promazine derivatives4b (R1=CF3, R2=4-Cl; X=Cl) and4c (R1=CF3; R2=3-Cl; X=Cl) inhibit actively growing and non-replicating Mycobacterium tuberculosis at <4 and <8μM, respectively.Quaternized chlorpromazine, triflupromazine, and promethazine derivatives were synthesized and examined as antitubercular agents against both actively growing and non-replicating Mycobacterium tuberculosis H37Rv. Impressively, several compounds inhibited non-replicating M. tuberculosis at concentrations equal to or double their MICs against the actively growing strain. All active compounds were non-toxic toward Vero cells (IC50>128μM). N-Allylchlorpromazinium bromide was only weakly antitubercular, but replacing allyl with benzyl or substituted benzyl improved potency. An electron-withdrawing substituent on the phenothiazine ring was also essential. Branching at the carbon chain decreased antitubercular activity. The optimum antitubercular structures possessed N-(4- or 3-chlorobenzyl) substitution on triflupromazine.

Keywords: Antitubercular; Promazine; Promethazine; Chlorpromazine; Triflupromazine; Quaternized


3-Mercaptopropionic acids as efficacious inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa) by Imadul Islam; Judi Bryant; Karen May; Raju Mohan; Shendong Yuan; Lorraine Kent; John Morser; Lei Zhao; Ron Vergona; Kathy White; Marc Adler; Marc Whitlow; Brad O. Buckman (pp. 1349-1354).
A novel series of cyclic potent, selective, small molecule, thiol-based inhibitors of activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa) are described. Inhibition of TAFIa with (rac)2a resulted in dose dependent acceleration of human plasma clot lysis in vitro and was efficacious as an adjunct to tPA in an in vivo rabbit jugular vein thrombolysis model.A novel series of cyclic potent, selective, small molecule, thiol-based inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa) and the crystal structures of TAFIa inhibitors bound to porcine pancreatic carboxypeptidase B are described. Three series of cyclic arginine and lysine mimetic inhibitors vary significantly in their selectivity against other human basic carboxypeptidases, carboxypeptidase N and carboxypeptidase B. (−)2a displays TAFIa IC50=3nM and 600-fold selectivity against CPN. Inhibition of TAFIa with (rac)2a resulted in dose dependent acceleration of human plasma clot lysis in vitro and was efficacious as an adjunct to tPA in an in vivo rabbit jugular vein thrombolysis model.

Keywords: TAFI; Fibrinolysis; Carboxypeptidase


Anti-mycobacterial activity of a bis-sulfonamide by Brendan L. Wilkinson; Laurent F. Bornaghi; Anthony D. Wright; Todd A. Houston; Sally-Ann Poulsen (pp. 1355-1357).
A bis-arylsulfonamide,7, has been identified that exhibits growth inhibition of Mycobacterium smegmatis at less than 25μg/mL, but has no such activity against Escherichia coli or Staphylococcus aureus. A closely related bis-arylsulfonamide (8) was much less active, but was the only other compound among 54 arylsulfonamides tested with detectable growth inhibition of M. smegmatis.

Keywords: Sulfonamide; Mycobacterium; Mycobacterium smegmatis; Triazole


Inhibition of Src kinase activity by 7-ethynyl-4-phenylamino-3-quinolinecarbonitriles: Identification of SKS-927 by Diane H. Boschelli; Ana Carolina Barrios Sosa; Jennifer M. Golas; Frank Boschelli (pp. 1358-1361).
Of a series of 7-ethynyl-3-quinolinecarbonitriles, the most potent Src inhibitory activity was observed with SKS-927.Of a series of 7-ethynyl-3-quinolinecarbonitriles, the most potent Src inhibitory activity was observed with 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[4-(4-methylpiperazin-1-yl)but-1-ynyl]-3-quinolinecarbonitrile (SKS-927). Variation of the solubilizing amine tail or removal of the methoxy group from either C-6 of the quinoline core or C-5 of the aniline headpiece led to reduced activity.

