Graphical contents list

Bioorganic & Medicinal Chemistry Letters Volume 24, Issue 1, 2014

Contents

BMCL DIGESTS

Design of small molecule epigenetic modulators pp 21–32

Boobalan Pachaiyappan, Patrick M. Woster*

Drug discovery considerations in the development of covalent inhibitors pp 33–39

Robert Mah, Jason R. Thomas, Cynthia M. Shafer*

REGULAR ARTICLES

Design, synthesis and anti-Alzheimer properties of dimethylaminomethyl-substituted curcumin derivatives pp 40–43

Lei Fang, Shaohua Gou*, Xuying Liu, Feng Cao*, Lin Cheng

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1–20

Contents lists available at ScienceDirect

Bioorganic & Medicinal Chemistry Letters

journal homepage: www.elsevier .com/ locate/bmcl

Sortase A inhibitory metabolites from the roots of Pulsatilla koreana pp 44–48

Sooryun Lee, Inn-Hye Song, Jung-Ho Lee, Woo-Young Yang, Ki-Bong Oh*, Jongheon Shin*

O

OCH3

OR2

OR1

H3CO

HO

3 R1=H,4 R1=Glc,

R2=HR2=H

OHO

H3CO

OHOCH3

O

6

GlcO

Synthesis and biological evaluation of a-hydroxyalkylphosphonates as new antimicrobial agents pp 49–53

Ana Maria Faísca Phillips*, Maria Teresa Barros*, Marta Pacheco, Ricardo Dias

Synthesis, biological evaluation and SAR of 3-benzoates of ingenol for treatment of actinic keratosisand non-melanoma skin cancer

pp 54–60

Gunnar Grue-Sørensen, Xifu Liang, Kristoffer Månsson, Per Vedsø, Morten Dahl Sørensen, Anke Soor, Martin Stahlhut,Malene Bertelsen, Karen Margrethe Engell, Thomas Högberg*

O

O HOHO OH

H

H

HO

X

Lactam based 7-amino suberoylamide hydroxamic acids as potent HDAC inhibitors pp 61–64

Maurizio Taddei*, Elena Cini, Luca Giannotti, Giuseppe Giannini*, Gianfranco Battistuzzi, Davide Vignola, Loredana Vesci,Walter Cabri

28, ST8078AA1

H

O

H O

O

HN

N O

H

OHNN

CF3

2 Contents / Bioorg. Med. Chem. Lett. 24 (2014) 1–20

Novel anthraquinone based chalcone analogues containing an imine fragment: Synthesis, cytotoxicityand anti-angiogenic activity

pp 65–71

Branka Kolundzija, Violeta Markovic, Tatjana Stanojkovic, Ljubinka Joksovic, Ivana Matic, Nina Todorovic, Marijana Nikolic,Milan D. Joksovic*

The discovery of potent, orally bioavailable pyrazolo and triazolopyrimidine CXCR2 receptor antagonists pp 72–76

David W. Porter*, Michelle Bradley, Zarin Brown, Riccardo Canova, Steven Charlton, Brian Cox, Peter Hunt, David Kolarik,Sarah Lewis, Des O’Connor, John Reilly, Carsten Spanka, Lauren Tedaldi, Simon J. Watson, Roland Wermuth, Neil J. Press

NNN

HOS

Me

NNN

SHO

N

FF

Novartis archive hit 1 Triazolopyrimidine 14

A hit-to-lead optimisation programme was carried out on the Novartis archivescreening hit, pyrazolopyrimidine 2-methyl-5-((phenylthio)methyl)pyrazo-lo[1,5-a]pyrimidin-7-ol 1, resulting in the discovery of CXCR2 receptorantagonist 2-benzyl-5-(((2,3-difluorophenyl)thio)methyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-ol 14. The SAR was investigated by systematic variation of thependant thiol, alkyl and pyrimidinol groups. Replacement of the pyrazolopyr-imidine core with a triazolo alternative led to a dual series of antagonists withfavourable biological and pharmacokinetic properties.

Rationally designed hybrid molecules with appreciable COX-2 inhibitory and anti-nociceptive activities pp 77–82

Palwinder Singh*, Shaveta, Surbhi Sharma, Rajbir Bhatti

Verrulactone C with an unprecedented dispiro skeleton, a new inhibitor of Staphylococcus aureusenoyl-ACP reductase, from Penicillium verruculosum F375

pp 83–86

Nyung Kim, Mi-Jin Sohn, Hiroyuki Koshino, Eun-Hee Kim, Won-Gon Kim*OO

HO

OCH3

OH

OH

O

CH3O

OOH

H3CO

O

OO

HO

OCH3

OH

OH

1

2An highly quaternary and unprecedented dispiro compound, verrulactone C (1), with the knowncompound, altenuisol (2), were isolated from a culture broth of the fungal strain Penicilliumverruculosum F375. Verrulactone C and altenuisol showed FabI-selective inhibition. Especially,altenuisol had the high correlation between FabI-inhibition and whole cell antibacterial activityagainst S. aureus and MRSA with MICs of 8–32 lg/mL.

