Graphical contents list

Bioorganic & Medicinal Chemistry Letters Volume 23, Issue 5, 2013

Contents

ARTICLE

Publisher’s Note pp 1166–1167

BMCL DIGEST

Understanding drugs and diseases by systems biology? pp 1168–1176

Hans-Christoph Schneider, Thomas Klabunde*

REGULAR ARTICLES

Highly potent and selective cannabinoid receptor 2 agonists: Initial hit optimization of an adamantyl hit seriesidentified from high-through-put screening

pp 1177–1181

Matthias Nettekoven*, Jürgen Fingerle, Uwe Grether, Sabine Grüner, Atsushi Kimbara, Bernd Püllmann, Mark Rogers-Evans,Stephan Röver, Franz Schuler, Tanja Schulz-Gasch, Christoph Ullmer

O

NH

CO2Et

O

N

Xn

R'

R

high-throughput screening hit

hit evaluation& optimization

initial SAR established

Discovery of novel inhibitors targeting the Mycobacterium tuberculosis O-acetylserine sulfhydrylase(CysK1) using virtual high-throughput screening

pp 1182–1186

Variam Ullas Jean kumar, Ömer Poyraz, Shalini Saxena, Robert Schnell, Perumal Yogeeswari, Gunter Schneider*,Dharmarajan Sriram*

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1145–1165

Contents lists available at SciVerse ScienceDirect

Bioorganic & Medicinal Chemistry Letters

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

Design and synthesis of imidazole and triazole derivatives as Lp-PLA2 inhibitors and the unexpecteddiscovery of highly potent quaternary ammonium salts

pp 1187–1192

Kai Wang, Wenwei Xu, Yang Liu, Wei Zhang, Wenyi Wang, Jianhua Shen*, Yiping Wang*

NN

NN

N

O

S

F

CF3

N

Br F

22c

91% inhibition of Lp-PLA2 acitivity @ 10nM in rabbit plasma,95% @1nM in human plasma

NX

NN

N

O

S

F

CF3

R2

X= N, CH

N

ON

N

O

S

F

CF3

NEt2

darapladib

Synthesis and antibacterial activities of new piperidine substituted (5R)-[1,2,3]triazolylmethyl and(5R)-[(4-F-[1,2,3]triazolyl)methyl] oxazolidinones

pp 1193–1196

Hyo-Nim Shin, Seon Hee Seo, Hyunah Choo, Gyochang Kuem, Kyung Il Choi*, Ghilsoo Nam*

NR1

R2N

R1

R2N

R1

R2

O

F

N ON

Piperidine

N N

R

R = H or F

Piperidine = NR1

12

34 5AB

5(R)-[1,2,3]Triazolylmethyl and (5R)-[(4-F-[1,2,3]triazolyl)methyl]oxazolidinones having various piperidine groups as a modification of morpholine C-ring of linezolid, weresynthesized and evaluated antibacterial activity.

Identification of acidic heterocycle-substituted 1H-pyrazolo[3,4-b]pyridines as soluble guanylate cyclasestimulators

pp 1197–1200

Nils Griebenow*, Hartmut Schirok, Joachim Mittendorf, Alexander Straub, Markus Follmann, Johannes-Peter Stasch,Andreas Knorr, Karl-Heinz Schlemmer, Gorden Redlich

NN

N

F

NHN N

N

NN

N

F

NHON

O

Rabbit Aorta IC50 = 8.60 µMSolubility = 150 mg/L

Rabbit Aorta IC50 = 1.26 µMSolubility = 320 mg/L

Synthesis of hemslecin A derivatives: A new class of hepatitis B virus inhibitors pp 1201–1205

Rui-Hua Guo, Chang-An Geng, Xiao-Yan Huang, Yun-Bao Ma, Quan Zhang, Li-Jun Wang, Xue-Mei Zhang, Rong-Ping Zhang*,Ji-Jun Chen*

O

HHO

HO

HO

HO

OAc

1

OH

23

56

25

1146 Contents / Bioorg. Med. Chem. Lett. 23 (2013) 1145–1165

Synthesis and structure–activity relationship analysis of caffeic acid amides as selective matrixmetalloproteinase inhibitors

pp 1206–1211

Zhi-Hao Shi, Nian-Guang Li*, Qian-Ping Shi, Hao Tang, Yu-Ping Tang*, Wei Li, Lian Yin, Jian-Ping Yang, Jin-Ao Duan*

OH

OHO

HO

Caffeic acid (CA) (3)

O

R2

R1

P1'New designed caffeicacid amide derivatives

NH

nR3

Four series of acid amides were synthesized, preliminary structure–activity relationship analysis indicated that caffeic acid amides with electron-donating groups at para-positionof amino phenyl group showed better inhibitory activities and selectivity than those with electron-withdrawing groups, and the presence of adjacent dihydroxy in the caffeoylgroup was very important for the MMP-2 and MMP-9 inhibitory activities.

Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: The discovery of AZD8055and AZD2014

pp 1212–1216

Kurt G. Pike*, Karine Malagu, Marc G. Hummersone, Keith A. Menear, Heather M.E. Duggan, Sylvie Gomez,Niall M.B. Martin, Linette Ruston, Sarah L. Pass, Martin Pass

N N

N

N

O

NO

OH

MeO

N N

N

N

O

NO

O

NH

14 (AZD8055) 21 (AZD2014)

The optimization of a novel series of highly potent and selective dual inhibitors of mTORC1 and mTORC2 is described culminating in the discovery of clinical candidates AZD8055(14) and AZD2014 (21).

