Bioorganic & Medicinal Chemistry Letters Volume 23, Issue 10, 2013

Contents

BMCL DIGESTS

Recent advances in malaria drug discovery pp 2829–2843

Marco A. Biamonte*, Jutta Wanner, Karine G. Le Roch

NN

N

NH

OH2N

F

F

GNF156 (Phase I)Imidazolopiperazines are activeagainst the liver stageof the murine P. yoelii.

Learning from our mistakes : The ‘unknown knowns’ in fragment screening pp 2844–2852

Ben J. Davis*, Daniel A. Erlanson*

REGULAR ARTICLES

A small molecule inhibitor of fungal histone acetyltrans ferase Rtt109 pp 2853–2859

Jessica Lopes da Rosa, Vineeta Bajaj, James Spoonamore, Paul D. Kaufm an*

-1 0 1 2 3 4 50

25

50

75

100

125

Log10 [compound] (nM)

% a

ctiv

ity

p300Gcn5

Rtt109

The histone acetyltransferase R1109 is required for pathogenesis in several clinically important fungal species. Via a high throughput chemical screen of >300,000 compounds, we discovered achemical inhibitor of R1109 that does not inhibit other acetyltransferase enzymes such as the yeast Gcn5 or human p300 enzymes.

Bioorganic & Medicinal Chemistry Letters 23 (2013) 2815–2828

Contents lists available at SciVerse ScienceDi rect

Bioorganic & Medicinal Chemi stry Letters

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

Kappa-op ioid receptor-s elective dicarboxyl ic ester-derive d salvinori n A ligands pp 2860–2862

Prabhakar R. Polepally , Kate White, Eyal Vardy, Bryan L. Roth, Daneel Ferreira, Jordan K. Zjawion y*

O

O

O

O

O

OMeO

H H

Salvinorin A (1)

O

O

O

O

O

OMeO

H H

nRO

OO

Dicarboxylic ester-derived salvinorin Aanalogues (4-16)

O

n = 1, 2, 3, 4, -CH = CH-etc.R = H, Me, Et, t-butyl

Salvia divinorum

Potency switch between CHK1 and MK2: Discover y of imidazo[1,2- a]pyrazi ne- and imidazo [1,2- c]pyrimidine-b ased kinase inhibitors

pp 2863–2867

Zhaoyan g Meng*, Jeffrey P. Ciavarri, Andre w McRiner, Yinyan Zhao, Lianyun Zhao, Pandurang a Adulla Reddy,Xingmin Zhang, Thierry O. Fischma nn, Charles Whitehurst , M. Arshad Siddiqui

NN

NNH

OH2N

HN

1CHK1 IC50 = 0.039 uM

MK2 IC50 = 0.65 uM

Cl NN

NNH

OH2N

H2N

8eCHK1 IC50 = 1.08 uMMK2 IC50 = 0.060 uM

Cl

16bCHK1 IC50 = 50.0 uM

MK2 IC50 = 4.0 uM

N N

N

NH

OH2N

H2N

ClN N

NNH

OH2N

HN

22aCHK1 IC50 = 0.018 uM

MK2 IC50 = 0.84 uM

Cl

Analysis of the molecula r interactio ns of the potent analgesic S1RA with the r1 receptor pp 2868–2871

Erik Laurini, Valentina Da Col, Bernhard Wünsch, Sabrina Pricl*

Design consideration s for PAMAM dendrim er therapeut ics pp 2872–2875

Sascha N. Goonewa rdena*, Jeremy D. Kratz, Hong Zong, Ankur M. Desai, Shengzhuan g Tang, Sarah Emery, James R. Baker Jr.,Baohua Huang*

2816 Contents / Bioorg. Med. Chem. Lett. 23 (2013) 2815–2828

Synthesis and antitum or activity of 1,3,4-oxadiaz ole possess ing 1,4-benzod ioxan moiety as a novel class of potent methioni ne aminopept idase type II inhibitors

pp 2876–2879

Juan Sun, Ming-Hui Li, Shao-Song Qian, Feng-Jiao Guo, Xiao-Fan g Dang, Xiao-Ming Wang*,Ya-Rong Xue*, Hai-Liang Zhu*

Compound 7a showed the most potent biological activity again st Human Umbilical Vein Endothelial cells. The results of apoptosis and flow cytometry (FCM) demonstrated that compound 7a induce cell apoptosis by the inhibition of MetAP2 pathway.