Contents / Bioorg. Med. Chem. Lett. 24 (2014) 1–20 3

Design and synthesis of tamoxifen derivatives as a selective estrogen receptor down-regulator pp 87–89

Takuji Shoda*, Keiichiro Okuhira, Masashi Kato, Yosuke Demizu, Hideshi Inoue, Mikihiko Naito, Masaaki Kurihara*

Design, synthesis and antibacterial activities of 5-(pyrazin-2-yl)-4H-1,2,4-triazole-3-thiol derivativescontaining Schiff base formation as FabH inhibitory

pp 90–95

Fei Zhang, Qing Wen, She-Feng Wang, Baloch Shahla Karim, Yu-Shun Yang, Jia-Jia Liu, Wei-Ming Zhang*, Hai-Liang Zhu*A series of novel schiff base derivatives (H1–H20) containing pyrazine and triazole moietyhave been designed and synthesized, and their biological activities were also evaluated aspotential inhibitors of b-ketoacyl-acyl carrier protein synthase III (FabH). These compoundswere assayed for antibacterial activity against Escherichia coli, Pseudomonas aeruginosa,Staphylococcus aureus, Bacillus subtilis and Bacillus amyloliquefaciens and selected compoundsamong them were tested for their Escherichia coli FabH inhibitory activity. Based on thebiological data, compound H17 showed the most potent antibacterial activity with MIC valuesof 0.39–1.56 lg/mL against the tested bacterial strains and exhibited the most potent E. coliFabH inhibitory activity with IC50 of 5.2 lM, being better than the positive control KanamycinB with IC50 of 6.3 lM. Furthermore, docking simulation was performed to position compoundH17 into the E. coli FabH active site to determine the probable binding conformation. Thisstudy indicated that compound H17 has demonstrated significant E. coli FabH inhibitoryactivity as a potential antibacterial agent and provides valuable information for the design ofE. coli FabH inhibitors.

Syntheses of novel b-carboline derivatives and the activities against five tumor-cell lines pp 96–98

Bing Bai, Xing-Yao Li, Li Liu, Yan Li*, Hua-Jie Zhu*

NN

OH

R3R3

R2

4i: 0.75 0.91 1.00 1.13 2.54HL-60 SMMC -7721 A-549 MCF-7 SW480

5q: 0.90 3.05 1.30 1.18 6.30Cisplatin 1.04 14.99 6.81 24.70 24.34

R2 R34i H H5q Me H

IC50 (uM)

TMEDA-derived biscationic amphiphiles: An economical preparation of potent antibacterial agents pp 99–102

Jacob W. Black, Megan C. Jennings, Julianne Azarewicz, Thomas J. Paniak, Melissa C. Grenier, William M. Wuest*,Kevin P.C. Minbiole*


A tetradecapeptide somatostatin dicarba-analog: Synthesis, structural impact and biological activity pp 103–107

Pablo Martín-Gago, Rosario Ramón, Eric Aragón, Jimena Fernández-Carneado, Pau Martin-Malpartida, Xavier Verdaguer,Pilar López-Ruiz, Begoña Colás, María Alicia Cortes, Berta Ponsati, Maria J. Macias*, Antoni Riera*

Structure activity relationships of fused bicyclic and urea derivatives of spirocyclic compounds as potentCCR1 antagonists

pp 108–112

Nafizal Hossain*, Marguérite Mensonides-Harsema, Martin E. Cooper, Tomas Eriksson, Svetlana Ivanova, Lena Bergström

NO

ClO

OHO

NH

O

NO

XO

OH NH

NH

OH

OR1

4: hCCR1 IC50 = 7.1 nM 44: X = Cl, R1 = methyl, hCCR1 IC50 = 1.3 nM48: X = Cl, R1 = cyclopropyl, hCCR1 IC50 = 0.89 nM50: X = F, R1 = cyclopropyl, hCCR1 IC50 = 0.63 nM

Azide–alkyne cycloaddition affording enzymatically tunable bisubstrate based inhibitors of histoneacetyltransferase PCAF

pp 113–116

Jeroen van Ameijde, Addy P.R. Zwiebel, Rob Ruijtenbeek, Rob M.J. Liskamp*

HS CoA S CoA

N3 N

NN

SCoA

OR OR

R = H / PO

O-O-

Fluorescent probes of the isoxazole–dihydropyridine scaffold: MDR-1 binding and homology model pp 117–121

Monika I. Szabon-Watola, Sarah V. Ulatowski, Kathleen M. George, Christina D. Hayes, Scott A. Steiger, Nicholas R. Natale*

Isoxazole-1,4-dihydropyridines (IDHPs) were tethered to fluorescent moieties using doubleactivation via a lanthanide assisted Weinreb amidation. IDHP–fluorophore conjugate 3cexhibits the highest binding to date for IDHPs at the multidrug-resistance transporter (MDR-1),and IDHP–fluorophore conjugates 3c and 7 distribute selectively in SH-SY5Y cells. A homologymodel for IDHP binding at hMDR-1 is presented which represents our current workinghypothesis.


Chemical synthesis and tyrosinase inhibitory activity of rhododendrol glycosides pp 122–125

Takehiro Iwadate, Yutaka Kashiwakura, Noriyoshi Masuoka, Yoichi Yamada, Ken-ichi Nihei*

IC50 = 4.75 µM IC50 = 2.30 µM

OH

HO

OGlc OH

HO

OGlc

Identification of quinones as HER2 inhibitors for the treatment of trastuzumab resistant breast cancer pp 126–131

Jayalakshmi Sridhar*, Mary E. Sfondouris, Melyssa R. Bratton, Thuy-Linh K. Nguyen, Ian Townley, Cheryl L. Klein Stevens,Frank E. Jones

4

5

Docking modes of the most potent compounds 4 and 5 in the ATP binding pocket of HER2 kinase.

