Pyrazole derivatives as antitumor, anti inflammatory and antibacterial pdf

Pyrazole derivatives play an important role in antitumor agents because of their good inhibitory activity against BRAFV600E, EGFR, telomerase, ROS Receptor Tyrosine Kinase and Aurora-A k

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Mini-Reviews in Medicinal Chemistry, 2013, 13, 1957-1966 1957 Pyrazole Derivatives as Antitumor, Anti-inflammatory and Antibacterial Agents

Jia-Jia Liu1+, Meng-yue Zhao1+, Xin Zhang1, Xin Zhao2* and Hai-Liang Zhu1*

1

State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, P.R China; 2 Nanjing

Institute of Environmental Science, Ministry of Environmental Protection of China, Nanjing 210042, P.R China

Abstract: Within the past years, many researches on the synthesis, structure-activity relationships (SAR), antitumor,

anti-inflammatory and anti-bacterial activities of the pyrazole derivatives have been reported Several pyrazole derivatives possess important pharmacological activities and they have been proved useful materials in drug research Pyrazole derivatives play an important role in antitumor agents because of their good inhibitory activity against BRAFV600E, EGFR,

telomerase, ROS Receptor Tyrosine Kinase and Aurora-A kinase In addition, pyrazole derivatives also show good

anti-inflammatory and anti-bacterial activities In this review, the bioactivities of the pyrazole derivatives mentioned above will be summarized in detail We sincerely hope that increasing knowledge of the SAR and cellular processes underlying

the bioactivity of pyrazole derivatives will be beneficial to the rational design of new generation of small molecule drugs

Keywords: Pyrazole derivatives, bioactivity, drug targets

1 INTRODUCTION

Nowadays, pyrazole and its derivatives have been widely

used in the fields of medicinal chemistry because of their

biological activities In particular, they have been reported

for a large range of pharmacological activities including

antiulcer, leishmanicidal, cancer, antimalarial,

anti-microbial, and cytotoxicity [1-7]

Researchers have already chosen many kinds of targets to

test the activity of pyrazole derivatives Cox has disclosed a

series of 4,5-dihydropyrazole derivatives as potent inhibitors

of KSP (Kinesin spindle protein) to treat human cancer with

good potency, pharmacokinetics and water solubility [8]

Some pyrazole derivatives have also been researched to be

potent inhibitors of EGFR and/or HER-2 with sound IC50

values [9] A series of

4-(pyridin-4-yl)-(3-methoxy-5-methylphenyl)-1H-pyrazoles has also been proved potent

against ROS Receptor Tyrosine Kinase[10] All of these

researches will be explained later in detail

Several pyrazole compounds have been considered to be

potential therapeutic agents for the treatment of

inflammation [11-12].Theyinclude the well-known selective

COX-2 drug, which has been proved well tolerated with

reduced gastrointestinal side effects [13]

What is more, many pyrazole derivatives are believed to

possess a wide range of antibacterial bioactivities [14-17]

Much attention has been paid to pyrazole and its derivatives

as potential antimicrobial agents after the discovery of the

*Address correspondence to these authors at the State Key Laboratory of

Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, P.R

China; E-mail: zhuhl@nju.edu.cn; and Nanjing Institute of Environmental

Science, Ministry of Environmental Protection of China, Nanjing 210042,

P.R China; E-mail: zhaoxin_8125@163.com

+

Both authors contributed equally to the work

natural pyrazole C-glycoside pyrazofurin which has shown a broad spectrum of antimicrobial activity [18]

In this review, the antitumor, inflammatory and anti-bacterial activity of the pyrazole derivatives mentioned above will be introduced in detail We sincerely hope that increasing knowledge of the SAR and cellular processes underlying the bioactivity of pyrazole derivatives will be useful for the rational design of new generation of small molecule drugs

2 PYRAZOLE DERIVATIVES AS ANTITUMOR AGENTS

2.1 BRAF V600E Inhibitory Activity

The serine threonine kinase BRAF is a member of the RAF kinase family, which is part of the RAF/MEK/ERK serine threonine kinase cascade This kinase cascade, also called the ERK/MAP kinase pathway is beneficial to regulate cell growth, survival and differentiation [19], and can be hyper-activated in approximately 30% of human cancers by many receptors [20], such as BRAF, the small G-proteins of the RAS family, receptor tyrosine kinases and so

on Approximately 90% of activating BRAF mutations in cancer lines are glutamic acids to valine substitution at position 600 [21-25] (V600E; formally identified as V599E)