Critical role of a methyl group on the c-lactone ring of annonaceous acetogenins in the potent inhibitionof mitochondrial complex I

pp 1217–1219

Naoto Kojima*, Masato Abe, Yuki Suga, Kazufumi Ohtsuki, Tetsuaki Tanaka, Hiroki Iwasaki, Masayuki Yamashita,Hideto Miyoshi*

Basic N-interlinked imipramines show apoptotic activity against malignant cells including Burkitt’slymphoma

pp 1220–1224

Sandra A. Bright*, Anne Brinkø, Maja Thim Larsen, Steffen Sinning, D. Clive Williams, Henrik H. Jensen

Contents / Bioorg. Med. Chem. Lett. 23 (2013) 1145–1165 1147

Synthesis of novel 2-alkyl triazole-3-alkyl substituted quinoline derivatives and their cytotoxic activity pp 1225–1227

P. Sambasiva Rao, C. Kurumurthy, B. Veeraswamy, G. Santhosh Kumar, P. Shanthan Rao, R. Pamanji, J. Venkateswara Rao,B. Narsaiah*

NN N

OHRNN N

NR PhN

R'

N NN R

5a-o4a-c2a-c

Novel 2-alkyl triazole-3-alkyl substituted quinoline derivatives 5a–o were prepared in series of steps and screened for antimicrobial and cytotoxicactivity. The promising compounds in each case have been identified.

1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanones as novel CCR1 antagonists pp 1228–1231

Andrew M.K. Pennell, James B. Aggen, Subhabrata Sen, Wei Chen, Yuan Xu, Edward Sullivan, Lianfa Li, Kevin Greenman,Trevor Charvat, Derek Hansen, Daniel J. Dairaghi, J.J. Kim Wright, Penglie Zhang*

Cl N NO

NN

H3CCl

CF3

14CCR1 binding IC50: 4 nM

MeO

Natural products inspired synthesis of neuroprotective agents against H2O2-induced cell death pp 1232–1237

Jehad Almaliti, Shadia E. Nada, Bryaune Carter, Zahoor A. Shah*, L.M. Viranga Tillekeratne*

O

O O

OOH

O

OOH

+

Inhibiting NF-jB-inducing kinase (NIK): Discovery, structure-based design, synthesis, structure–activityrelationship, and co-crystal structures

pp 1238–1244

Kexue Li*, Lawrence R. McGee, Ben Fisher, Athena Sudom, Jinsong Liu, Steven M. Rubenstein, Mohmed K. Anwer,Timothy D. Cushing, Youngsook Shin, Merrill Ayres, Fei Lee, John Eksterowicz, Paul Faulder, Bohdan Waszkowycz,Olga Plotnikova, Ellyn Farrelly, Shou-Hua Xiao, Guoqing Chen, Zhulun Wang

N N

NH2

NH

OH

N N

N

N

Me

NH2 Cl

1(HTS Hit) 28


Terpenoid mosquito repellents: A combined DFT and QSAR study pp 1245–1248

Jie Song*, Zongde Wang, Alexander Findlater, Zhaojiu Han, Zhikuan Jiang, Jinzhu Chen, Weiqing Zheng, Sarah Hyde

Interactions between low-toxicity terpenoid mosquito repellents and lactic acid are studied at the HF and B3LYP levels. The subsequent QSAR study shows that not only thestructure of repellents but also the repellent–lactic acid complexes may play an important role.

Discovery of (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide, a potent and orally efficacious mGlu5 receptor negative allostericmodulator

pp 1249–1252

Junliang Hao*, Veronique Dehlinger, Adam M. Fivush, Helene C.E. Rudyk, Thomas C. Britton, Sean P. Hollinshead,Benjamin P. Vokits, Barry P. Clark, Steven S. Henry, Steven M. Massey, Langu Peng, Bruce A. Dressman, Beverly A. Heinz,Edda F. Roberts, Mallorie R. Bracey-Walker, Steven Swanson, John T. Catlow, Patrick L. Love, Anita D. Tepool,Steven C. Peters, Rosa Maria A. Simmons, Smriti Iyengar, David L. McKinzie, James A. Monn

SN

NH

O

N

NN

24

HCI

Discovery and structure–activity relationships of small molecules that block the humanimmunoglobulin G–human neonatal Fc receptor (hIgG–hFcRn) protein–protein interaction

pp 1253–1256

Zhaolin Wang, Cara Fraley, Adam R. Mezo*

N

N N

NH

O O

IC50 > 150 μΜ

N

N N

NH

O

IC50 = 2 μΜ

O1 66

CN CN NO

Design, synthesis, and SAR of N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamideinhibitors of glycine transporter-1

pp 1257–1261

Christopher L. Cioffi*, Mark A. Wolf, Peter R. Guzzo, Kashinath Sadalapure, Visweswaran Parthasarathy, Dattatraya Dethe,Jun-Ho Maeng, Edmund Carulli, David T.J. Loong, Xiao Fang, Min Hu, Priya Gupta, Mark Chung, Mei Bai, Nick Moore,Michele Luche, Yuri Khmelnitsky, Patrick L. Love, Megan A. Watson, Andrew J. Mhyre, Shuang Liu

40> 175% increase in rat CSF glycine concentrations vs. vehicle control at 30 mg/kg (PO), p < 0.05

N

NN

OS

O

O

F

F

F F

H


Identification of diaryl 5-amino-1,2,4-oxadiazoles as tubulin inhibitors: The special case of3-(2-fluorophenyl)-5-(4-methoxyphenyl)amino-1,2,4-oxadiazole

pp 1262–1268

Andrei A. Gakh*, Andrey V. Sosnov, Mikhail Krasavin, Tam Luong Nguyen, Ernest Hamel

Inhibition of monoamine oxidase by phthalide analogues pp 1269–1273

Belinda Strydom, Jacobus J. Bergh, Jacobus P. Petzer*

Phthalides as highly potent MAO-A/B inhibitors

MAO-BMAO-A R IC50 (µM) IC50 (µM)