Synthesis and biological properties of thiazole-analogues of pyochelin, a siderophoreof Pseudomonas aeruginosa

pp 132–135

Sabrina Noël, Françoise Hoegy, Freddy Rivault, Didier Rognan, Isabelle J. Schalk, Gaëtan L.A. Mislin*

O

R2

S

NS

N

COOH

HR1

R = CH3, R1 = H, R2 = HR = H, R1 = OH, R2 = H R = CH3, R1 = OH, R2 = HR = H, R1 = NH2, R2 = H R = H, R1 = H, R2 = NH2

R = CH3, R1 = H, R2 = NH2

R = CH3, R1 = H, R2 = F

R

New titanocene derivatives with high antiproliferative activity against breast cancer cells pp 136–140

Carmela Saturnino, Esther Sirignano, Antonio Botta, Maria Stefania Sinicropi*, Anna Caruso, Assunta Pisano,Rosamaria Lappano, Marcello Maggiolini, Pasquale Longo

TiCl

Cl

H

H

TiCl

Cl

TiX

X

O

O


Synthesis and biological evaluation of cyclopentyl-triazolol-pyrimidine (CPTP) based P2Y12 antagonists pp 141–146

Wangyang Tu*, Jiang Fan, Haitang Zhang, Guoji Xu, Zhiwei Liu, Jian Qu, Fanglong Yang, Lei Zhang, Tianyu Luan, Jijun Yuan,Aishen Gong, Jun Feng, Piaoyang Sun, Qing Dong

HN

F

F

NN

N N

N

S

HO OH

HO

F

2dhuman PRP agg. IC50 = 0.22 μM

Synthesis and anticancer potential of benzothiazole linked phenylpyridopyrimidinones and their dionesas mitochondrial apoptotic inducers

pp 147–151

Ähmed Kamal*, Md. Ashraf, M.V.P.S. Vishnu Vardhan, Shaikh Faazil, V. Lakshma Nayak

N

HN

NH

SO2

O

OH

N NH

NH

O

S

N

FFF

N

N

O

S

N O

E7010 8b

Replacement of amide with bioisosteres led to a new series of potent adenosine A2A receptor antagonists pp 152–155

Zhaohui Yang, Xuan Li, Haikuo Ma, Jiyue Zheng, Xuechu Zhen, Xiaohu Zhang*

N N

NN

N NH

O

N N

NN

N NH

O

O

hA2A Ki 15 nM hA2A Ki 9.5 nM

N N

NN

N NH

N

N

hA2A Ki 1.1 nM

N

S

We have previously reported a series of 2,4,6-trisubstituted pyrimidines as potent A2A receptor antagonists. The leading compounds often feature a potentially labile acetamidefunctional group which tends to hydrolyze under acidic conditions. Here we report the replacement of the acetamide functional group with bioisosteres. This effort led us to anew series of adenosine A2A receptor antagonists with improved potency and chemical stability.

Discovery and optimization of N-(3-(1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yloxy)phenyl)benzenesulfonamides as novel GPR119 agonists

pp 156–160

Ming Yu*, Jian (Ken) Zhang, Yingcai Wang, Jiang Zhu, Frank Kayser, Julio C. Medina, Karen Siegler, Marion Conn, Bei Shan,Mark P. Grillo, Peter Coward, Jiwen (Jim) Liu

NH

OSO N

NO

O

R2

O

Cl

R1

5 (R1 = R2 = -cPr)

NH

OSO N

NO

O

O

Cl

F

22

The discovery and optimization of novel N-(3-(1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yloxy)phenyl)benzenesulfonamide GPR119 agonists is described. Modificationof the pyridylphthalimide motif of the molecule with R1 = –Me and R2 = –iPr substituents, incorporated with a 6-fluoro substitution on the central phenyl ring offered a potentand metabolically stable tool compound 22.


Synthesis and SAR of novel isoxazoles as potent c-jun N-terminal kinase (JNK) inhibitors pp 161–164

Yuanjun He, Derek Duckett, Weimin Chen, Yuan Yuan Ling, Michael D. Cameron, Li Lin, Claudia H. Ruiz, Philip V. LoGrasso,Theodore M. Kamenecka, Marcel Koenig*

N NH

NO

NO

F

3

N NH

N

NO

27

NN

N

N

N NH

N

NO

28

HNN

N

N

Isoxazoles 27 and 28 were discovered as novel c-jun N-terminal kinase (JNK) inhibitors with good biochemical potency and greatly improved selectivity over p38 as compared tothe lead compound 3. Extensive SAR and an efficient route for the formation of bis- and tris-substituted isoxazole groups will be described.

Synthesis and antimycobacterial activity of novel camphane-based agents pp 165–167

Georgi Stavrakov*, Irena Philipova, Violeta Valcheva, Georgi Momekov

Cassaine diterpene alkaloids from Erythrophleum fordii and their anti-angiogenic effect pp 168–172

Tran Manh Hung, To Dao Cuong, Jeong Ah Kim, Nara Tae,Jeong Hyung Lee, Byung Sun Min*

Two new mono cassaine diterpenoid amides (1, 5) and four known compounds (2–4, 6)were isolated from the bark of Erythrophleum fordii (Leguminosae). The effects of isolateson endothelial tube formation on Matrigel were investigated. Among them, compound 3was found to have the most potent inhibitory effect on the capillary-like structureformation of human umbilical vein endothelial cells (HUVECs).

pH-rate profiles of LL-arabinitol 4-dehydrogenase from Hypocrea jecorina and its application in LL-xyluloseproduction

pp 173–176

Manish Kumar Tiwari, Raushan Kumar Singh, Hui Gao, Taesu Kim, Suhwan Chang, Han S. Kim*, Jung-Kul Lee*