In cancer cells, BRAFV600E has been found to be 500-fold active than the wild-type protein26 BRAFV600E can contribute

to neoangiogenesis by stimulating vascular endothelial growth factor secretion [27] Overall, these data suggesting BRAFV600E as a therapeutic target [28] has offered many valuable and important opportunities for anticancer drug

research Andrew K has evaluated the SAR of a series of

imidazole inhibitors based on SB-590885 directing at BRAF kinase [29] Many small chemical molecules containing pyrazole skeleton have been considered as potent inhibitors

of BRAFV600E [30]

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A series of pyrazole derivatives have been synthesized in

our lab For example, Cui-Yun Li has found through the

results of the bioassays against BRAFV600E Several compounds

have shown potent activities with IC50 value in low

micromolar range and among them, compound 27e [31]

(Fig. 1),

(5-(4-Chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)6-methylpyridin-3-yl methanone)

(IC50 = 0.20 μM) bears the best bioactivity, which is

comparable with the positive control Erlotinib (IC50 = 0.06

μM) and vemurafeni (IC50 = 0.03 μM) Encouraged by the

positive results of pyrazole derivatives as BRAFV600E

inhibitors, Qing-Shan Li in the same lab also has sought to

design novel potential BRAFV600E inhibitors as antitumor

agents based on pyrazole skeleton In silico and in vitro

screening of their designed pyrazole derivatives have

identified Hit 1 (Table 1) [32] as good BRAFV600E

inhibitor

Based on the original structure and through further structural

modifications, compound 25 [32] (Fig 2) has exhibited the

most potent inhibitory activity with an IC50 value of 0.16 μM

for BRAFV600E

Yu-Shun Yang [33]in the same lab also has discovered

that Compound C14 (Fig 3) he synthesized showed the most

potent biological activity against BRAFV600E (IC50 = 0.11 μM)

while D10 (Fig 4) performed the best in the D series (IC50 =

1.70 μM)

N

N O

N

OCH3

Cl

Fig (1) Compound 27e

HO

N O

N

OCH3

Cl Cl

Fig (2) Compound 25

A series of

N-(5-amino-1-(4-methoxybenzyl)-1H-pyrazol-4-yl amide derivatives and their antiproliferative

activities against A375P melanoma cell line have been

researched by Mi-hyun Kim [34] Among the compounds, 7c

(Fig. 5) exhibited the most potent and selective BRAFV600E

(IC50 = 0.26 μM) inhibitor

O O

N Br

F

Fig (3) Compound C14

O O

N

F

Fig (4) Compound D10

N

N PMB NH2

N H

O HN

CF3 Cl

Fig (5) Compound 7c

2.2 EGFR Inhibitory Activity

EGFR has been reported to exist on the cell surface and

is activated by binding of its specific ligands, including epidermal growth factor and transforming growth factor (TGF) Activation of EGFR will result in constitutive activation or autocrine expression of ligand [35,36] The role

of EGFR has been most carefully studied in breast cancer, where it is overexpressed in 25–30% of cases and is correlated with poor prognosis EGFR overexpression has also been found in ovarian cancer, lung cancer (especially lung adenocarcinomas) and in hormone-refractory prostate cancer Compounds that have been identified to inhibit the kinase activity of EGFR after binding of its cognate ligand are of potential importance as new therapeutic antitumor

agents [37,38] Peng-Cheng Lv in Zhu’s lab has discovered

that compound 5 (Fig 6) [9] displayed the most potent

EGFR inhibitory activity with IC50 of 0.07 μM, bearing the

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best bioactivity comparable with the positive control

Erlotinib (IC50 = 0.03 μM). Compound 11 (Fig 7) also

displayed the most potent EGFR inhibitory activity with IC50

of 0.06 μM What is more, Compound D14 (Fig 8) created

by Wen Yang and Yu-Shun Yang [37] in the same lab

displayed the most potent activity against EGFR (IC50 = 0.05

μM) Meanwhile, compound C14 (Fig 9) displayed the most

potent activity against HER-2 and MCF-7 cell line (IC50 =

0.88 μM)