6b 4-ClC6H4(CH2)O– 0.172 0.0028

6m C6H5(CH2)3O– 0.096 0.0062

6o 4-ClC6H4O(CH2)2O– 0.137 0.011

6r C6H11CH2O– 0.185 0.012

O

OR

6

Synthesis, crystal structure and antibacterial activity of new highly functionalized ionic compoundsbased on the imidazole nucleus

pp 1274–1278

Mebarek Bahnous, Abdelmalek Bouraiou, Meryem Chelghoum, Sofiane Bouacida, Thierry Roisnel, Farida Smati,Chafia Bentchouala, Philippe C. Gros, Ali Belfaitah*

NN

R

ZY

Me

R'O

BrNN H (Me)

Structural analysis of the active sites of dihydrofolate reductase from two species of Candida uncoversligand-induced conformational changes shared among species

pp 1279–1284

Janet L. Paulsen, Kishore Viswanathan, Dennis L. Wright*, Amy C. Anderson*


Synthesis and structure–activity relationship of pyripyropene A derivatives as potent and selectiveacyl-CoA:cholesterol acyltransferase 2 (ACAT2) inhibitors: Part 1

pp 1285–1287

Masaki Ohtawa, Hiroyuki Yamazaki, Satoshi Ohte, Daisuke Matsuda,Taichi Ohshiro, Lawrence L. Rudel, Satoshi �Omura, Hiroshi Tomoda*,Tohru Nagamitsu*

O

OO N

O

HO

O

O

O

O

O

Pyripyropene A

7

ACAT1 IC50 >80 μMACAT2 IC50 0.07 μMSelectivity >1000

O

OO N

O

HO

O

O

O

O

O

CN

7

New derivative 3i

ACAT1 IC50 4.16 μMACAT2 IC50 0.0009 μMSelectivity 4622.0

H

H

H

H

20,40-BNA/LNA aptamers: CE-SELEX using a DNA-based library of full-length 20-O,40-C-methylene-bridged/linked bicyclic ribonucleotides

pp 1288–1292

Yuuya Kasahara, Yuuta Irisawa, Hiroaki Ozaki, Satoshi Obika, Masayasu Kuwahara*

Anti-malarial activity of new N-acetyl-LL-leucyl-LL-leucyl-LL-norleucinal (ALLN) derivatives againstPlasmodium falciparum

pp 1293–1296

Hwa-Jung Choi, Minghua Cui, Da-Yu Li, Hyun-Ok Song, Hak Sung Kim*, Hyun Park*

NH

O

NH O

NNH

CbzR1

R2n

R3

R1, R2 = monoalkyl, dialkyl, cycloalkyl

R3 = Boc or substituted benzyl

n = 1 or 2

Design and synthesis of dimethylaminomethyl-substituted curcumin derivatives/analogues: Potentantitumor and antioxidant activity, improved stability and aqueous solubility compared with curcumin

pp 1297–1301

Xubin Fang, Lei Fang*, Shaohua Gou*, Lin Cheng

O O

HO

(H3C)2N

OH

OCH3

O

HO

(H3C)2N

OH

N(CH3)2n

potent antitumor activity

potent antioxidant activity

good stability

improved aqueous solubility compared with curcuminn = 0, 2, 3


Synthesis and micellar mimic properties of bile acid trimers pp 1302–1305

Jinrong Lu, Chulong Liu, Jun Hu*, Yong Ju*

Regioselective synthesis of isoxazole–mercaptobenzimidazole hybrids and their in vivo analgesic andanti-inflammatory activity studies

pp 1306–1309

Shravankumar Kankala*, Ranjith Kumar Kankala, Prasad Gundepaka, Niranjan Thota, Srinivas Nerella, Mohan Rao Gangula,Hanmanthu Guguloth, Mukkanti Kagga, Ravinder Vadde*, Chandra Sekhar Vasam*

N

NS NO2

NO2

R

NO

Ar6a-l

R = H, Br, OCH3, NO2

Ar = 4-OCH3C6H4, 4-FC6H4, 4-CNC6H4,

Synthesis and biological evaluation of nucleoside analogues than contain silatrane on the basis of thestructure of acyclovir (ACV) as novel inhibitors of hepatitis B virus (HBV)

pp 1310–1314

Anyue Han, Lingna Li, Kuiyou Qing, Xiaolu Qi, Leping Hou, Xintong Luo, Shaohua Shi, Faqing Ye*

In this study, we used the combination principle to design andsynthesize nucleoside analogues that contain silatrane on thebasis of the structure of ACV. We found that the compounds wereeffective inhibitors of HBV, both in vitro and in vivo.

Design, synthesis, characterization and anti-inflammatory evaluation of novel pyrazole amalgamatedflavones

pp 1315–1321

Hemant V. Chavan, Babasaheb P. Bandgar*, Laxman K. Adsul, Valmik D. Dhakane, Pravin S. Bhale, Vishnu N. Thakare,Vijay Masand

O

N

N

O

O

O

A B

C

Presence of H-bondinggroup is favourable

essential for activity

Useful forlipophilic interaction

Presence of electron withdrawinggroup is unfavourable

Presence of groupwith +I effectis favourable{Can be replaced by

heterocyclic ring

A series of novel pyrazole amalgamated flavones have been designed, synthesized and evaluated for their anti-inflammatory potential.


Syntheses of lipophilic chalcones and their conformationally restricted analogues as antitubercularagents

pp 1322–1325

Imran Ahmad, Jay Prakash Thakur, Debabrata Chanda, Dharmendra Saikia, Feroz Khan, Shivani Dixit, Amit Kumar,Rituraj Konwar, Arvind Singh Negi, Atul Gupta*

O

O

ONR

O R'H3CO

O

O

ON

R'

R

Lipophilic chalcones and their conformationally restricted analogues were synthesized and evaluated for their antitubercular efficacy against Mycobacteriumtuberculosis H37Rv strain. Compounds 16, 24, 25a and 25c were found to be active MIC at 60, 30, 3.5 and 7.5 lg-mL)1. In vitro cytotoxicity of compounds 16,24, 25a, 25c and 26 in non-cancerous human epithelial kidney cell line (HEK-293) showed that most active compound 25a was approximately 2.85 timesselective towards tubercular versus healthy cells whereas compound 24 was found to be 16 times selective.