Novel racemic tetrahydroc urcumino id dihydropyr imidinone analogues as potent acetylcho linesterase inhibitor s

pp 2880–2882

Sarawalee Arunkha mkaew, Anan Athipor nchai, Nuttapon Apiratikul, Apichart Suksamrarn , Vachiraporn Ajavako m*

N

N

O

HO

HO

OH

H

OCH3

IC50 = 1.34 ± 0.03 Mμ

Synthesis and antimicr obial activity of novel amphiphili c aromatic amino alcohols pp 2883–2887

Angelina M. de Almeida, Thiago Nasciment o, Bianca S. Ferreir a, Pedro P. de Castro, Vânia L. Silva, Claúdio G. Diniz,Mireille Le Hyaric*

Discovery of a new HIV-1 inhibitor scaffold and synthesis of potential prodrug s of indazoles pp 2888–2892

Se-Ho Kim*, Benjamin Markovit z, Richard Trovato, Brett R. Murphy, Harry Austin, Adam J. Willardsen, Vijay Baichwal,Scott Morham, Ashok Bajji

NNH

HN

O

NN

N

HN

O

N

Cl

O

O CO2HX2

X3

X1

4d: X1 = H, X2 = H, X3 = Cl

4k: X1 = H, X2 = OMe, X3 = OMe

Aqueous solubility: 60μM (at pH 7.4)Aqueous solubility: 0.2 μM (at pH 7.4)

EC50 = 0.42 μM, TI = 50, MT4 cells

11b

prodrugdesign

Contents / Bioorg. Med. Chem. Lett. 23 (2013) 2815–2828 2817

27-Nor-D4-dafachron ic acid is a synthetic ligand of Caenorha bditis elegans DAF-12 receptor pp 2893–2896

Gisela A. Samaja, Olga Castro, Lautaro D. Alvarez, María V. Dansey, Daiana S. Escudero , Adriana S. Veleiro, Adalí Pecci,Gerardo Burton*

Triazole derivatives: A series of Darapladi b analogues as orally active Lp-PLA 2 inhibito rs pp 2897–2901

Kai Wang, Wenwei Xu, Wei Zhang, Mingguang Mo, Yiping Wang*, Jianhua Shen*

NN

NN

N

O

S

F

CF3

R

NNEt 2

2c

rhPLA 2 IC 50R

0.91

NN2f 0.67

NNEt 2

4a 0.24

Relative serum Lp-PLA 2 Activition in C57 mice after a single dose (50mg/kg, po, n = 5).

Synthesis and biologica l evalua tion of Germaniu m(IV)–polyphenol complexe s as potentia l anti-cancer agents pp 2902–2908

Jiang Pi, Jing Zeng, Jian-Jun Luo, Pei-Hui Yang*, Ji-Ye Cai

Thermal stability of oligodeoxy nucleotide duplexes contai ning LL-deoxynu cleotide at termini pp 2909–2911

Hidehito Urata*, Shuji Ogawa, Shun-ichi Wada

Terminal chiral modifications of oligodeoxynuc leotide duplexes show much less effects on duplex destabiliza tion and to show a similar tenden cy in base pairing selectivity, compared with internal chiral modifications.

2818 Contents / Bioorg. Med. Chem. Lett. 23 (2013) 2815–2828

Conforma tional restriction approach to BACE1 inhibitor s II: SAR study of the isocytosine derivat ives fixed with a cis-cyclopro pane ring

pp 2912–2915

Shuji Yonezaw a*, Hidekun i Yamaka wa, Chie Muto, Motoko Hosono, Takahiko Yamamoto, Kazunari Hattori,Masahiro Sakagami , Hiroko Togame, Yoshikazu Tanaka, Toru Nakano, Hirosh i Takemoto, Mitsuhiro Arisawa, Satoshi Shuto*

N

N

O

NH2

IC50: 6.7μM LE = 0.27

OMe

N

N

O

NH2

N

N

O

NH2

Insertion ofa spacer

R

XAr

Modification ofthe terminal Ar ring

Rhodamin e-based ‘turn-on’ fluorescent probe for Cu(II) and its fluorescence imaging in living cells pp 2916–2919