N N

H2N

S H3CO

N N S N F

Cl

N N Cl

Cl

Fig (8) Compound D14

N

S

Cl

Fig (9) Compound C14

2.3 Telomerase Inhibitory Activity

Telomerase is a ribonucleoprotein that is an enzyme

which adds DNA sequence repeats ("TTAGGG" in all

vertebrates) to the 3' end of DNA strands in the telomere

regions, which is found at the ends of eukaryotic

chromosomes Telomerase is also a reverse transcriptase that

carries its own RNA molecule, which is used as a template

when it elongates telomeres, which is shortened after each

replication cycle Telomerase remain active in the early

stages of life maintaining telomere length It turns dormant

in most somatic cells during adulthood In cancer cells, however, it has been discovered that telomerase gets reactivated to maintain the length of telomere, leading to their immortality [38] The essential role of telomerase in cancer and aging makes it an important target for the development of therapies to treat many kinds of disorders such as cancer and other age-associated disorders Telomere and telomerase are closely related to the occurrence and

development of human cancer [39] A series of novel

N-phenylacetyl (sulfonyl) 4,5-dihydropyrazole derivatives as potential telomerase inhibitors have been synthesized by

Xin-Hua Liu in Zhu’s lab [40] The bioassay results showed

that compound 4a (Fig 10) can inhibit telomerase with IC50

value of 4.0 μM

Andrew et al [41] revealed the telomerase key active site

with X-ray in 2008, which was three-dimensional structure

of TERT protein catalysis subunit At present, Yin-Luo’s

group has designed and synthesized several kinds of telomerase inhibitors All of these compounds had the

similar skeleton structure 2H-pyrazole Telomerase

inhibition and anti-proliferative assay results demonstrated that compound 16A (Fig 11) possessed the most potent

enzyme inhibition activity (IC50 = 0.9 μM for telomerase)

and anticancer activity (IC50 = 5.34 μM for B16-F10 and IC50

= 18.07 μM for SGC-7901), bearing the best bioactivity

comparable with the positive control 5-fluorouracil (IC50 =

21.41 μM for B16-F10 and IC50 = 46.35 μM for SGC-7901)

N N O

OH

Fig (10) Compound 4a

H3CO

N N O

O O

Fig (11) Compound 16A

2.4 Aurora-A kinase Inhibitory Activity

Aurora kinases are serine/threonine kinases that are essential for cell proliferation The enzyme is beneficial to the dividing cell dispense its genetic materials to its daughter cells, so the Aurora kinases is a family of highly conserved serine/threonine protein kinases that play a very meaningful role in regulating many pivotal processes of mitosis and completion of cell division by controlling chromatid segregation [42-46] Defects in this segregation can cause genetic instability, a condition which is highly associated

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with tumorigenesis In mammals, three Aurora kinases are

found: Aurora-A, Aurora-B and Aurora-C [47] Aurora A

and B, are well known for their distinct roles in regulating

mitosis, but the role of Aurora C is still unclear With the

presumption that the pyrazole group is a common nucleus of

Aurora-A kinase inhibitors by binding to its ATP side [48],

so a series of N-1,3-triphenyl-1H-pyrazole-4-carboxamide

derivatives have been designed, synthesized and evaluated

by Xi-Li in Zhu’s lab for their potential anti-proliferation

activity and Aurora-A kinase inhibitory activity [49]

Compound 10e (Fig 12) exhibited significant Aurora-A

kinase inhibitory activity (IC50 =0.16 μM) comparing with

the positive control VX-680 (IC50 = 0.13 μM). The result of

western blotting of compound 10e has been showed in Fig

13 [49]

N N

NH O

OEt

O2N

Fig (12) Compound 10e

2.5 ROS Receptor Tyrosine Kinase Inhibitory Activity

Receptor tyrosine kinases (RTKs) are key players in the

process of signal transduction and cellular communication

They act as the cell surface receptors for many important

growth factors and hormones c-Ros is a proto-oncogenic

receptor tyrosine kinase whose expression is tightly

restricted during its development It normally expressed in

adult murine and human epithelial cells of the epididymis A

series of new

4-(pyridin-4-yl)-(3-methoxy-5-methylphenyl)-1H-pyrazoles (6a-k) (Fig 14 and 15) have been rationally

designed by Byung Sun Park10 Based on the structure of the

lead compound KIST301080 (Fig. 16), a selective c-Ros

receptor tyrosine kinase inhibitor has been discovered in order to study the activity of c-Ros of this new class of inhibitors The compounds have been synthesized and screened against c-Ros kinase Among them, compound 6h