Keywords: Src; 3-Quinolinecarbonitrile


Synthesis and HIV-1 integrase inhibitory activity of spiroundecane(ene) derivatives by Elvira E. Shults; Elena A. Semenova; Allison A. Johnson; Svetlana P. Bondarenko; Irina Y. Bagryanskaya; Yuri V. Gatilov; Genrikh A. Tolstikov; Yves Pommier (pp. 1362-1368).
Fifteen 2,4-dioxaspiro[5.5]undecane ketone and 2,4-dioxa-spiro[5.5]undec-8-ene (spiroundecane(ene)) derivatives were synthesized using the Diels–Alder reaction. Inhibition of human immunodeficiency virus integrase (IN) was examined. Eight spiroundecane(ene) derivatives inhibited both 3′-processing and strand transfer reactions catalyzed by IN. SAR studies showed that the undecane core with at least one furan moiety is preferred for IN inhibition. Moreover, crosslinking experiments showed that spiroundecane derivatives did not affect IN–DNA binding at concentrations that block IN catalytic activity, indicating spiroundecane derivatives inhibit preformed IN–DNA complex. The moderate toxicity of spiroundecane(ene) derivatives encourages the further design of therapeutically relevant analogues based on this novel chemotype of IN inhibitors.

ortho-Substituted azoles as selective and dual inhibitors of VEGF receptors 1 and 2 by Alexander S. Kiselyov; Evgueni L. Piatnitski; Alexander V. Samet; Victor P. Kisliy; Victor V. Semenov (pp. 1369-1375).
A novel series of potent ortho-substituted azole derivatives active against kinases VEGFR-1 and VEGFR-2 is described. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified.We have developed a series of novel potent ortho-substituted azole derivatives active against kinases VEGFR-1 and VEGFR-2. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase activity and selectivity could be controlled by varying the arylamido substituents at the azole ring. The most specific molecule (17) displayed >10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in enzymatic and cell-based assays were in the range of activities for reported clinical and development candidates (IC50<100nM), including Novartis’ PTK787 ( Vatalanib)™. High permeability of active compounds across the Caco-2 cell monolayer (>30×10−5cm/min) is indicative of their potential for intestinal absorption upon oral administration.

Keywords: Vascular endothelial growth factor receptor; KDR; VEGFR-2; VEGFR-1; Receptor tyrosine kinase; Dual kinase inhibitors; Angiogenesis


Potent, selective, and orally active adenosine A2A receptor antagonists: Arylpiperazine derivatives of pyrazolo[4,3- e]-1,2,4-triazolo[1,5- c]pyrimidines by Bernard R. Neustadt; Jinsong Hao; Neil Lindo; William J. Greenlee; Andrew W. Stamford; Deen Tulshian; Ennio Ongini; John Hunter; Angela Monopoli; Rosalia Bertorelli; Carolyn Foster; Leyla Arik; Jean Lachowicz; Kwokei Ng; Kung-I Feng (pp. 1376-1380).
Starting from the known adenosine A2A antagonist SCH 58261, SAR-guided structural optimization led to SCH 420814, which is a potent and selective A2A antagonist, with good pharmacokinetics and excellent oral activity in rodent models of Parkinson’s disease.Antagonism of the adenosine A2A receptor offers great promise in the treatment of Parkinson’s disease. Employing the known pyrazolo[4,3- e]-1,2,4-triazolo[1,5- c]pyrimidine A2A antagonist SCH 58261 as a starting point, we identified the potent and selective (vs. A1) antagonist 11h, orally active in the rat haloperidol-induced catalepsy model. We further optimized this lead to the methoxyethoxyethyl ether12a (SCH 420814), which shows broad selectivity, good pharmacokinetic properties, and excellent in vivo activity.

Keywords: Adenosine A; 2A; Parkinson’s; Catalepsy; Pyrazolo[4,3-; e; ]-1,2,4-triazolo[1,5-; c; ]pyrimidine


Structural simplification of bioactive natural products with multicomponent synthesis: Dihydropyridopyrazole analogues of podophyllotoxin by Igor V. Magedov; Madhuri Manpadi; Elena Rozhkova; Nikolai M. Przheval’skii; Snezna Rogelj; Scott T. Shors; Wim F.A. Steelant; Severine Van slambrouck; Alexander Kornienko (pp. 1381-1385).
A three-component condensation of 5-amino-3-methylpyrazole, tetronic acid, and various aromatic, heteroaromatic, and aliphatic aldehydes leads to the formation of dihydropyridopyrazole analogues of a cytotoxic lignan podophyllotoxin. This new heterocyclic scaffold-based library allows a drastic reduction of the structural complexity of the natural product with the retention of its potent cytotoxic properties. Similarly to podophyllotoxin, the presented analogues induce apoptosis in Jurkat cells.