Mao-Zhon g Tian, Ming-Ming Hu, Jiang-Li Fan*, Xiao-Jun Peng, Jing-Yun Wang,Shi-Guo Sun, Rong Zhang

RO1 exhibited highly sensitive and exclusively selective fluorescence respons e toward Cu 2+ over other metal ions with a detection limit of 0.56 ppb in mixed aqueous solution. The fluorescence was pH-independent in the wide range pH 3.1–11.6. probe RO1 can penetrate the cell membrane and be applied for in vitro imaging of Cu 2+ in living cells.

Discovery of novel orally bioavailab le GPR40 agonists pp 2920–2924

Hejun Lu*, Hongbo Fei, Fanglong Yang, Suxin Zheng, Qiyue Hu, Lei Zhang, Jijun Yuan, Jun Feng, Piaoyang Sun, Qing Dong

R

O

OO

OH

O

hGRP40 EC5028a, R = Br, 13.5nM30a, R = Cl, 34.2nM

Chemothe rapy of leishma niasis. Part XII: Design, synthesis and bioevalu ation of novel triazole integra ted phenyl heterote rpenoids as antileishmani al agents

pp 2925–2928

S.N. Suryaw anshi*, Avinash Tiwari, Santosh Kumar, Rahul Shivahare, Monika Mittal, Padam Kant, Suman Gupta

Contents / Bioorg. Med. Chem. Lett. 23 (2013) 2815–2828 2819

Structure–activity relationshi p of potent antimic robial peptide analogs of Ixosin-B amide pp 2929–2932

Yu-Shan Wu*, Zih-Jie Liao, Kai-Shiuan Wang, Feng-Di T. Lung

Conjuga tion of LL-NAME to prenyloxyci nnamic acids improve s its inhibitory effects on nitric oxide productio n

pp 2933–2935

Salvatore Genovese*, Francesco Epifano, Serena Fiorito, Massimo Curini, Mariange la Marrelli, Francesco Menichi ni,Filomena Confor ti

R1 = H or isopentenyl

R2 = H or OCH3O

R1

R2

O

N

H

COOCH3

N

H

N

N

H

NO2

H

Design and synthesis of 2-N-subs tituted indazolone derivativ es as non-carbox ylic acid glycogen synthas eactivators

pp 2936–2940

Yimin Qian*, David Bolin, Karin Conde-Kn ape, Paul Gillespie, Stuart Hayden, Kuo-Sen Huang, Andrée R. Olivier,Tsutomu Sato, Qing Xiang, Weiya Yun, Xiaolei Zhang

O

F

F

R2HN

O OO

F

F

R2HN

N O

R1

A new synthesi s of 40-resvera trol esters and evaluati on of the potent ial for anti-depres sant activity pp 2941–2944

Mark J. Acerson, Kimberly M. Fabick, Yong Wong, Crystal Blake, Edwin D. Lephart, Merritt B. Andrus*

2820 Contents / Bioorg. Med. Chem. Lett. 23 (2013) 2815–2828

Cytotoxic azaphilone alkaloi ds from Chaetomium globosum TY1 pp 2945–2947

Xiang Li, Ye Tian, Sheng-x iang Yang, Ya-mei Zhang, Jian-chun Qin*

N

CH3

CH3O

Cl

OH3C

O OH3C

H3C

OH

NCH3

CH3O

Cl

OH3C

O OH3C

H3C

OH

OH

N

CH3

CH3O

Cl

OH3C

O OH3C

H3COHO

1 2 3

Conforma tionally restricted homotry ptamines. Part 6: Indole- 5-cycloalk yl methylamines as selective serotonin reuptake inhibito rs

pp 2948–2950

Jonathan L. Ditta*, Derek J. Denhart , Jeffrey A. Deskus, James R. Epperso n, Zhaoxing Meng, Qi Gao, Gail K. Mattson,Mellissa A. LaPaglia, Matthew T. Taber, Thaddeu s F. Molski, Nicholas J. Lodge, Ronald J. Mattson , John E. Macor