(Fig. 15) has showed good inhibitory activity with an IC50

value of 6.25 μM His lab has also discovered that compound

12b [50] (Fig 17) showed good potency with IC(50) value of

209 nM against ROS tyrosine kinases

3 PYRAZOLE DERIVATIVES AS ANTI-INFLAMMATORY AGENTS

3.1 COX Inhibitory Activity

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for the treatment in various inflammatory diseases such as arthritis, rheumatisms and pain of everyday life [51-54] NSAIDs are usually indicated for the treatment

of acute or chronic conditions where pain and inflammation are present The most prominent members of this group of drugs are aspirin, ibuprofen, and naproxen, all of which are available in most countries However, long-term use of the NSAIDs has been associated with gastrointestinal ulceration, bleeding and nephrotoxicity [51-54] Therefore the discovery

of new anti-inflammatory drugs may be a challenging goal for such a research area The currently available NSAIDs belong to different chemical classes [55] The compound 4c

(Fig. 18) which emerged as the most active compound has

been synthesized by P D Gokulan [56]and also exhibited wonderful analgesic and anti-inflammatory activities The mechanism of NSAIDs (nonsteroidal anti-inflammatory drugs) in reducing inflammatory reactions involves the inhibition of COX enzymes COX is the key enzyme which catalyses the conversion of arachidonic acid to prostaglandins and thromboxane [57-60] It is cyclooxygenase enzymes that catalyses second step of prostaglandin synthesis There are two types of cyclooxygenase enzymes, COX-1 and COX-2 COX-1 is a constitutive enzyme, produced in many tissues such as the kidney and the gastrointestinal tract, while

COX-2 is inducible and is expressed during inflammation at the site of injury [61] The biological studies demonstrated increasing in COX activity in a variety of cells after exposure to endotoxin, pro-inflammatory, cytokines, growth factors, hormones, and tumor promoters Anti-inflammatory screening indicated that compounds 4d, 4e and 4h (Fig 19)

synthesized by Shridhar Malladi [62] were biologically

active

Fig (13) Compound 10e was examined by Western blotting

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N N CN

O

N CN OH

N

N N CN O

N

6b

N CN O

N

6c

N

N N

CN O

N

N N

CN O

N

6d

6e

Fig (14) Compound 6a-6e

N

N N CN O

N CN OH

6f

N

N N

N

6g

N

N N

H

O

6h

N

N N

CN O

N

6i

N

N N CN O

N

6j

N CN

Fig (15) Compound 6f-6k

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N N

N

CN

N

Fig (16) Compound KIST301080

OH

N N

N

N NC

Fig (17) Compound 12b

Miguel A Iñiguez has analyzed the effects on T cell

activation of novel 4,5-dihydro-3 trifluoromethyl pyrazole

anti-inflammatory drugs with different potencies as COX-2

inhibitors, namely 6087, 6232, 6231, 6036 and

E-6259 (Fig. 20) [63] as well as the chemically related COX-2

inhibitor Celecoxib Their findings suggest that

4,5-dihydro-3-trifluoromethyl pyrazole NSAIDs display

COX-independent immunomodulatory and anti-inflammatory

actions through the inhibition of NF-B and

NFAT-dependent transcription, leading to down-regulation of T cell

activation The result of western blotting of compounds

E-6087, E-6232, E-6231, E-6036 and E-6259 have been

showed in Fig. 21 [63]

N N HN

HN

SCH3 COOC2H5

Fig (18) Compound 4C

N N N N

S HN

N

C2H5

N N N N

S HN

N

C3H7

4e

N N N N

S HN

N

C3H7

Cl

4h

Fig (19) Compound 4d, 4e and 4h

N N F F

S O O

H2N

S

N N

F F F

F

O

O CH

3

N N F F F

S O O

H2N

H

N N F F F

S O O

H2N

H

E-6087

E-6036

E-6231

E-6232 S

N

F O

H3C

F

N S N

O

O NH

2

CH3 E-6259

celecoxib

Fig (20) Compound E-6087, E-6232, E-6231, E-6036 and E-6259

Fig (21) The result of western blotting of compound E-6087,

E-6232, E-6231, E-6036 and E-6259.