Keywords: Multicomponent synthesis; Antimitotic agents; Podophyllotoxin


Challenges in the development of mGluR5 positive allosteric modulators: The discovery of CPPHA by Zhijian Zhao; David D. Wisnoski; Julie A. O’Brien; Wei Lemaire; David L. Williams Jr.; Marlene A. Jacobson; Marion Wittman; Sookhee N. Ha; Herve Schaffhauser; Cyrille Sur; Doug J. Pettibone; Mark E. Duggan; P. Jeffrey Conn; George D. Hartman; Craig W. Lindsley (pp. 1386-1391).
This Letter describes, for the first time, the synthesis and SAR, developed through an iterative analog library approach, that led to the discovery of the positive allosteric modulator (PAM) of the metabotropic glutamate receptor mGluR5 CPPHA. Binding to a unique allosteric binding site distinct from other mGluR5 PAMs, CPPHA has been the focus of numerous pharmacology studies by several laboratories.

Keywords: MGluR5; Allosteric modulator; Potentiation


A potent and orally active HIV-1 integrase inhibitor by Melissa S. Egbertson; H. Marie Moritz; Jeffrey Y. Melamed; Wei Han; Debra S. Perlow; Michelle S. Kuo; Mark Embrey; Joseph P. Vacca; Matthew M. Zrada; Amanda R. Cortes; Audrey Wallace; Yvonne Leonard; Daria J. Hazuda; Michael D. Miller; Peter J. Felock; Kara A. Stillmock; Marc V. Witmer; William Schleif; Lori J. Gabryelski; Gregory Moyer; Joan D. Ellis; Lixia Jin; Wei Xu; Matthew P. Braun; Kellem Kassahun; Nancy N. Tsou; Steven D. Young (pp. 1392-1398).
A 1,6-naphthyridine inhibitor of HIV-1 integrase has been discovered with excellent inhibitory activity in cells, good pharmacokinetics, and an excellent ability to inhibit virus with mutant enzyme.

Keywords: HIV; AIDS; Integrase; Strand transfer; 1,6-Naphthyridine


Dopamine/serotonin receptor ligands. Part 15: Oxygenation of the benz-indolo-azecine LE 300 leads to novel subnanomolar dopamine D1/D5 antagonists by Christoph Enzensperger; Susann Kilian; Marit Ackermann; Anne Koch; Kristin Kelch; Jochen Lehmann (pp. 1399-1402).
To explore SAR, the synthesis of novel azecine-styled dopamine antagonists and screening was performed at all human-cloned dopamine receptor subtypes. The benz-indolo-azecine with the highest affinity for D5 until now, turned out to be3e Ki=0.23nM.Relying on the high affinities of the benz-indolo-azecine LE 300 (1) and the hydroxylated dibenz-azecine LE 404 (2b) for the D1/D5 receptor subtypes, we synthesized methoxylated, hydroxylated and an indole-N methylated derivatives of1 (). Hydroxylation of azecine derivatives is beneficial with regard to the affinities and selectivities for all the dopamine receptor subtypes. The ‘serotonin-derived’ 3-oxygenated target compounds but not the 11-oxygenated analogues were superior to the unsubstituted LE 300. 11-Methoxy-7,14-dimethyl-6,7,8,9,14,15-hexahydro-5 H-indolo[3,2- f][3]benzazecine (3e) was found to be the most potent antagonist at D2/D3/D4 and D5 receptor subtypes ( Ki for D5=0.23nmol) of all known benz-indolo-azecines.

Keywords: Dopamine receptor ligands; Azecines; LE 300; Oxygenation; N-methylation


Quinazoline and benzimidazole MCH-1R antagonists by Rosa Arienzo; Sue Cramp; Hazel J. Dyke; Peter M. Lockey; Dennis Norman; Alan G. Roach; Phil Smith; Melanie Wong; Stephen P. Wren (pp. 1403-1407).
The discovery, synthesis, evaluation and structure–activity relationships of a series of quinazolines and benzimidazoles as MCH-1R antagonists are described.We have modified the previously reported 2-aminoquinoline1 to provide two novel series of MCH-1R antagonists. Representative compounds from the quinazoline and benzimidazole series have been shown to be potent and selective, with promising in vitro eADME profiles.