The identification of AF38469: An orally bioavailable inhibitor of the VPS10P family sorting receptorSortilin

pp 177–180

Tenna Juul Schrøder, Søren Christensen, Samsa Lindberg, Morten Langgård, Laurent David, Philip J. Maltas,Jørgen Eskildsen, Jan Jacobsen, Lena Tagmose, Klaus Bæk Simonsen, Lars Christian Biilmann Rønn,Inge E.M. de Jong, Ibrahim J. Malik, Jens-Jakob Karlsson, Christoffer Bundgaard, Jan Egebjerg,Jeffrey B. Stavenhagen, Dorthe Strandbygård, Søren Thirup, Jacob Lauwring Andersen, Srinivas Uppalanchi,Sridhar Pervaram, Shiva Prasad Kasturi, Pradheep Eradi, Durga Rao Sakumudi, Stephen P. Watson*

OH

O

NH

O

N

CF3

AF38469 Sortilin NTS IC50 = 330nM

The identification of the novel, selective, orally bioavailable Sortilin inhibitor AF38469 is described. Structure–activity relationships and synthesesare reported, along with an X-ray crystal structure of the sortilin-AF38469 protein-inhibitor complex.

Synthesis of licochalcone analogues with increased anti-inflammatory activity pp 181–185

Si-Jun Kim, Cheol Gi Kim, So-Ra Yun, Jin-Kyung Kim, Jong-Gab Jun*

HO

O

MeO OHOH

LicoD (4)

HO

O

MeO OHOH

LicoB (1)

HO

O

MeO OHOH

2

HO

O

MeO OHOH

3

OHHO

5

HO

O

MeO OHOH

6

HO

O

MeO OHOH

IC50 values of 1–6 showed 9.94, 4.72, 10.1, 4.85, 2.37 and 4.95 lM, respectively.

Cytotoxic activity of gypenosides and gynogenin against non-small cell lung carcinoma A549 cells pp 186–191

Dao-Jin Chen, Hui-Min Liu, Shao-Fang Xing, Xiang-Lan Piao*

Compound IC50 (μg/ml)

Gypenoside XLVI

Gypenoside LVI

Gypenoside L

Gypenoside LI

2α-OH-PPD

20S- Rg3

52.63 ±8.31

105.89 ±2.48

34.94 ±4.23

50.96 ±9.55

12.54 ±0.53

55.36 ±3.20 Five dammarane-type compounds were isolated from Gynostemma pentaphyllum. Based on the structure–activityrelationships of them, 20S-dammar-24-en-2a,3b,12b,20-tetrol (2a-OH-PPD) showed the strongest activity against A549cells.

Synthesis and evaluation of novel azoles as potent antifungal agents pp 192–194

Liangjing Li, Hao Ding, Baogang Wang, Shichong Yu, Yan Zou, Xiaoyun Chai*, Qiuye Wu*

Twenty novel azoles have been designed and synthesized as potential antifungal agents. All the title compounds exhibited excellent activity with a broadspectrum of antifungal activity.


Linker modification reduced the renal uptake of technetium-99m-labeled Arg-Ala-Asp-conjugatedalpha-melanocyte stimulating hormone peptide

pp 195–198

Jianquan Yang, Adam M. Flook, Changjian Feng, Yubin Miao*

T

Asp Cys Cys GluHis

DPheArgTrpCys

Arg

Pro

Val-NH2

DTyrAsp

Arg

NH

NH

OO

Arg

Ala99mTc

99mTc-RAD-Arg-(Arg11)CCMSH

Modulating the interaction between CDK2 and cyclin A with a quinoline-based inhibitor pp 199–203

Yongqi Deng*, Gerald W. Shipps Jr., Lianyun Zhao, M. Arshad Siddiqui, Janeta Popovici-Muller, Patrick J. Curran,Jose S. Duca, Alan W. Hruza, Thierry O. Fischmann, Vincent S. Madison, Rumin Zhang, Charles W. McNemar,Todd W. Mayhood, Rosalinda Syto, Allen Annis, Paul Kirschmeier, Emma M. Lees, David A. Parry, William T. Windsor*

NO

HN

O O OH

OHO

Cl

2

Compound 2 has been discovered that both disrupt cyclin dependent 2 (CDK2) interaction with its cyclin A subunit and act as ATP competitive inhibitors.

Correlation between chemotype-dependent binding conformations of HSP90a/b and isoformselectivity—Implications for the structure-based design of HSP90a/b selective inhibitors for treatingneurodegenerative diseases

pp 204–208

Justin T. Ernst*, Michael Liu, Harmon Zuccola, Timothy Neubert, Kevin Beaumont, Amy Turnbull, Adam Kallel,Bryan Vought, Dean Stamos

Synthesis of 30-O-fluorescently mono-modified reversible terminators and their usesin sequencing-by-synthesis

pp 209–213

Da-Rae Kim, Taek-Soo Kim, Eunsun Kim, Sun-Joon Min, Dongyun Shin*, Dae-Ro Ahn*


Oxidative cleavage of DNA by pentamethine carbocyanine dyes irradiated with long-wavelength visiblelight

pp 214–219

Carla T. Mapp, Eric A. Owens, Maged Henary*, Kathryn B. Grant*

NR

NRX

I

R = Me or

X = Br, Cl, or H

(pUC19 plasmid)