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Compound 5a (Fig 22) synthesized by Ke-Ming Qiu [64]

displayed the most potent COX-2 inhibitory activity with

IC50 of 0.5 μM, but was weak against COX-1 The result of

western blotting of compound 5a has been showed in Fig 23

[64]

N N N S O

Fig (22) Compound 5a

4 PYRAZOLE DERIVATIVES AS ANTI-BACTERIAL

AGENTS

4.1 DNA Gyrase Inhibitory Activity

DNA gyrase, a typical of type II topoisomerases, has

been known to cause DNA replication, transcription and

recombination [65] DNA gyrase catalyzes the ATP-dependent

introduction of negative supercoils into bacterial DNA as well as the decatenation and unknotting of DNA [66]

Hoffmann–La Roche’s group [67,68] has developed a new

lead DNA gyrase inhibitor (compound 1) (Fig 24)

Which has strong inhibitory activity against DNA gyrase and this inhibitory effect can cause bacterial cell death Ten new 1-(5-(2-chlorophenyl)-3-(2,4-dichlorophenyl)-4,5-dihydropyrazol-1-yl) oxime ester derivatives have been

synthesized by Xin-Hua Liu’s group [69] and all the compounds have been evaluated for their antibacterial

potential in vitro against Bacillus subtilis, Staphylococcus

aureus, Escherichia coli and Pseudomonas aeruginosa The

results showed that 7c and 7f possess good activity with the

minimum inhibitory concentrations (MIC) values being

about 1.562 μg/mL against all four bacterias Compounds 7c, 7d and 7f (Fig 25) showed moderate inhibition against the

DNA gyrase (IC501.6 - 2.5 μg/mL)

What is more, a series of new 2-(1-(2-(substituted- phenyl)-5-methyloxazol-4-yl)-3-(2-substitued-phenyl)-4,5-

dihydro-1H-pyrazol-5-yl)-7-substitued-1,2,3,4-tetrahydroiso-quinoline derivatives have also been synthesized by Xin-Hua

Liu [70] The results showed that compounds 9q and 10q

Fig (23). The result of western blotting of compound 5a

N

S N

O

NH2

N N

H3C

C CH3 ROCON

O

H N N

O

HN

N N

H3C

C

H3C O

O

CH3

F F F

celecoxib

2

3 1

Fig (24). Recently disclosed pyrazole as antibacterial inhibitors

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(Fig. 26) can strongly inhibit Staphylococcus aureus DNA

gyrase and Bacillus subtilis DNA gyrase (with IC50 of 0.125

and 0.25 μg/mL against S aureus DNA gyrase, 0.25 and

0.125 μg/mL against B subtilis DNA gyrase), comparing

with Novobiocin (with IC50 of 0.125 μg/mL against S aureus

DNA gyrase, 0.5 μg/mL against B subtilis DNA gyrase)

4.2 Fatty Acid Biosynthesis (FAB) Inhibitory Activity

FAB is an essential metabolic process for prokaryotic

organisms and is required for cell viability and growth [71]

The -ketoacyl-acyl carrier protein synthase III (FabH) is

one of key enzymes in FAS II, playing an important

regulatory role in the bacterial FAB cycle [72] Many

attributes suggest that small molecule inhibitors of FabH

enzymatic activity could be potential development

candidates leading to selective, nontoxic and broad-spectrum

antibacterial agents [73-75] Fifty-six

1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives have been synthesized

by Peng-Cheng Lv [76] and developed as potent inhibitors of

FabH This inhibitor class demonstrated strong antibacterial

activity Escherichia coli FabH inhibitory assay and docking

simulation indicated that the compound 12 and 13 (Fig 27)

were potent inhibitors of E coli FabH with IC50 of 4.2 μM

and 7.6 μM

CONFLICT OF INTEREST

The authors confirm that this article content has no conflicts of interest

ACKNOWLEDGEMENTS

This work was supported by 2012-NIES Specific Founds for Basic Scientific Research by Central Nonprofit Research Institutes and by the project (No BY2012136) from the Science & Technology Agency of Jiangsu Province and by the projects (Nos CXY1213 & CXY1222) from the Science

& Technology Bureau of Lianyuangang City of Jiangsu Province

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Cl

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