NH

NCN

11hSERT IC50 = 6.0 nM

NH

CN

N23ahSERT IC50 = 3.8 nM

NH

CN

N25ahSERTIC50 = 18 nM

Novel ROS-activa ted agents utilize a tethered amine to selectiv ely target acute myeloid leukemia pp 2951–2954

Tiffany R. Bell-Horwa th, Anish K. Vaduko ot, Fathima Shazna Thowfeik, Guorui Li, Mark Wunderlich, James C. Mulloy,Edward J. Merino*

Novel quinoline derivativ es as inhibito rs of bacterial DNA gyrase and topoisom erase IV pp 2955–2961

Mark J. Mitton-Fry *, Steven J. Brickner, Judith C. Hamel, Lori Brennan,Jeffrey M. Casavant, Michael Chen, Tao Chen, Xiaoyu an Ding, James Driscoll,Joel Hardink, Thuy Hoang, Erbing Hua, Michael D. Huband , Meghan Maloney,Anthony Marfat, Sandra P. McCurdy, Dale McLeod, Michae l Plotkin, Usa Reilly,Shaughn Robinson, John Schafer, Richard M. Shepard, James F. Smith,Gregory G. Stone, Chakrapani Subrama nyam, Kwansik Yoon,Wei Yuan, Richard P. Zaniewski, Christo pher Zook

N

HO

N

O

HO

O

F

FS. aureus DNA gyrase IC50 = 3.0 μMS. aureus TopoIV IC50 = 9.6 μMS. aureus MIC90 = 0.25 μg/mL

12

Contents / Bioorg. Med. Chem. Lett. 23 (2013) 2815–2828 2821

Novel VEGFR-2 kinase inhibitors identified by the back-to-fr ont approach pp 2962–2967

Kingkan Sanphanya, Suvara K. Wattanapit ayakul, Suwadee Phowichit , Valery V. Fokin, Opa Vajragup ta*

C919

E885

D1046

VH02 bound to KDR kinase domain IC50 (KDR) 0.56 μM

IC50 (EA.hy926) 4 μM

Identification of new peptide amides as selectiv e cathepsin L inhibitors: The first step towards selectiv eirreversi ble inhibit ors?

pp 2968–2973

Ana Torkar, Brigita Lenarc ˇic ˇ, Tamara Lah, Vincent Dive, Laurent Devel*

Synthesis, cytotoxi city and topoisom erase II inhibito ry activity of lomefloxacin derivat ives pp 2974–2978

You Zhou, Xiaoli Xu, Yuan Sun, Huaping Wang, Haopeng Sun*, Qidon g You*

O

NN

O

O

OH

A B CD

E

Break

X

N

R2

N YR1 Z

R3

FO

N

X

R2

N Y

O

R1

F

R3

Z

N

O

O2N

N

OF

NFBreak NH

5

N

OF

NF NH

NH

OAr

A facile chemo-, regio- and stereosel ective synthesis and choline sterase inhibitory activity of spirooxind ole–pyrrolizine–piperidine hybrids

pp 2979–2983

Yalda Kia, Hasnah Osman*, Raju Suresh Kumar*, Viknesw aran Muruga iyah, Alireza Basiri, Subbu Perumal,Ibrahim Abdul Razak

N

Ar

O

Ar O

NH

O

O NH

N

Ar

O

N

O

HN

O

HH

MeOH

Ar

Cl

Cl

COOH+

Reflux, 5 h

+

2822 Contents / Bioorg. Med. Chem. Lett. 23 (2013) 2815–2828

Design, synthesis and evaluatio n of some new 4-aminopyr idine derivatives in learning and memory pp 2984–2989

Saurabh K. Sinha, Sushant K. Shrivasta va*

Some new anili des and imide s were synth esized using 4-am inopy r- idine (4AP), succ inic and maleic anhy dride which were furth er eval uated for thei r antia mnes ic, cog niti on enha ncing and antic -holi nest erase prope rties. Amo ng the comp ounds tested , imide deri vativ e of 4AP and male ic anhy dride exhib ited highe r potenc ythan sta ndard drug donep ezil and also show ed an affinity to prop erly bind with the key per iphera l anioni c site resi dues Trp-2 86. Tyr-1 24 and Tyr-3 41 of AChE in dock ing stud y.Doc king model of most active comp ound 4APMb at the activ e site s of AChE. The hydro gen bonds are dis played as dashe d yell ow.Ef fect of synth esized deri vative s and donep ezil (5 and 10 mg/k g) on accty lcho linest eras e (AchE) acti vity on diffe rent reg ion of rat brain [A] prefr ontal cort ex [B] hippoc ampus [C] hypo thala mus. Res ults are expr essed as mean ± SEM (n = 6).