DNA Cleavage

1O2

1O2

1O2

OH OH

NBr

irradiated at575 nm, 588 nm, 623 nm, or 700 nm

Synthesis and biological evaluation of the pirfenidone derivatives as antifibrotic agents pp 220–223

Zhen Ma, Youlu Pan, Wenhai Huang, Yewei Yang, Zunyuan Wang, Qin Li, Yin Zhao, Xinyue Zhang, Zhengrong Shen*

N ON O

ON

IC50 14.44mM 1.36 mM

pirfenidone 6eN

Discovery of hybrid Hsp90 inhibitors and their anti-neoplastic effects against gefitinib-resistantnon-small cell lung cancer (NSCLC)

pp 224–227

Chul-Ho Jeong, Hee Baek Park, Won Jun Jang, Su Hyun Jung, Young Ho Seo*

HO

Cl

HNN

OH

OMe

O

HO OH

Cl

OMe

OMeOMe

N

N N

N

NH2

PU3 (3)VER-49009 (2)

+

MeO OMe

OMenBu

O

chalcone

hybrid inhibitor (1f)

CONHEt

New anti-inflammatory cembranoid diterpenoids from the Vietnamese soft coral Lobophytum crassum pp 228–232

Nguyen Phuong Thao, Bui Thi Thuy Luyen, Nguyen Thi Thanh Ngan, Seok Bean Song, Nguyen Xuan Cuong,Nguyen Hoai Nam, Phan Van Kiem, Young Ho Kim*, Chau Van Minh*

HO

OH

OH

OH

HO

HO

OH

O

HO OH

1

HO

OH

O

HO OH

HO

OH

OH

OH

HO

2

3 4


Rational design, synthesis and antitubercular evaluation of novel 2-(trifluoromethyl)phenothiazine-[1,2,3]triazole hybrids

pp 233–236

Dinesh Addla, Anvesh Jallapally, Divya Gurram, Perumal Yogeeswari, Dharmarajan Sriram, Srinivas Kantevari*

S

N

NN

CF3

Trif luoperazineO

OH OH

O

NNN

NH

O

NO

I-A09

N

S

O

CF3

NNN

R

'22' new analogues

Compound MIC (µg/mL)

5c 6.255l 6.255o 6.25

Synthesis of a novel series of artemisinin dimers with potent anticancer activity involving Sonogashiracross-coupling reaction

pp 237–239

Pori Buragohain, Bishwajit Saikia, Naresh Surineni, Nabin C. Barua*, Ajit K. Saxena, Nitasha Suri

Linker

O

O

H

OO

O

OO

H

O OO

OO

H

OOO

Sulfonamide inhibition studies of the c-carbonic anhydrase from the oral pathogenPorphyromonas gingivalis

pp 240–244

Daniela Vullo, Sonia Del Prete, Sameh M. Osman, Viviana De Luca, Andrea Scozzafava, Zeid AlOthman, Claudiu T. Supuran*,Clemente Capasso*

S

NN

SO2NH2AcNH

NH

Cl NH

S

SO2NH2

O O

Ki = 324 nM Ki = 131 nM

Novel pyrazole integrated 1,3,4-oxadiazoles: Synthesis, characterization and antimicrobial evaluation pp 245–248

Srikantamurthy Ningaiah, Umesha K. Bhadraiah*, Shridevi D. Doddaramappa, Shubakara Keshavamurthy,Chethan Javarasetty

Ar1

NNPh

OO Ar1

NNPh

O

NN Ar2


Design, synthesis and evaluation of dual pharmacology b2-adrenoceptor agonists and PDE4 inhibitors pp 249–253

Ling Huang, Wenjun Shan, Qi Zhou, Jiaxing Xie, Kefang Lai*, Xingshu Li*

HNO

HO

OH HN

O NN

O

OO

(R, R)-11c

A novel series of formoterol–phthalazinone hybrids were synthesised and evaluated as dual pharmacology b2-adrenoceptor agonists and PDE4 inhibitors. Mostof the hybrids displayed high b2-adrenoceptor agonist and moderate PDE4 inhibitory activities. The most potent compound, (R,R)-11c, exhibited agonist(EC50 = 1.05 nM, pEC50 = 9.0) and potent PDE4B2 inhibitory activities (IC50 = 0.092 lM).

Concise and high-yield synthesis of T808 and T808P for radiosynthesis of [18F]-T808, a PET tau tracer forAlzheimer’s disease

pp 254–257

Mingzhang Gao, Min Wang, Qi-Huang Zheng*

N

NN

N

[18F]-T808

18F

(E)-Alkenes as replacements of amide bonds: Development of novel and potent acyclic CGRP receptorantagonists

pp 258–261

June J. Kim*, Michael R. Wood, Shawn J. Stachel, Pablo de Leon, Ashley Nomland, Craig A. Stump, Melody A. McWherter,Kathy M. Schirripa, Eric L. Moore, Christopher A. Salvatore, Harold G. Selnick

N

NHO

N

F

FO

N

9aKi = 0.04 nM

2

NHOH

N

ON

F

FO

N

Ki = 0.03 nM

Imidazole-derived agonists for the neurotensin 1 receptor pp 262–267

Paul M. Hershberger*, Michael P. Hedrick, Satyamaheshwar Peddibhotla,Arianna Mangravita-Novo, Palak Gosalia, Yujie Li, Wilson Gray,Michael Vicchiarelli, Layton H. Smith, Thomas D.Y. Chung,James B. Thomas, Marc G. Caron, Anthony B. Pinkerton,Lawrence S. Barak, Gregory P. Roth


A novel indigoid anti-tuberculosis agent pp 268–270

Larry L. Klein*, Valentina Petukhova, Baojie Wan, Yuehong Wang, Bernard D. Santasiero, David C. Lankin, Guido F. Pauli,Scott G. Franzblau

NH

O

O

NO

1

The structure of a novel indigoid component was characterized by X-ray crystallography. This compound exhibited excellent anti-tuberculosisactivity against Mycobacterium tuberculosis H37Rv in whole cell culture showing a submicromolar minimum inhibitory concentration (MIC). Asynthesis of this molecule was designed and carried out to produce sufficient material for further testing. The in vitro profile, structure, and firstsynthesis of this indigoid component is reported.