Keywords: Obesity; Melanin-concentrating hormone; MCH-1


A molecular modeling analysis of novel non-hydroxamate inhibitors of TACE by James E. Sheppeck II; Andrew Tebben; John L. Gilmore; Anle Yang; Zelda R. Wasserman; Carl P. Decicco; James J.-W. Duan (pp. 1408-1412).
We have developed a number of hydroxamate and non-hydroxamate inhibitors of TACE that possess the selective quinolinemethoxy P1′ group. Using the X-ray co-crystal structure of our hydroxamate IK682 and TACE, and a co-crystal structure of a pyrimidinetrione in MMP-8, we have developed a highly plausible pharmacophore model of how our pyrimidinetrione and hydantoin inhibitors bind to TACE.Recently, an X-ray co-crystal structure of our hydroxamate inhibitor IK682 and TACE [Niu, X.; Umland, S.; Ingram, R.; Beyer, B. M.; Liu, Y.-H.; Sun, J.; Lundell, D.; Orth, P. Arch. Biochem. Biophys.2006, 451, 43–50] was published that explicitly shows the orientation of the hydroxamate and the TACE-selective 4-[(2-methyl-4-quinolinyl)methoxy]phenyl P1′ group in the S1′ and S3′ sites. The preceding paper described a novel series of potent and TACE-selective hydantoins and we previously described pyrimidinetrione (barbiturate) inhibitors of TACE, both of which contain the same P1′ group as IK682. Using this TACE-selective P1′ group as an anchor, stereochemical and conformational constraints in the inhibitors, and restrictions to the active site Zn coordination geometry, we developed a highly plausible and predictive pharmacophore model that rationalizes the observed TACE activity of all three inhibitors.

Keywords: TACE; TACE inhibitor; Modeling; Hydantoin; Barbiturate; Hydroxamate; MMP; Metalloprotease; Metalloproteinase; TNF; Non-hydroxamate


Discovery of novel hydantoins as selective non-hydroxamate inhibitors of tumor necrosis factor-α converting enzyme (TACE) by James E. Sheppeck II; John L. Gilmore; Anle Yang; Xiao-Tao Chen; Chu-Biao Xue; John Roderick; Rui-Qin Liu; Maryanne B. Covington; Carl P. Decicco; James J.-W. Duan (pp. 1413-1417).
We have discovered novel hydantoins that are drug-like, non-hydroxamate inhibitors of the matrix metalloprotease TACE with nM potency. Synthesis and SAR of these inhibitors is described as well as their selectivity against other MMPs.A series of novel hydantoins was designed and synthesized as structural alternatives to hydroxamate inhibitors of TACE. 5-Mono- and di-substituted hydantoins exhibited activity with IC50 values of 11–60nM against porcine TACE in vitro and excellent selectivity against other MMPs.

Keywords: TACE; TACE inhibitor; Non-hydroxamate; MMP; Matrix metalloprotease; Matrix metalloproteinase; TNF


Synthesis and evaluation of novel chromogenic aminopeptidase substrates for microorganism detection and identification by Arthur L. James; John D. Perry; Annette Rigby; Stephen P. Stanforth (pp. 1418-1421).
The amides8ae and10ac were prepared as chromogenic aminopeptidase substrates. A range of microorganisms were grown in the presence of these compounds and coloured colonies were produced in several cases after addition of acetic acid—thus giving potential methods for the detection of aminopeptidase activity and for microorganism identification.

Keywords: Aminopeptidase; Microorganism identification; Microorganism detection; Diagnostic reagents; Chromogenic reagents; 9-(4′-aminophenyl)acridines


Discovery of 2-iminobenzimidazoles as a new class of trypanothione reductase inhibitor by high-throughput screening by Georgina A. Holloway; Jonathan B. Baell; Alan H. Fairlamb; Patrizia M. Novello; John P. Parisot; John Richardson; Keith G. Watson; Ian P. Street (pp. 1422-1427).
A high-throughput screening campaign of a library of 100,000 lead-like compounds identified 2-iminobenzimidazoles (L) as a novel class of trypanothione reductase inhibitors. These 2-iminobenzimidazoles display potent trypanocidal activity against Trypanosoma brucei rhodesiense, do not inhibit closely related human glutathione reductase and have low cytotoxicity against mammalian cells.A high-throughput screening campaign of a library of 100,000 lead-like compounds identified 2-iminobenzimidazoles as a novel class of trypanothione reductase inhibitors. These 2-iminobenzimidazoles display potent trypanocidal activity against Trypanosoma brucei rhodesiense, do not inhibit closely related human glutathione reductase and have low cytotoxicity against mammalian cells.