Identification of novel SIRT3 inhibito r scaffolds by virtual screening pp 2990–2995

Heikki S. Salo, Tuomo Laitinen, Antti Poso, Elina Jarho*, Maija Lahtela-Ka kkonen*

O

N

N

SNH

OHON

O

HN

O

Cl

Cl

39% SIRT3 inhibitionat 200µM

71% SIRT3 inhibitionat 200µM

Discovery of ML326: The first sub-micromo lar, selectiv e M5 PAM pp 2996–3000

Patrick R. Gentry, Thomas M. Bridges, Atin Lamsal, Paige N. Vinson, Emery Smith, Peter Chase, Peter S. Hodder,Julie L. Engers, Colleen M. Niswender, J. Scott Daniels, P. Jeffrey Conn, Michae l R. Wood, Craig W. Lindsley*

NO

O

O

F3CO

N

F3COO

O

O

ML129hM5 EC50 = 1.1 µM (91% AChmax)

hM5 ACh fold shif t (@30 µM) = 14-foldhM1 - hM4 EC50 > 30 µM

isatin replacements

modificationsN

F3COO

O

O

isatinessential

iterativeparallel

synthesis

ML326hM5 EC50 = 409 nM (91% AChmax)

hM5 ACh fold shif t (@30 µM) = 20-foldhM1 - hM4 EC50 > 30 µM

4-Azolylphe nyl isoxazol ine insecticid es acting at the GABA gated chloride channel pp 3001–3006

George P. Lahm*, Daniel Cordova, James D. Barry, Thomas F. Pahutski, Ben K. Smith, Jeffrey K. Long, Eric A. Benner,Caleb W. Holyoke, Kathleen Joraski, Ming Xu, Mark E. Schroeder, Ty Wagerle, Michael J. Mahaffey, Rejane M. Smith,My-Hahn Tong

NOF3CBr

BrN

CN N

N

Contents / Bioorg. Med. Chem. Lett. 23 (2013) 2815–2828 2823

Flaxseed (Linum usitatissim um L.) extract as well as (+)-secoisolariciresinol diglucos ide and its mamma lian derivatives are potent inhibitors of a-amylase activity

pp 3007–3012

Christophe Hano*, Sullivan Renouard , Roland Molinié, Cyrielle Corbin, Esmatullah Barakzoy, Joël Doussot, Frédéric Lamblin,Eric Lainé

Synthesis and evaluati on of 2,3-dinorp rostaglandi ns: Dinor-PGD 1 and 13- epi-dinor-PG D1 are peroxisome proliferat or-activate d receptor a/c dual agonists

pp 3013–3017

Ayato Sato, Kosuke Dodo, Makoto Makish ima, Yuichi Hashimot o, Mikiko Sodeoka*

PGD1 dinor-PGD1

PPARγγ agonist PPARα/γ agonistSelectivity switch

O

HO

OH

COOH

O

HOCOOH

OH

We synthesized 2,3-dinorprostagla ndins, dinor-PGD 1, 13- epi-dinor-PGD 1, and 13-deoxy- D10,12-dinor-PGJ1, and examined their effects on the activity of peroxisome proliferator-activated receptors (PPARs). Dinor-PGD 1 and 13- epi-dinor-PGD1 were dual agonists for PPAR a/c, in contrast to the highly PPAR c-selective prostaglandins derived from arachidonic acid.