Preparation and evaluation of deconstruction analogues of 7-deoxykalafungin as AKT kinase inhibitors pp 271–274

Sudha Korwar, Thuy Nguyen, Keith C. Ellis*

Sulfonamide inhibition studies of the d-carbonic anhydrase from the diatom Thalassiosira weissflogii pp 275–279

Daniela Vullo, Sonia Del Prete, Sameh M. Osman, Viviana De Luca, Andrea Scozzafava, Zeid AlOthman, Claudiu T. Supuran*,Clemente Capasso*

SO2NH2

NH2

BrS S

NHEt

O O

SO2NH2S

NSO2NH2

EtO

TweCA: Ki = 94.6 nM 49.6 nM 85.1 nM

High-throughput docking for the identification of new influenza A virus polymerase inhibitors targetingthe PA–PB1 protein–protein interaction

pp 280–282

Cristina Tintori, Ilaria Laurenzana, Anna Lucia Fallacara, Ulrich Kessler, Beatrice Pilger, Lilli Stergiou, Maurizio Botta*

N

N

SNH

OBr

Br

PA-PB1 interac�on inhibitor

Lys643

Val621

Gln408

Val621

Cys415

Phe411

Val628

Phe658Phe707

Leu666

Phe710

PA-PB1 interac�on

Lys643

Gln408

Trp706

Gln670

Arg673

High-throughput docking


Synthesis and preliminary evaluation of a new fluorine-18 labelled triazine derivative for PET imaging ofcannabinoid CB2 receptor

pp 283–287

Laurent Hortala, Joëlle Arnaud, Pascale Roux, Didier Oustric,Laurent Boulu, Florence Oury-Donat, Patrick Avenet,Thomas Rooney, David Alagille, Olivier Barret,Gilles Tamagnan, Francis Barth*

Discovery and optimization of Lu AF58801, a novel, selective and brain penetrant positive allostericmodulator of alpha-7 nicotinic acetylcholine receptors: Attenuation of subchronic phencyclidine (PCP)-induced cognitive deficits in rats following oral administration

pp 288–293

Jørgen Eskildsen*, John P. Redrobe, Anette G. Sams, Kim Dekermendjian, Morten Laursen, Jette B. Boll, Roger L. Papke,Christoffer Bundgaard, Kristen Frederiksen, Jesper F. Bastlund

NH

O

HTS hit

(S)(S) N

H(R)

O

Optimized lead

OH

O

Discrimination between 5-hydroxymethylcytosine and 5-methylcytosine in DNA by selective chemicallabeling

pp 294–297

Jianlin Hu, Yuqi Chen, Xiaowei Xu, Fan Wu, Xiwen Xing, Zhenghao Xu, Jiahui Xu, Xiaocheng Weng, Xiang Zhou*

N

N

O

NH2

HO

N

N

O

NH2N

HN

N

ON

Ox-Labeling

Triazino indole–quinoline hybrid: A novel approach to antileishmanial agents pp 298–301

Rashmi Sharma, Anand Kumar Pandey, Rahul Shivahare, Khushboo Srivastava, Suman Gupta, Prem M.S. Chauhan*

IC50 = 0.36 μMCC50 = >400 μMSI = >1111

7b

NN

NNS

R'

NH

N

Cln

R

n = 2R = HR' = Me

n = 2R = HR' = H

IC50 = 1.11 μMCC50 = 74.34 μMSI = 67

7a


Synthesis, anti-HIV activity, integrase enzyme inhibition and molecular modeling of catechol,hydroquinone and quinol labdane analogs

pp 302–307

Rohan Pawar, Tiyasa Das, Sanjay Mishra, Nutan*, Boskey Pancholi, Satish K. Gupta*, Sujata V. Bhat*

1,2,3-Triazole-derived naphthalimides as a novel type of potential antimicrobial agents: Synthesis,antimicrobial activity, interaction with calf thymus DNA and human serum albumin

pp 308–313

Jing-Song Lv, Xin-Mei Peng, Baathulaa Kishore, Cheng-He Zhou*

NO O

Br

N

NNN N

NN

R3 R3R2

R1 R1

R2

9e: R1 = H, R2 = Cl, R3 = ClMIC = 1 μg/mL (E. coli )

A near-infrared fluorescence dye for sensitive detection of hydrogen sulfide in serum pp 314–316

Xuanjun Wu, Jiaqi Shi, Liu Yang, Jiahuai Han, Shoufa Han*

NCl

NH2S

N NSH

Thiolation

Cy-ClDeep colored and fluorescent

Cy-SHWeakly colored and nonfluorescent

Cy-Cl, a cationic near-infrared cyanine dye, readily reacts with hydrogen sulfide (H2S) via nucleophilic thiolation to give dose-dependent ‘turn-off’fluorescence and colorimetric read-out, allowing selective detection of low levels of H2S in serum and imaging of mitochondrial H2S in living cells.