Keywords: Tropical diseases; Trypanosomiasis therapeutics; Trypanothione reductase inhibitors; High-throughput screening; Medicinal chemistry; Iminobenzimidazoles


Ac2-DPD, the bis-( O)-acetylated derivative of 4,5-dihydroxy-2,3-pentanedione (DPD) is a convenient stable precursor of bacterial quorum sensing autoinducer AI-2 by Marine Frezza; Laurent Soulère; Damien Balestrino; Michel Gohar; Christian Deshayes; Yves Queneau; Christiane Forestier; Alain Doutheau (pp. 1428-1431).
Ac2-DPD induces bioluminescence in Vibrio harveyi and β-galactosidase activity in Salmonella enterica Typhimurium, and inhibits biofilm formation in Bacillus cereus. Its biological activity is most likely due to in situ hydrolysis into DPD. Ac2-DPD can thus be considered as a stable and storable precursor of DPD.Ac2-DPD, the bis-( O)-acetylated derivative of 4,5-dihydroxy-2,3-pentanedione (DPD), was prepared both as a racemic mixture and in the optically active form found in naturally occurring DPD. It was shown to exhibit the same ability as DPD to induce bioluminescence in Vibrio Harveyi and β-galactosidase activity in Salmonella enterica Typhimurium, both Gram-negative bacteria. Likewise, it was also shown to inhibit biofilm formation in Gram-positive Bacillus cereus. The most likely hypothesis is that Ac2-DPD activity is due to the release of DPD by in situ hydrolysis of the ester groups. Importantly, by contrast with DPD, Ac2-DPD proved to be a stable compound which can be purified and stored.

Keywords: Quorum sensing; Autoinducer; AI-2; DPD


Pyrazole-based factor Xa inhibitors containing N-arylpiperidinyl P4 residues by Jennifer X. Qiao; Xuhong Cheng; Joanne M. Smallheer; Robert A. Galemmo; Spencer Drummond; Donald J.P. Pinto; Daniel L. Cheney; Kan He; Pancras C. Wong; Joseph M. Luettgen; Robert M. Knabb; Ruth R. Wexler; Patrick Y.S. Lam (pp. 1432-1437).
The synthesis, SAR, pharmacokinetic profile, and modeling studies of both monocyclic and fused pyrazoles containing substituted N-arylpiperidinyl P4 moieties that are potent and selective factor Xa inhibitors will be discussed. Fused pyrazole analog16a, with a 2′-methylsulfonylphenyl piperidine P4 group, was shown to be the best compound in this series (FXa Ki=0.35nM) based on potency, selectivity, and pharmacokinetic profile.The synthesis, SAR, pharmacokinetic profile, and modeling studies of both monocyclic and fused pyrazoles containing substituted N-arylpiperidinyl P4 moieties that are potent and selective factor Xa inhibitors will be discussed. Fused pyrazole analog16a, with a 2′-methylsulfonylphenyl piperidine P4 group, was shown to be the best compound in this series (FXa Ki=0.35nM) based on potency, selectivity, and pharmacokinetic profile.

Keywords: Factor Xa inhibitors; Pyrazole-based; SAR; N; -Arylpiperidine


Synthesis and structure–activity relationship of N-acyl-Gly-, N-acyl-Sar- and N-blocked-boroPro inhibitors of FAP, DPP4, and POP by Thuy Tran; Clifford Quan; Conrad Yap Edosada; Mark Mayeda; Christian Wiesmann; Dan Sutherlin; Beni B. Wolf (pp. 1438-1442).
The structure–activity relationship of various N-acyl-Gly-, N-acyl-Sar-, and N-blocked-boroPro derivatives against three prolyl peptidases (FAP, DPP4, and POP) was explored.The structure–activity relationship of various N-acyl-Gly-, N-acyl-Sar-, and N-blocked-boroPro derivatives against three prolyl peptidases was explored. Several N-acyl-Gly- and N-blocked-boroPro compounds showed low nanomolar inhibitory activity against fibroblast activation protein (FAP) and prolyl oligopeptidase (POP) and selectivity against dipeptidyl peptidase-4 (DPP4). N-Acyl-Sar-boroPro analogs retained selectivity against DPP4 and potent POP inhibitory activity but displayed decreased FAP inhibitory activity.