Structure–activity relationshi p of cytochro me bc1 reductase inhibitor broad spectrum antifungal ilicicolin H

pp 3018–3022

Sheo B. Singh*, Weigu o Liu, Xiaohua Li, Tom Chen, Ali Shafiee, Sarah Dreikorn, Viktor Hornak, Maria Meinz, Janet C. Onishi

O

CH3

CH3

CH3

OH

NH

O

HOH

H

-CH2OCOCH3-CH2OCOCH(CH2)2

N

HN

OO

CH3

CH3

CH3

OH

NH

O

HOH

H

Ilicicolin HBroad-spectrum AFstrong serum bindingpoor in vivo activity

58 analogs withmodifications red sites

Semisynthesis improved activityserum binding

improved activityserum binding

Chemicalbiotransformation

Ostreol A: A new cytotoxic compou nd isolated from the epiphytic dinoflagellate Ostreops is cf. ovata from the coastal waters of Jeju Island, Korea

pp 3023–3027

Buyng Su Hwang, Eun Young Yoon, Hyung Seop Kim, Wonho Yih, Jae Yeon Park, Hae Jin Jeong*, Jung-Rae Rho*

O

O

OH

OH

OH

OH

OHOH

OH

OH

OHHO

OHOHOH

NH

O

OH

OH

OH

OHOHOHOHH2N

HH

H

H

2824 Contents / Bioorg. Med. Chem. Lett. 23 (2013) 2815–2828

Synthesis and evaluati on of carbamoyl methylen e linked prodrug s of BMS-582949, a clinical p38 a inhibitor pp 3028–3033

Chunjian Liu*, James Lin, Gerry Everlo f, Christoph Gesenbe rg, Hongjian Zhang, Punit H. Marath e, Mary Malley,Michael A. Galella, Murray Mckinno n, John H. Dodd, Joel C. Barrish, Gary L. Schieven, Katerina Leftheris

NN

N

HNOO

NPrn

HN

OO

O

O

2 , a prodrug of 1

CO2H

N N

N

HNOO

NHPrn

HN

1, a clinical p38 inhibitor

Synthesis and structure–activity relatio nships of 2-amino- 3-carboxy-4 -phenylthio phenes as novel atypical protein kinase C inhibito rs

pp 3034–3038

Paul M. Titchenel l, H.D. Hollis Showalter , Jean-François Pons, Alistair J. Barber, Yafei Jin, David A. Antonetti*

S

OMeMeO

NH2

6:OO

MeMe IC50 = 6 uM (PKCζ)

EC50 = 3 nM (TNF-induced NFκB activation)EC50 = 1 nM (TNF/VEGF-induced endothelial

permeability)

Discovery of a small-m olecule inhibitor and cellular probe of Keap1–Nrf2 protein–protein interaction pp 3039–3043

Longqin Hu*, Sadagopan Magesh, Lin Chen, Lili Wang, Timothy A. Lewis, Yu Chen, Carol Khodier, Daigo Inoyama,Lesa J. Beamer, Thomas J. Emge, Jian Shen, John E. Kerrigan , Ah-Ng Tony Kong, Sivaraman Dandapan i, Michelle Palmer,Stuart L. Schreiber, Benito Munoz

Structure- based design of HSPA5 inhibitors: From peptide to small molecule inhibitors pp 3044–3050

Meilan Huang*, Zhuo Li, Dawei Li, Steven Walker,Caroline Greenan , Richard Kennedy

By combined in silico screening and cancer viability and tumor cell inhibition assays, we identified a small-molecule compound HM03 with promising inhibitive activity and comparable binding mode with the tetra-peptid e YZLP that was derived from a Dnak peptide inhibitor.

Contents / Bioorg. Med. Chem. Lett. 23 (2013) 2815–2828 2825

The design and synthesi s of a potent glucagon receptor antago nist with favorable physicochem ical and pharma cokinetic propertie s as a candidate for the treatmen t of type 2 diabetes mellitus

pp 3051–3058

Angel Guzman -Perez*, Jeffrey A. Pfefferkor n, Esther C.Y. Lee, Benjamin D. Stevens, Gary E. Aspnes, Jianwei Bian,Mary T. Didiuk, Kevin J. Filipski, Dianna Moore, Christian Perreault , Matthew F. Sammons , Meihua Tu, Janice Brown,Karen Atkinson, John Litchfield, Beijing Tan, Brian Samas, William J. Zavados ki, Christopher T. Salatto, Judith Treadw ay