Comparative properties of Ab1–42, Ab11–42, and [Pyr11]Ab11–42 generated from O-acyl isopeptides pp 1326–1329

Youhei Sohma*, Moe Yamasaki, Hiroyuki Kawashima, Atsuhiko Taniguchi, Masayuki Yamashita, Kenichi Akaji,Hidehito Mukai, Yoshiaki Kiso*

Rapid microwave-enhanced synthesis of C5-alkynyl pyranonucleosides as novel cytotoxic antitumoragents

pp 1330–1333

Athina Dimopoulou, Stella Manta, Christos Kiritsis, Dimitra-Niki Gkaragkouni,Ioannis Papasotiriou, Jan Balzarini, Dimitri Komiotis*

OHO

HOOH

OH N

N

X

O

R

OHO

HOOH

OH

NHN

O

O

XY

15a: X = N, Y = C15b: X = C, Y = N

4a: X = OH, 4b: X = NH2, R = C3H75a: X = OH, 5b: X = NH2, R = C5H116a: X = OH, 6b: X = NH2, R = Ph7a: X = OH, 7b: X = NH2, R = p-CH3(CH2)4C6H48a: X = OH, 8b: X = NH2, R = p-(CH3)3CC6H49a: X = OH, 9b: X = NH2, R = Me3Si10a: X = OH, 10b: X = NH2, R = H

A microwave-assisted, one-pot, coupling reaction for the synthesis of C5-alkynyl-uracil and cytosine glucopyranonucleosides has been developed.Among them, 5-phenylethynyluracil pyranonucleoside derivative 6a, effectively inhibited tumor cell proliferation (IC50 of 5.2-6.2 lM).

Bioactive polyhydroxylated steroids from the Hainan soft coral Sinularia depressa Tixier-Durivault pp 1334–1337

Lin-Fu Liang, Xu-Jie Wang, Hai-Yan Zhang, Hai-Li Liu, Jia Li, Le-Fu Lan, Wen Zhang*, Yue-Wei Guo*

HO144 PTP1B IC50= 19.5 μM amyloid-β25-35 20.1%

serum deprivation 16.6%{O

SHY5Y cell viability

PTP1B IC50= 15.3 μM


Microbial transformation of acetyl-11-keto-b-boswellic acid and their inhibitory activity on LPS-inducedNO production

pp 1338–1342

Yan Sun, Dan Liu, RongGang Xi, Xiaobo Wang*, Yan Wang, Jie Hou, Baojing Zhang, Changyuan Wang, Kexin Liu, Xiaochi Ma*

C. blakesleana AS 3.970

C. elegans AS 3.1207

O

AcO

HOOC

1

4 6

89

11

14 16

18

19 21

22

23

25 2628

29

30

AKBA

O

AcO

HOOCR1

R2

R5

R4

R3

R1= OH R2= H R3= H R4= H R5= H1

R1= OH R2= OH R3= H R4= H R5= OH2

R1= OH R2= H R3= H R4= H R5= H3

R1= H R2= H R3=OH R4= H R5= H4

R1= OH R2= OH R3= H R4= H R5= H5

R1= H R2= H R3= H R4= H R5= OH6

R1= OH R2= OH R3= H R4= H R5= OH7

Synthesis and in vitro cytotoxic activity evaluation of novel heterocycle bridged carbothioamide typeisosteviol derivatives as antitumor agents

pp 1343–1346

Song-Lin Zhu, Ya Wu, Cong-Jun Liu, Chang-Yong Wei, Jing-Chao Tao*, Hong-Min Liu*

COOEt

N

N

NH

S

R121

COOEt

NO

NH

S

R

9COOH

O

Two series of novel carbothioamide-substituted pyrazole and isoxazolidine derivatives were facilely prepared. Within all compounds, 12p (IC50 = 6.51 lM) showed the highestcytotoxic activity against Raji cell.

Discovery of olmesartan hexetil: A new potential prodrug of olmesartan pp 1347–1350

Mohammed I. El-Gamal, Hanan S. Anbar, Hye Jin Chung, Hyun-Il Kim, Young-Jin Cho, Bong Sang Lee, Sun Ahe Lee,Ji Yun Moon, Dong Jin Lee, Dow Kwon, Won-Jai Choi, Hong-Ryeol Jeon, Chang-Hyun Oh*

N

NOH

O

O

NNN

NH

Olmesartan hexetil (1)

O O

O

Spiro heterocycles as potential inhibitors of SIRT1: Pd/C-mediated synthesis of novel N-indolylmethylspiroindoline-3,20-quinazolines

pp 1351–1357

D. Rambabu, Guttikonda Raja, B. Yogi Sreenivas, G.P.K. Seerapu, K. Lalith Kumar, Girdhar Singh Deora, Devyani Haldar*,M.V.Basaveswara Rao*, Manojit Pal*

NH

O

HNN

O

NS

R

R1O

ONH2

NH2

O

Sir 2


Relationship between antimold activity and molecular structure of cinnamaldehyde analogues pp 1358–1364

Yuanyuan Zhang, Shujun Li*, Xianchao Kong

Experimental logAR

Cal

cula

ted

logA

R

Experimental logAR

Cal

cula

ted

logA

R

QSAR molding has been applied to cinnamaldehyde analogues. Both the two satisfactory multilinear regression models of Aspergillus niger and Paecilomyces variotii include fourdescriptors.