Keywords: Prolyl peptidase; Dipeptidyl peptidase; BoroPro; FAP; DPP4; POP


4-[6-(2-Aminoethyl)naphthalen-2-yl]benzonitriles are potent histamine H3 receptor antagonists with high CNS penetration by Lawrence A. Black; Diana L. Nersesian; Padam Sharma; Yi-Yin Ku; Youssef L. Bennani; Kennan C. Marsh; Thomas R. Miller; Timothy A. Esbenshade; Arthur A. Hancock; Marlon Cowart (pp. 1443-1446).
The synthesis and SAR of a series of naphthylethylaminesI as histamine H3 receptor antagonists with a high brain to plasma concentration ratio is reported.4-[6-(2-Tertiaryaminoethyl)naphthalen-2-yl]benzonitriles are conformationally constrained histamine H3 receptor antagonists with high potency and selectivity. The analogs were designed around a naphthalene core, with the goal of enhancing lipophilicity and CNS penetration, as compared to a previously reported benzofuran series. The SAR of the tertiary amine moiety is similar to that reported for the benzofuran series, with analogs bearing a 2-methylpyrrolidine substituent possessing the greatest rat and human H3 receptor binding affinities.

Keywords: Histamine H3 receptor antagonists; Naphthalene; High CNS penetration


N-Alkyl- N-alkyloxycarbonylaminomethyl (NANAOCAM) prodrugs of carboxylic acid containing drugs by Susruta Majumdar; Kenneth B. Sloan (pp. 1447-1450).
N-Alkyl- N-alkyloxycarbonylaminomethyl and N-aryl- N-alkyloxycarbonylaminomethyl derivatives of carboxylic acids hydrolyse to the parent carboxylic acid both chemically and thereby serving as useful prodrugs of carboxylic acid containing drugs.Synthesis and hydrolysis in aqueous buffers of novel N-alkyl- N-alkyloxycarbonylaminomethyl (NANAOCAM) and N-aryl- N-alkyloxycarbonylaminomethyl (NArNAOCAM) derivatives of carboxylic acid containing drugs were carried out. The hydrolysis follows a SN1 type mechanism and is dependent on the nucleofugacity of the leaving group. Topical delivery of the NANAOCAM derivative of naproxen from IPM across hairless mice skin was examined in in vitro diffusion cell experiments. The prodrug was 4.5-fold less lipid soluble, 2.4-fold less water soluble and 3.6-fold less permeable than the parent drug.

Keywords: Prodrugs; NANAOCAM; NArNAOCAM; Chemically labile; Topical delivery; Dermal delivery; Permeation; Soft alkylation


Novel membrane-localizing TEMPO derivatives for measurement of cellular oxidative stress at the cell membrane by Shizuka Ban; Hidehiko Nakagawa; Takayoshi Suzuki; Naoki Miyata (pp. 1451-1454).
We designed and synthesized membrane-localizing TEMPO derivatives and demonstrated that a synthesized probe1 localized and detected oxidative stress in the cell membrane in an activated macrophage-like cell line.Oxidative stress affecting lipid membranes is considered to be closely related to cardiovascular disease and brain ischemia. In this study, we designed and synthesized membrane-localizing TEMPO derivatives and demonstrated that one of these synthesized probes, compound1, localized and detected oxidative stress in the cell membrane in an endotoxic model of a mouse macrophage-like cell line. Compound1 is therefore a potentially useful probe for evaluating oxidative stress at the cell membrane.

Keywords: Fluorescein; Redox; Electron spin resonance; Reactive oxygen species; Superoxide; Inflammation


Structure–activity relationship analysis of a novel necroptosis inhibitor, Necrostatin-5 by Ke Wang; Jinfeng Li; Alexei Degterev; Emily Hsu; Junying Yuan; Chengye Yuan (pp. 1455-1465).
Structural effect of substituents on Nec-5, a new class of small molecule inhibitors of necroptosis, was described. Significant influence was found in structural variation of R, R1, R2, and Xn in the parent molecule.Necrostatin-5 (Nec-5) is a novel potent small-molecule inhibitor of necroptosis structurally distinct from previously described Necrostatin-1 (Nec-1), and therefore, represents a new direction for the inhibition of this cellular caspase-independent necrotic cell death mechanism. Here, we describe a series of structural modifications of Nec-5 and the structure–activity relationship (SAR) of Nec-5 series in inhibiting necroptosis.