O

NN

CF3

O

NH

17logD = 2.5

OH

O

Discovery and synthesi s of novel 4-aminopyr rolopyrimi dine Tie-2 kinase inhibitor s for the treatmen t of solid tumors

pp 3059–3063

Joel T. Arcari, Jean S. Beebe, Martin A. Berliner, Vincent Bernard o, Merin Boehm, Gary V. Borzillo, Tracey Clark,Bruce D. Cohen, Richard D. Connell, Heather N. Frost, Deborah A. Gordon, William M. Hungerford , Shefali M. Kakar,Aaron Kanter, Nandell F. Keene, Elizabeth A. Knauth, Susan D. LaGreca , Yong Lu, Louis Martinez-A lsina, Matthew A. Marx,Joel Morris, Nandini C. Patel*, Doug Savage, Cathy I. Soders trom, Carl Thompson, George Tkalcevic, Norma J. Tom, Felix F. Vajdos, James J. Valentine, Patrick W. Vincent, Matthew D. Wessel, Jinshan M. Chen*

N

N N

O

HNNH

OCl

NH 2

15

The synthesis and biolog ical evaluation of novel Tie-2 kinase inhibitors are prese nted. Based on the pyrrolopyrimidine chemotyp e,several new series are described, including the benzimidazole series by linking a benzimidazole to the C5-posit ion of the 4-amino- pyrrolopyrimidine core and the ketophenyl series synthesized by incorporating a ketophenyl group to the C5-position. Medicinal chemistry efforts led to potent Tie-2 inhibitors. Compound 15, a ketophenyl pyrrolopyrimidine urea analog with impro ved physicochemical properties, demonstrated favorable in vitro attributes as well as dose respons ive and robust oral tumor growth inhibition in animal models.

Substituted imidazopyr idazines are potent and select ive inhibitor s of Plasm odium falciparu mcalcium-d ependent protein kinase 1 (PfCDPK1)

pp 3064–3069

Timothy M. Chapman*, Simon A. Osborne, Nathalie Bouloc, Jonathan M. Large, Claire Wallace, Kristian Birchall,Keith H. Ansell, Hayley M. Jones, Debra Taylor, Barbara Clough, Judith L. Green, Anthony A. Holder

N N

N

NH

N

N

NH

PfCDPK1 enzyme IC50 = 13 nMP. falciparum anti-parasite EC50 = 400 nM46% reduction in parasitaemia in vivo

17

Arylsulf onamide pyrimidines as VLA-4 antagonists pp 3070–3074

Ying-zi Xu*, Andrei W. Konradi, Frederiqu e Bard, Michael Dappen, Lilibeth Dofiles, Mark Dreyer, Ian Gallager,Caroline Garrido , Mike Krimm, Zhenmei Liao, Elizabeth Messersmi th, Linda Mutter, Michael A. Pleiss, Bhushan Samant,Christopher M. Semko, Jennifer Smith, Frank Stappen beck, Brian Stupi, Chris Vandervert, Brent Welch, Brian Wipke,Ted Yednock

NH

OHN

S

O

O

O N

OS OO

NN

1

NH

OH

O

O N

ONN

N

NS

O

OF

11p

FN Cell Adhesion IC50 = 2 nM FN Cell Adhesion IC50 = 2 nMF% = 56

2826 Contents / Bioorg. Med. Chem. Lett. 23 (2013) 2815–2828

Design and synthesis of thiophene dihydroisoq uinolines as novel BACE1 inhibitor s pp 3075–3080

Ying-zi Xu*, Shendong Yuan, Simeon Bowers, Roy K. Hom, Wayman Chan, Hing L. Sham, Yong L. Zhu, Paul Beroza, Hu Pan,Eric Brecht, Nanhua Yao, Julie Lougheed , Jiangli Yan, Danny Tam, Zhao Ren, Lany Ruslim, Michael P. Bova, Dean R. Artis

N

HNOH

O

S

N

HN

Cl

8Alpha assay IC50 = 0.008 uMFP BACE IC50 = 0.4 uMFP CatD IC50 > 30 uM

N

HNOH

O

1Alpha assay IC50 = 27.1 uMFP BACE IC50 > 1000 uM

SAR and evalua tion of novel 5H-benzo[c][1,8]naph thyridin-6-one analogs as Aurora kinase inhibito rs pp 3081–3087

Srinivasa Karra*, Yufang Xiao, Xiaoling Chen, Lesley Liu-Bujalsk i, Bayard Huck, Amanda Sutton, Andreas Goutopoul os,Ben Askew, Kristopher Josephson, Xuliang Jiang, Adam Shutes , Vikram Shankar, Tom Noonan , Gaianne Garcia-Berrio s,Rong Dong, Mohanr aj Dhanab al, Hui Tian, Zhenxio ng Wang, A. Clark, Samantha Goodstal

N NH

OA B

C

1The structure-based design, synthesis, and SAR of a novel series of Aurora kinase inhibito rs based on the 5H-benzo[c][1,8 ]naphthyridin-6-one scaffold 1 are described.