Antimycobacterial activity evaluation, time-kill kinetic and 3D-QSAR study of C-(3-aminomethyl-cyclohexyl)-methylamine derivatives

pp 1365–1369

Deepak Kumar, K. Kranthi Raj, MaiAnn Bailey, Torey Alling, Tanya Parish, Diwan S. Rawat*

9h

9iEntry MIC (μM) S.D.R = 4-n-Pr 4.2 1.0

R = 4-i-Pr 4.4 1.0

R = 4-n-But 2.4 0.3

R = 4-t-But 1.1 0.2

R = 4-n-Pentyl 6.7 1.6

R = 4-n-Hexyl 5.6 1.1

R = 4-n-Heptyl 3.1 0.3

R = 4-n-Octyl 3.2 0.9

Ethambutol 2-3

NH2

NH2

NH

NH

2HCl 44 Examples

R

R

Potent and selective tariquidar bioisosters as potential PET radiotracers for imaging P-gp pp 1370–1374

Marialessandra Contino, Laura Zinzi, Maria Grazia Perrone, Marcello Leopoldo, Francesco Berardi, Roberto Perrone,Nicola Antonio Colabufo*

N

NH

O

NH

O

N

O

O

O

O

*

N

ON

NO

O

S

R

A B C

99mTc-(Me)FGCDEVD, a potential tracer for apoptosis detection pp 1375–1378

Pierre Bohn*, Florian Mouchard, Jean Rouvet, Anne-Caroline de Boisgrollier, Pierre Vera


Five new phenolic glycosides from Hedyotis scandens pp 1379–1382

Guo-Cai Wang*, Tao Li, Fang-Ye Deng, Yao-Lan Li, Wen-Cai Ye*

A facile three-component [3+2]-cycloaddition for the regioselective synthesis of highly functionaliseddispiropyrrolidines acting as antimycobacterial agents

pp 1383–1386

Ang Chee Wei, Mohamed Ashraf Ali*, Yeong Keng Yoon, Rusli Ismail, Tan Soo Choon,Raju Suresh Kumar

O

NCH3

O

4.43, t, J=9.0 Hz50.5

2.63, d, J = 17.7 Hz2.91, d, J = 17.7 Hz

35.0

2.22, s35.6

82.0207.1

67.6

208.4

3.74, t, J = 9.0 Hz4.16, t, J = 9.3 Hz

59.9

6.80-8.10, maromatic

Br

H

Compound 40-(4-bromophenyl)-10-methyldispiro[acenaphthylene-1,20-pyrrolidine-30 ,200-indane]-2,100(1H)-dione (4c) was found to be the most active with MIC of 12.50 lM.

Synthesis and antibacterial activity of 9-oxime ether non-ketolides, and novel binding mode of alkylideswith bacterial rRNA

pp 1387–1393

Jian-Hua Liang*, Wei Lv, Xiao-Li Li, Kun An, Mark Cushman, He Wang, Ying-Chun Xu

The docking poses of the alkylides 17, 18, 19 and 20 overlapped with the crystal structure of clarithromycin. Our molecular modeling results for 17–20shed light on the reason why the sidechains’ conformational flexibility at the 3-O position has a significant impact on their antibacterial activity.

Preparation and evaluation of a 99mTcN–PNP complex of sanazole analogue for detecting tumor hypoxia pp 1394–1397

Anupam Mathur, Madhava B. Mallia, Sharmila Banerjee*, H.D. Sarma, M.R.A. Pillai


Discovery and structure–activity relationship of 1,3-cyclohexyl amide derivatives as novel mGluR5negative allosteric modulators

pp 1398–1406

Hao Zhou, Sidney W. Topiol, Michel Grenon,Hermogenes N. Jimenez, Michelle A. Uberti, Daniel G. Smith,Robbin M. Brodbeck, Gamini Chandrasena, Henrik Pedersen,Jens Christian Madsen, Darío Doller, Guiying Li*

HN

HN

O ONCl

24dKi = 30 nMhCLint =13 L/minmouse B/P = 0.8Efficacious in the mouse marbleburying test at 30 mpk, sc.

HN

O

NO

Cl

N

15fKi = 205 nMhCLint = 1.1 L/minmouse B/P = 0.3hPPB = 93.5%rat brain free fraction = 13%bioavailability in rat = 80%

The design, syntheses and structure–activity relationships (SAR) of novel 1,3-cyclohexyl amide derivatives as mGluR5 negative allosteric modulators are described.

Discovery of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides as potent agonists of TGR5 viasequential combinatorial libraries

pp 1407–1411

Allyn T. Londregan*, David W. Piotrowski, Kentaro Futatsugi, Joseph S. Warmus, Markus Boehm, Philip A. Carpino,Janice E. Chin, Ann M. Janssen, Nicole S. Roush, Joanne Buxton, Terri Hinchey

Phosphonic analogues of glutamic acid as irreversible inhibitors of Staphylococcus aureusendoproteinase GluC: An efficient synthesis and inhibition of the human IgG degradation

pp 1412–1415

Ewa Burchacka, Marcin Skorenski, Marcin Sienczyk, Józef Oleksyszyn*

NH

O

P

OHO

O

OO

HN

ONH

O

O

k2/Ki = 8 540 M-1s-1

Synthesis and antitubercular activity of amino alcohol fused spirochromone conjugates pp 1416–1419

M. Mujahid, R.G. Gonnade, P. Yogeeswari, D. Sriram, M. Muthukrishnan*

R = alkyl, arylB = cyclopentyl, cyclohexyl, N-piperidinyl

21 examples

O

O

O B

OHHN

R


Novel naphthoquinone derivatives: Synthesis and activity against human African trypanosomiasis pp 1420–1423

Bhupesh S. Samant*, Chikomborero Chakaingesu

3H-1,2,4-Dithiazol-3-one compounds as novel potential affordable antitubercular agents pp 1424–1427

Jianzhong Yang, Weiyi Pi, Li Xiong, Wei Ang, Tao Yang, Jun He, Yuanyuan Liu, Ying Chang, Weiwei Ye, Zhenling Wang*,Youfu Luo*, Yuquan Wei

The readily available 3H-1,2,4-dithiazol-3-one molecule compound 4n was shown to be potent against the virulent Mycobacterium tuberculosis H37Rvstrain by a microdilution method, demonstrating a better safety profile on human normal liver L02 cells than the lead compound HT1171, which wasreported as a potent proteasome inhibitor of Mycobacterium bovis var. bacilli Calmette–Guérin (BCG).