Keywords: Necroptosis; SAR; Inhibitor; Nec-5; Caspase-independent cell death; Fused pyrimidinon-thiophene derivatives; Ischemic brain injury


Bis-styrylpyridine and bis-styrylbenzene derivatives as inhibitors for Aβ fibril formation by Seong Rim Byeon; Ji Hoon Lee; Ji-Hoon Sohn; Dong Chan Kim; Kye Jung Shin; Kyung Ho Yoo; Inhee Mook-Jung; Won Koo Lee; Dong Jin Kim (pp. 1466-1470).
The new bis-styrylpyridine and bis-styrylbenzene derivatives were designed and synthesized. Most of them showed excellent inhibitory activities for Aβ fibril formation at IC50 of 0.1–2.7μM which is comparable to curcumin (IC50 of 0.8μM). In particular,I7 andII-2 exhibited the best combination of inhibitory activity and compound cytotoxicity.New bis-styrylpyridine and bis-styrylbenzene derivatives were designed and synthesized. These 34 compounds were evaluated by Aβ fibril formation inhibitory assay using thioflavin T as a dye (named ThT assay). Most of them showed excellent inhibitory activities for Aβ fibril formation at IC50 of 0.1–2.7μM which is comparable to curcumin (IC50 of 0.8μM). Among them, nine compounds were screened for their cytotoxicities on HT-22 cell by MTT assay at 1, 10, and 50μM. In particular,I-7 andII-2 exhibited the best combination of inhibitory activity and compound cytotoxicity.

Keywords: Aβ fibril formation inhibitor; Alzheimer disease; Bis-styrylpyridine; Bis-styrylbenzene; Amyloid β


Discovery of novel phosphorus-containing steroids as selective glucocorticoid receptor antagonist by Weiqin Jiang; James J. Fiordeliso; George Allan; Olivia Linton; Pamela Tannenbaum; Jun Xu; Peifang Zhu; Joseph Gunnet; Keith Demarest; Scott Lundeen; Zhihua Sui (pp. 1471-1474).
The synthesis and biological activities of the glucocorticoid receptor antagonists4 and5 are reported.Mifepristone is a non-selective antagonist of 3-oxosteroid receptors with both abortifacient and anti-diabetic activities. For glucocorticoid receptor (GR) program, we sought an unexplored, synthetically accessible phosphorus-containing steroidal mimetic of mifepristone, suitable for parallel synthesis of analogues. One compound4a, with high oral bioavailability (59%) in rat, exhibited functional antagonism of GR in oral glucose tolerance test (OGTT). Thus this series of compounds might be potentially useful for the treatment of type II diabetes.

Keywords: Phosphorus-containing steroids; Selective glucocorticoid receptor antagonist


Synthesis and cytotoxic activity of 17-carboxylic acid modified 23-hydroxy betulinic acid ester derivatives by Yi Bi; Jinyi Xu; Xiaoming Wu; Wencai Ye; Shengtao Yuan; Luyong Zhang (pp. 1475-1478).
The derivatives5a–f of 23-hydroxy betulinic acid have better cytotoxicity than 23-hydroxy betulinic acid and betulinic acid in vitro. And they are also more potent than 23-hydroxy betulinic acid in vivo. The research results have been applied China Patent: CN 10040277.2, 2006.New 17-carboxylic acid modified 23-hydroxy betulinic acid ester derivatives were prepared and tested for cytotoxic activity on five cancer cell lines in vitro: all tested compounds showed stronger cytotoxic activity than 23-hydroxy betulinic acid and betulinic acid. In addition, compound5a was tested for anti-tumor activity in vivo: it had much better anti-tumor activity than 23-OH betulinic acid and had similar anti-tumor activity with cyclophosphamide and 5-fluorouracil.

Keywords: 23-Hydroxy betulinic acid; 17-Carboxylic acid modified ester derivatives; Anti-tumor activity

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