Voulkens in C–E, new 11-oxo cassane-typ e diterpenoi ds and a steroid glycoside from Caesalpi nia volkensii stem bark and their antiplasmo dial activiti es

pp 3088–3095

Charles O. Ochieng *, Lawrenc e A.O. Manguro , Philip O. Owuor, Hosea Akala

H

H

H

H

H

O

O

OOHO

H

HO

HOH

HO

HO

H

OH

H

H

H

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OR1

2. R = H/H; R1 = H1. R = H/H R1 =

3. R = CH3/H; R1 = H

Caffeoyl

H

H

H

4

4. IC50 = 4.44 μM and 2.74 μ M

1. IC50 = 11.63 μM and 16.53 μM2. IC50 = 17.26 μM and 22.79 μM

3. IC50 = 18.69 μM and 15.57 μ M

Antiplasmodial activities

D6 W2

Isoniazid: Radical-indu ced oxidation and reducti on chemistry pp 3096–3100

Kimberly A. Rickman , Katy L. Swancutt, Stephen P. Mezyk, James J. Kiddle*

NN

OKatG/H2O2 NH2

NNH

ONH2 O2

NN

ONH2

OO

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The mechanism of action of isoniazid is re-examined under in vitro radical conditions.

Contents / Bioorg. Med. Chem. Lett. 23 (2013) 2815–2828 2827

Synthesis, character ization and anti-tumo r activity of novel thymoquin one analogs against pancreati ccancer

pp 3101–3104

Mujahid Yusufi, Sanjeev Banerjee, Momin Mohammad , Sandhya Khatal, K. Venkateswar a Swamy, Ejazuddin M. Khan,Amro Abouka meel, Fazlul H. Sarkar*, Subhash Padhye*

Discovery of novel Jak2–Stat pathw ay inhibitors with extended residen ce time on target pp 3105–3110

Huiping Guan, Michelle L. Lamb, Bo Peng, Shan Huang, Nancy DeGrace, Jon Read, Syeed Hussain, Jiaquan Wu,Caroline Rivard, Marat Alimzhanov , Geraldine Bebernitz, Kirsten Bell, Minwei Ye, Michael Zinda, Stephanos Ioannidis*

N N

HN

HN

N N

S

N

F

FN

N

NHN

HN

N N

S

N

F

N

F

O O

N

N

X

Y N

F

N

R3Thiazole

HN

NHN

R1

N4 N2 Pyrazole

R2

Quantitat ive protein analysis using 13C7-labeled iodoacetani lide and d5-labeled N-ethylmale imide by nano liquid chromatogr aphy/nano electrospray ionization ion trap mass spectromet ry

pp 3111–3118

Sadamu Kurono, Yuka Kaneko, Satomi Niwayama*

*Correspon ding author Supplem entary data available via SciVerse ScienceDi rect

COVER

An unusual non-nucleo side inhibitor bound to HIV-1 reverse transcript ase. The inhibit or is dimeric in an NNRTI-lin ker-NNRTI motif. It is compute d to extend beyond the NNRTI binding site into the entrance channel. A precedent is set for other constructs that could effective ly incorporate two drugs in one compou nd [Ekkati, A. R.; Bollini, M.; Domaoal, R. A.; Spasov, K. A.; Anderso n, K. A.; Jorgensen, W. L. Discovery of dimeric inhibito rs by extension into the entrance channel of HIV-1 reverse transcript ase. Bioorg. Med. Chem. Lett. 2012, 22, 1565–1568].

Available online at www.sciencedirect.com

2828 Contents / Bioorg. Med. Chem. Lett. 23 (2013) 2815–2828