Novel di-tertiary-butyl phenylhydrazones as dual cyclooxygenase-2/5-lipoxygenase inhibitors: Synthesis,COX/LOX inhibition, molecular modeling, and insights into their cytotoxicities

pp 317–324

Shibnath Ghatak, Alok Vyas, Suniti Misra*, Paul O’Brien,Ajit Zambre, Victor M. Fresco, Roger R. Markwald,K. Venkateshwara Swamy, Zahra Afrasiabi,Amitava Choudhury, Madhukar Khetmalas, Subhash Padhye*

ORTEP of DTPNHZ Docking of DTPNHZ in COX-2 Docking of DTPNHZ in 5-LOX

The novel structural analogs 3,5 di-tert-butyl hydrazones represent apotent class of compounds inhibiting the COX/LOX pro-inflammatorycytokines efficiently at lower micromolar concentrations. Our resultsshow that the novel COX–LOX inhibitors inhibit the proliferation of apanel of human colon cancer cell lines including HCA-7, HT-29, SW480and Apc10.1 cells as well as the hyaluronan synthase-2 (Has2) enzymeover-expressed in colon cancer cells, through inhibition of thehyaluronan/CD44v6 cell survival pathway.


Stereoselective total synthesis of a novel regiomer of herbarumin I and its cytotoxic and antimicrobialactivities

pp 325–327

Paramesh Jangili, Jajula Kashanna, C. Ganesh Kumar, Y. Poornachandra, Biswanath Das*

OO

O

HOH

TBDPSO

O OMOMHO

O

O

O

HO OH

Synthesis and biological evaluation of novel N-substituted 1H-dibenzo[a,c]carbazole derivatives ofdehydroabietic acid as potential antimicrobial agents

pp 328–331

Wen Gu*, Chao Qiao, Shi-Fa Wang, Yun Hao, Ting-Ting Miao

NAD-based inhibitors with anticancer potential pp 332–336

Krzysztof Felczak, Robert Vince, Krzysztof W. Pankiewicz*

O O

OHHO

N

N

N

N

NH2

P CH2

O

OHPO

OH O

O

CH3

CH3O

OOH

X

Adenine-X-substituted MAD analogues

O

OHHO

N

N

N

N

NH2

O

CH3

H3CO

OHCH3 O

OX

Mycophenolic esters and amidesX = O, NH, or amino-acid

Discovery of potent and efficacious cyanoguanidine-containing nicotinamide phosphoribosyltransferase(Nampt) inhibitors

pp 337–343

Xiaozhang Zheng*, Timm Baumeister, Alexandre J. Buckmelter, Maureen Caligiuri, Karl H. Clodfelter, Bingsong Han,Yen-Ching Ho, Nikolai Kley, Jian Lin, Dominic J. Reynolds, Geeta Sharma, Chase C. Smith, Zhongguo Wang,Peter S. Dragovich, Angela Oh, Weiru Wang, Mark Zak, Yunli Wang, Po-wai Yuen, Kenneth W. Bair

N

NH

N

NH

N

SO O

OCF3

Nampt IC50 = 4.4 nMA2780 IC50 = 2.2 nM

O

NH

SN

O O

Nampt IC50 = 9 nMA2780 IC50 = 10 nM

NHN


Dactyloditerpenol acetate, a new prenylbisabolane-type diterpene from Aplysia dactylomela withsignificant in vitro anti-neuroinflammatory activity

pp 344–348

Carlos Jiménez-Romero, Alejandro M.S. Mayer, Abimael D. Rodríguez*

Evaluation of benzoic acid derivatives as sirtuin inhibitors pp 349–352

Yi-Pei Chen, Chad C. Catbagan, Jeannette T. Bowler, Trevor Gokey, Natalie D.M. Goodwin, Anton B. Guliaev, Weiming Wu,Taro Amagata*

Streptomyces sp. CP27-53

Design, synthesis and structure–activity relationships of substituted oxazole–benzamide antibacterialinhibitors of FtsZ

pp 353–359

Neil R. Stokes, Nicola Baker, James M. Bennett, Pramod K. Chauhan, Ian Collins, David T. Davies, Maruti Gavade,Dushyant Kumar, Paul Lancett, Rebecca Macdonald, Leanne MacLeod, Anu Mahajan, Jeffrey P. Mitchell, Narendra Nayal,Yashodanand Nandan Nayal, Gary R.W. Pitt, Mahipal Singh, Anju Yadav, Anil Srivastava, Lloyd G. Czaplewski,David J. Haydon*

Br

F

NH2

O

F

O

HO

N

O

F F

F

F F

F

FNH 2

O

FO

OHO

OO

BrO

NR

Rα

R4

R5

F

NH2

O

F

O N

O

Identification through structure-based methods of a bacterial NAD+-dependent DNA ligase inhibitor thatavoids known resistance mutations

pp 360–366

Kerry Murphy-Benenato*, Hongming Wang, Helen M. McGuire, Hajnalka E. Davis,Ning Gao, D. Bryan Prince, Haris Jahic, Suzanne S. Stokes, P. Ann Boriack-Sjodin

In an attempt to identify novel inhibitors of NAD+-dependent DNA ligase (LigA)that are not affected by a known resistance mutation, a detailed analysis of thebinding sites of a variety of bacterial ligases was performed. This analysisrevealed several similarities to the adenine binding region of kinases, whichenabled a virtual screen of known kinase inhibitors. From this screen, athienopyridine scaffold was identified that was shown to inhibit bacterial ligase.