Inhibitory effect on NO production of triterpenes from the fruiting bodies of Ganoderma lucidum pp 1428–1432

Nguyen The Tung, To Dao Cuong, Tran Manh Hung, Jeong Hyung Lee,Mi Hee Woo, Jae Sue Choi, Jaewang Kim, Sung Ho Ryu, Byung Sun Min*

HO

O

OO

OAc O

O

O

O

OO

OAc O

O

HO

O

OHO

OAc O

O

O

O

OH

O

O12

34

OH

Four new lanostane triterpenes, butyl lucidenate P (1), butyl lucidenate D2 (2), butyl lucidenate E2 (3) and butyl lucidenate Q (4) along with 11 knowncompounds (5–15) were isolated from the fruiting bodies of Ganoderma lucidum. Their anti-inflammatory activity was evaluated against LPS-induced NOand COX-2 productions in macrophage RAW 264.7 cells.

N-1, C-3 substituted indoles as 5-LOX inhibitors—In vitro enzyme immunoaasay, mass spectral andmolecular docking investigations

pp 1433–1437

Palwinder Singh*, Pooja

N

O

O

N

SO O

CH3

N

O

O

N

O

N

O

O

N

O

N

O

O

NH3CO

N

O

O

N

SO O

CH3

O

H3CO

5a 5b 5c 6a6b

IC50 0.6 μM 1 μM 5 μM 1 μM 1 μM Ka 1.2 × 105 0.99 × 105 0.53 × 105 1.06 × 105 1.96 × 105

A series of highly promising 5-LOX inhibitors was identified.


Characterization of a key aminoglycoside phosphotransferase in gentamicin biosynthesis pp 1438–1441

Lei Shao, Junsheng Chen, Chunxia Wang, Ji-an Li, Yumin Tang, Daijie Chen*, Wen Liu*

NH2

NH2

HOO

OO OH

HO

CH3

NHCH3

O

H2N

H3CNH2

HOHO

NH2

NH2

HOO

OO OH

HO

CH3

NHCH3

O

H2N

H3CNH2

Gentamicin C1a

JI-20A

O

OH

H2N

HOH2N

OH

HOONH2

HO

NH2

NH2

HOO

OO

OH

OHNH2

O

H2N

H2NH2CHO

HO

HOH2C

Kanamycin B

NH2

NH2

HOO

OO OH

HO

CH3

NHCH3

O

H2N

H3CNH2

HOH2O3PO

Paromamine

3'

NH2

NH2

HOO

OO

OH

OHNH2

O

H2N

H2NH2CHO

H2O3PO

HOH2C

Phosphorylated kanamycin B

NH2

NH2

HOO

OO

OH

OHNH2

O

H2N

H2NH2C

HOH2C

DibekacinGntI

5-((1-Aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones as potentialanticancer agents with anti-inflammatory properties

pp 1442–1446

Narsimha Reddy Penthala, Purushothama Rao Ponugoti, Vinod Kasam, Peter A. Crooks*

Compound 3k exhibited the most potent growth inhibition against melanoma MDA-MB-435 cells (GI50 = 850 nM). The structurallyrelated compound 3s had a GI50 value of 1.77 lM against MDA-MB-435 cells. The N-naphthoyl analogue 3t had GI50 values of 1.30 lMagainst HOP-92 non-small cell lung cancer cell lines. The related analogue 3w had GI50 values of 1.09 lM against HOP-92 non-smallcell lung cancer cell lines. Docking of the two active molecules 3k and 3w into the active site of COX-2 indicates that these compoundsare COX-2 ligands with strong hydrophobic and hydrogen bonding interactions.

Synthesis and enzymatic incorporation of a-LL-threofuranosyl adenine triphosphate (tATP) pp 1447–1449

Su Zhang, John C. Chaput*

Pharmacological properties and predicted binding mode of arylmethylene quinuclidine-like derivativesat the a3b4 nicotinic acetylcholine receptor (nAChR)

pp 1450–1455

David C. Kombo*, Terry A. Hauser, Vladimir P. Grinevich, Matthew S. Melvin, Jon-Paul Strachan, Serguei S. Sidach,Joseph Chewning, Nikolai Fedorov, Kartik Tallapragada, Scott R. Breining, Craig H. Miller


A novel class of 3-(phenoxy-phenyl-methyl)-pyrrolidines as potent and balanced norepinephrine andserotonin reuptake inhibitors: Synthesis and structure–activity relationships

pp 1456–1461

Lori Jean Van Orden*, Priscilla M. Van Dyke, D. Roland Saito, Timothy J. Church, Ray Chang, Jacqueline A.M. Smith,William J. Martin, Sarah Jaw-Tsai, Eric L. Stangeland

HN

O

FF

FF

39b

Polyoxometalate–biomolecule conjugates: A new approach to create hybrid drugs for cancertherapeutics

pp 1462–1466

Hai-Kuan Yang, Yi-Xing Cheng, Ming-Ming Su, Yu Xiao, Min-Biao Hu, Wei Wang*, Qian Wang*

Apoptosis-inducing activity of the actin-depolymerizing agent aplyronine A and its side-chainderivatives

pp 1467–1471

Osamu Ohno, Maho Morita, Kazuhiro Kitamura, Toshiaki Teruya, Kozo Yoneda, Masaki Kita, Hideo Kigoshi,Kiyotake Suenaga*

Aplyronine A (1)

Aplyronine A side-chain derivative 6

Phase contrast

Actin filaments

Cell nuclei

1 nM 1 30 μM 6Control

10 μm

Synthesis and biological evaluation of 2-(arylethynyl)quinoline derivatives as mGluR5 antagonists forthe treatment of neuropathic pain

pp 1472–1476

Myung-Hee Son, Ji Young Kim, Eun Jeong Lim, Du-Jong Baek, Kihang Choi, Jae Kyun Lee, Ae Nim Pae, Sun-Joon Min*, YongSeo Cho*