Preparation of 8-hydroxyquinoline derivatives as potential antibiotics against Staphylococcus aureus pp 367–370

Kim-Hung Lam*, Roberto Gambari, Kenneth Ka-Ho Lee, Yi-Xin Chen, Stanton Hon-Lung Kok, Raymond Siu-Ming Wong,Fung-Yi Lau, Chor-Hing Cheng, Wai-Yeung Wong, Zhao-Xiang Bian, Albert Sun-Chi Chan, Johnny Cheuk-On Tang*,Chung-Hin Chui*

Copper ion as a delivery platform for taxanes and taxane complexes pp 371–377

Thomas J. Manning*, Dennis Phillips, Greg Wylie, Benjamin Bythell, Shannon Clark,Ryenne Ogburn, Kaitlyn Ledwitch, Chad Collis, Stephanie Patterson, Landon Lasseter

A number of delivery agents, such as proteins, liposomes, micelles, and nanoparticles, are utilized fortransporting pharmaceutical agents in a physiological environment. This Letter focuses on the use ofthe copper(II) ion and its potential role as a delivery agent for the taxanes and taxol couple to amalaria drug. Nuclear magnetic resonance (NMR, 1H, 13C, 15N), Mass Spectrometry (LC-MS, MALDI-TOF, FT-ICR) and computational methods are used to examine the structure of the complex. TheNational Cancer Institute’s benchmark 60 cell line panel is used to compare the efficacy of thecopper–taxol and copper–taxol–hydroxychloroquin complexes to that of iron–taxol and pure taxol.

Design and synthesis of an aminopiperidine series of c-secretase modulators pp 378–381

Tomonori Kobayashi, Seiji Iwama, Akira Fusano, Yoshihiro Kato, Atsushi Ikeda, Yasuhiro Teranishi, Akemi Nishihara,Masanori Tobe*

O

NN

O

NN

3(S)-aminopiperidine

NH

ON

Br

N

O

F

Asymmetric synthesis and receptor activity of chiral simplified resiniferatoxin (sRTX) analogues astransient receptor potential vanilloid 1 (TRPV1) ligands

pp 382–385

Myeong Seop Kim, Yooran Ki, Song Yeon Ahn, Suyoung Yoon, Sung-Eun Kim, Hyeung-Geun Park, Wei Sun, Karam Son,Minghua Cui, Sun Choi, Larry V. Pearce, Timothy E. Esch, Ian A. DeAndrea-Lazarus, Peter M. Blumberg, Jeewoo Lee*

R1

HN

S

HNO

OR2

2 R1=OH, R2=OCH33 R1=NHSO2CH3, R2=F*


Simplified captopril analogues as NDM-1 inhibitors pp 386–389

Ningning Li, Yintong Xu, Qiang Xia, Cuigai Bai, Taiyi Wang, Lei Wang, Dingdi He, Nannan Xie, Lixin Li, Jing Wang,Hong-Gang Zhou, Feng Xu, Cheng Yang, Quan Zhang, Zheng Yin*, Yu Guo*, Yue Chen*

N

O

HS

HO O

NHS

O

R2OHHSOHHS

SHD-catopril Compound 31

R1

Amides: R3 = Me, R4 = H; or R3 = H, R4 = MeCompound 22: R1 = H, R2 = BnNH, R3 = H, R4 = Me

Compound 32

R3 R4

IC50 = 7.9μM Compound 22: IC50 = 1.0 μM IC50= 15 μM IC50 = 10 μM

Captopril is a New Delhi metallo-b-lactamase-1 (NDM-1) inhibitor with an IC50

value of 7.9 lM. It is composed of two units: a 3-mercapto-2-methylpropanoylfragment and a proline residue. In this study, we synthesized simple amidederivatives of 3-mercapto-2-methylpropanoic acid, and then tested them asNDM-1 inhibitors in order to identify the pharmacophore for NDM-1 inhibition.We found that the lead compound 22 had an IC50 value of 1.0 lM. Furtherstructure simplification provided compounds 31 and 32, which had IC50 values of15 and 10 lM, respectively. As compound 32 is a clinically used antidote formetal poisoning, it has great potential to be repurposed to treat bacterialinfections.

Inhibition of serine and proline racemases by substrate-product analogues pp 390–393

Matthew Harty, Mitesh Nagar, Logan Atkinson, Christina M. LeGay, Darren J. Derksen*, Stephen L. Bearne*

Detection of hepatitis C virus by single-step hairpin primer RT-PCR pp 394–396

Fumie Takei, Hideki Tani, Yoshiharu Matsuura, Kazuhiko Nakatani*

C5'

3'

hairpin primerRT enzyme

HCV RNA

<Reverse transcription>

Taq polymerase

cDNA

C<PCR>

GC

C

C

We developed a novel single-step virus detection system using the fluorescent molecule with a hairpin primer on the RT-PCR. The method was applied to detect hepatitis C (HCV)from patients’ sera. The RT-PCR proceeded and selectively detected HCV-RNA in contaminant materials solution.

Corrigenda pp 397–398

*Corresponding authorSupplementary data available via ScienceDirect

COVER

Illustrated is the workflow for a competitive ABPP platform to discover selective inhibitors of serine hydrolases. This platform was used toidentify selective and cell-active carbamate inhibitors for the lipid hydrolase lipoprotein-associated phospholipase A2 (Lp-PLA2; accessionnumber 3F96). See Nagano, J. M. et al. Bioorg. Med. Chem. Lett. 2013, 23, 839–843. Cover image designed and generated by Megan Blewett(TSRI).


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