N

XY

R1 = H, OH, MeO, EtO, tBuCO2, Cl, BrX, Y = CH or NR2 = F, Me, CN, CF3, MeO

R1

R2


Cinnamic acid derivatives as inhibitors for chorismatases and isochorismatases pp 1477–1481

Florian Hubrich, Silja Mordhorst, Jennifer N. Andexer*

Synthesis and evaluation of 4,5-dihydro-5-methylisoxazolin-5-carboxamide derivatives as VLA-4antagonists

pp 1482–1485

Ajay Soni*, Abdul Rehman, Keshav Naik, Sunanda Dastidar, M.S. Alam, Abhijit Ray, Tridib Chaira, Vanya Shah,Venkata P. Palle, Ian A. Cliffe, Viswajanani J. Sattigeri

NH

O

O

OH

N

R

O

ON

R 1

NH

O

O

OH

Pyrolidine ring in the N-acylphenylalanine class of VLA-4 antagonists has been successfully replaced by a 4,5-dihydro-5-methylisoxazoline and resulting derivative (14p) found tobe potent in the series and also found to be metabolically stable in vitro.

Development of amino-pyrimidine inhibitors of c-Jun N-terminal kinase (JNK): Kinase profiling guidedoptimization of a 1,2,3-benzotriazole lead

pp 1486–1492

Wylie S. Palmer*, Muzaffar Alam, Humberto B. Arzeno, Kung-Ching Chang,James P. Dunn, David M. Goldstein, Leyi Gong, Bindu Goyal, Johannes C. Hermann,J. Heather Hogg, Gary Hsieh, Alam Jahangir, Cheryl Janson, Sue Jin,R. Ursula Kammlott, Andreas Kuglstatter, Christine Lukacs,Christophe Michoud, Linghao Niu, Deborah C. Reuter, Ada Shao,Tania Silva, Teresa A. Trejo-Martin, Karin Stein, Yun-Chou Tan,Parcharee Tivitmahaisoon, Patricia Tran, Paul Wagner, Paul Weller,Shao-Yong Wu

N NN

N

NHN

NHSO2Me

N

N

NHN

O SO2Me

N O

HO24f

IC50(JNK1/2) = 16/66 nM1

IC50(CDK2) = 300 nM

Structure and kinase profiling guided the optimization of a CDK2 1,2,3-benzotriazole hit to give a series of indoles that are selective and potent dual JNK1 and 2inhibitors. An advanced compound, 24f (IC50 JNK1/2 = 16/66 nM), was developed and suitable for in vivo pharmacological evaluation of JNK inhibition.

Synthesis and biological evaluation of phosphonate analogues of nevirapine pp 1493–1497

Jay Parrish*, Leah Tong, Michael Wang, Xiaowu Chen, Eric B. Lansdon, Carina Cannizzaro, Xubin Zheng, Manoj C. Desai,Lianhong Xu

N

N

N N

O

O

PO

OEtEtO16

EC50 (HIV RT WT) = 3.1 nMEC50 (HIV RT Y181C) = 9 nM

A series of nevirapine-based analogues containing the phosphonate functionality were prepared and evaluated in vitro against HIV RT.


Design and synthesis of D1 agonist/D2 antagonist for treatment of schizophrenia pp 1498–1501

Andrew Giovanni, Joachim Roehr, Shannon Dwyer, Kent Neuenschwander, Anthony Scotese, Neil D. Moorcroft, Larry Davis,Zhongli Gao*

HON

HO

OCF3

H

OCH3

D1 binding ki = 2.0 nM; agonism EC50 = 5.0 nMD2 binding ki = 4.0 nM; antagonism EC50 = 6.0 nM

New imidazo[1,2-a]pyridines carrying active pharmacophores: Synthesis and anticonvulsant studies pp 1502–1506

Shrikanth Ulloora, Ramakrishna Shabaraya, Syed Aamir, Airody Vasudeva Adhikari*

N N

N

NC

O

R F

N NH2

+

N N

N

NNH2

R F

+

N N

NNH

RF

New imidazo[1,2-a]pyridines carrying active pharmacophores were synthesized and screened for their in vivo anticonvulsant activities as well as toxicity studies.Compounds bearing 4-fluorophenyl substituent at 2nd position display enhanced activities. New compounds exhibit their activity at a small test dose of 10 mg/kg.

Synthesis of 2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes via LiAlH4-induced reductivecyclization of 2-(4-chloro-2-cyano-2-phenylbutyl)aziridines and evaluation of their antimalarial activity

pp 1507–1510

Matthias D’hooghe*, Karel Vervisch, Karl W. Törnroos, Tom Verhaeghe, Tom Desmet, Carmen Lategan, Peter J. Smith,Kelly Chibale, Norbert De Kimpe*

LiAlH4

THFN

NH

CN

Cl

N

R

CN

Cl

N

R

LiAlH4

THFN

NH R R

Bifunctional inhibition of HIV-1 reverse transcriptase: A first step in designing a bifunctionaltriphosphate

pp 1511–1518

Dongyuan Piao, Aravind Basavapathruni, Pinar Iyidogan, Guangxiu Dai, Wolfgang Hinz, Adrian S. Ray, Eisuke Murakami,Joy Y. Feng, Fei You, Ginger E. Dutschman, David J. Austin, Kathlyn A. Parker, Karen S. Anderson*


Synthesis and biological evaluation of 5-nitropyrimidine analogs with azabicyclic substituents asGPR119 agonists

pp 1519–1521

Zunhua Yang, Yuanying Fang, Tuan-Anh N. Pham, Jongkook Lee, Haeil Park*

NN

NO2

X

NH

R

H3CO2S

(R=H,F; X=O,N ; n=0,1)

Nn O

O

NX

NN

NO2

NH O

O

H3CO2S

F

8 X = N, EC50 = 1.5 nM, 99%max12 X = O, EC5 0= 1.5 nM, 116%max

The interaction of imidazole-, imidazolium-, and tetrazolium-containing compounds with DNA pp 1522–1528

Ian E. Crandall*, Bohang Zhao, Jason Z. Vlahakis, Walter A. Szarek*

2INNN N CH2n

B

2HClNNN N CH2n

A

N

NN

N

R2

R1

N

NN

N

R2

R1

R3 R3C

2Cl

Series of bivalent imidazole (A), imidazolium (B), and tetrazolium (C) compounds, as well as of monovalent imidazolium and tetrazolium compounds, were examined using thedisplacement of SYBR Green I as a measure of competitive binding to DNA.

Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structureguided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymaticactivity

pp 1529–1536

Leslie W. Tari*, Michael Trzoss, Daniel C. Bensen, Xiaoming Li, Zhiyong Chen, Thanh Lam, Junhu Zhang, ChristopherJ. Creighton, Mark L. Cunningham, Bryan Kwan, Mark Stidham, Karen J. Shaw, Felice C. Lightstone, Sergio E. Wong, ToanB. Nguyen, Jay Nix, John Finn

Ki nM

E. faecalis BryG

F. tularensis GyrB

E. faecalis ParE

F. tularensis EraP

E. coliParE

< 1 < 1 2 < 1 < 1

Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE), Part II: Developmentof inhibitors with broad spectrum, Gram-negative antibacterial activity

pp 1537–1543

Micheal Trzoss, Daniel C. Bensen, Xiaoming Li, Zhiyong Chen, Thanh Lam, Junhu Zhang, Christopher J. Creighton,Mark L. Cunningham, Bryan Kwan, Mark Stidham, Kirk Nelson, Vickie Brown-Driver, Amanda Castellano, Karen J. Shaw,Felice C. Lightstone, Sergio E. Wong, Toan B. Nguyen, John Finn, Leslie W. Tari*

N

N

O

NHCl N

N

H2NH

H N

MIC μg/mL

S. aureus S. pneumoniae E. coli A. baumannii P. aeruginosa

0.06 0.06 4 4 8


Structural analogs of huperzine A improve survival in guinea pigs exposed to soman pp 1544–1547

Hendra Gunosewoyo, Suresh K. Tipparaju, Marco Pieroni, Ying Wang, Bhupendra P. Doctor, Madhusoodana P. Nambiar,Alan P. Kozikowski*

Hybrids consisting of the pharmacophores of salmeterol and roflumilast or phthalazinone:Dual b2-adrenoceptor agonists-PDE4 inhibitors for the treatment of COPD

pp 1548–1552

Anqiu Liu, Ling Huang, Zhiren Wang, Zonghua Luo, Fei Mao, Wenjun Shan, Jiaxing Xie, Kefang Lai*, Xingshu Li*

HO

HO

HN

OH

On-1O

O

HN N

Cl

Cl

11a-d: n = 3, 4, 5, 6 17a-d, n = 3, 4, 5, 6

HO

HO

OH HN

NN

O

OO

n-1

A novel class of dual pharmacology bronchodilators targeting both b2-adrenoceptor and PDE4 was designed and synthesised by combining the pharmacophores ofsalmeterol and roflumilast or phthalazinone. All the compounds exhibited better b2-adrenoceptor agonist activities (pEC50 = 8.47–9.20) than the referencecompound salmeterol (pEC50 = 8.3) and good inhibitory activities on PDE4B2 (IC50 = 0.235–1.093 lM).

Amides of 4-hydroxy-8-methanesulfonylamino-quinoline-2-carboxylic acid as zinc-dependentinhibitors of Lp-PLA2

pp 1553–1556

Yi Hu, Emme C.K. Lin, Lan M. Pham, Julia Cajica, Christopher M. Amantea, Eric Okerberg, Heidi E. Brown, Allister Fraser,Lingling Du, Yasushi Kohno, Junichi Ishiyama, John W. Kozarich, Kevin R. Shreder*

Synthesis and SAR of 99mTc/Re-labeled small molecule prostate specific membrane antigen inhibitorswith novel polar chelates

pp 1557–1563

Genliang Lu, Kevin P. Maresca, Shawn M. Hillier, Craig N. Zimmerman, William C. Eckelman, John L. Joyal, John W. Babich*

O

OHNH

O

NH

OHO

O

HO

HN linker chelate

O

OHNH

O

NH

OHO

O

HO

linker chelateON

N

N

N

N

HO O

HO O

N

N

N

N

N

N O

N O

OH

O

OHO

OHO

O

OH

Re(CO)3Re(CO)3

chelate:

or


*Corresponding authorSupplementary data available via SciVerse ScienceDirect

COVER

An unusual non-nucleoside inhibitor bound to HIV-1 reverse transcriptase. The inhibitor is dimeric in an NNRTI-linker-NNRTI motif. It iscomputed to extend beyond the NNRTI binding site into the entrance channel. A precedent is set for other constructs that could effectivelyincorporate two drugs in one compound [Ekkati, A. R.; Bollini, M.; Domaoal, R. A.; Spasov, K. A.; Anderson, K. A.; Jorgensen, W. L. Discovery ofdimeric inhibitors by extension into the entrance channel of HIV-1 reverse transcriptase. Bioorg. Med. Chem. Lett. 2012, 22, 1565–1568].

Available online at www.sciencedirect.com

Indexed/Abstracted in: Beilstein, Biochemistry & Biophysics Citation Index, CANCERLIT, Chemical Abstracts, ChemistryCitation Index, Current Awareness in Biological Sciences/BIOBASE, Current Contents: Life Sciences, EMBASE/Excerpta Medica,MEDLINE, PASCAL, Research Alert, Science Citation Index, SciSearch, TOXFILE. Also covered in the abstract and citationdatabase SciVerse Scopus�. Full text available on SciVerse ScienceDirect�

ISSN 0960-894X


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