Send Orders for Reprints to reprints@benthamscience.net 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* State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, P.R China; 2Nanjing 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, antiinflammatory 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 antiinflammatory 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 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, anti-cancer, antimalarial, antimicrobial, 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-5methylphenyl)-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] They include 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 18-57/13 $58.00+.00 natural pyrazole C-glycoside pyrazofurin which has shown a broad spectrum of antimicrobial activity [18] In this review, the antitumor, anti-inflammatory and antibacterial 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 PYRAZOLE DERIVATIVES AS ANTITUMOR AGENTS 2.1 BRAFV600E 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 Gproteins 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] © 2013 Bentham Science Publishers 1958 Mini-Reviews in Medicinal Chemistry, 2013, Vol 13, No 13 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)-4,5dihydro-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 (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 Liu et al O O O N N Br F Fig (3) Compound C14 O O N 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 O F Fig (4) Compound D10 N OCH3 Cl CF3 N N O HN O HN Cl Fig (1) Compound 27e OCH3 Cl N O N PMB N H NH2 Fig (5) Compound 7c 2.2 EGFR Inhibitory Activity N N O HO Cl Fig (2) Compound 25 A series of N-(5-amino-1-(4-methoxybenzyl)-1Hpyrazol-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 BRAF V600E (IC50 = 0.26 μM) inhibitor 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 (Fig 6) [9] displayed the most potent EGFR inhibitory activity with IC50 of 0.07 μM, bearing the Pyrazole Derivatives as Antitumor, Anti-inflammatory and Antibacterial Agents 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) H3CO N N H2N Mini-Reviews in Medicinal Chemistry, 2013, Vol 13, No 13 1959 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 Nphenylacetyl (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) S Fig (6) Compound F N N N S Cl Fig (7) Compound 11 O Cl N N Cl N N OH Fig (10) Compound 4a Fig (8) Compound D14 O Cl O H3CO Cl N N N N NH2 S 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 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 1960 Mini-Reviews in Medicinal Chemistry, 2013, Vol 13, No 13 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] OEt O2N O NH N N 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 Fig (13) Compound 10e was examined by Western blotting Liu et al 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 PYRAZOLE DERIVATIVES INFLAMMATORY AGENTS AS ANTI- 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 COX2 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 Mini-Reviews in Medicinal Chemistry, 2013, Vol 13, No 13 Pyrazole Derivatives as Antitumor, Anti-inflammatory and Antibacterial Agents OH O O N N N CN N N N CN N 6a N CN N N 6b N O N N N N CN N N O N CN 6c 6d N N N N O N CN 6e Fig (14) Compound 6a-6e OH O H N N N N N CN CN N N N O N N 6h O CN 6f O N N CN O N N N N N CN N N N 6g CN O N N 6i N N N CN O Fig (15) Compound 6f-6k 6k 6j 1961 1962 Mini-Reviews in Medicinal Chemistry, 2013, Vol 13, No 13 Liu et al N S HN N OH N N S HN N N N N N N C3H7 C2H5 N N CN 4e 4d Cl N N N S HN N N N N C3H7 Fig (16) Compound KIST301080 4h Cl N N Fig (19) Compound 4d, 4e and 4h NC H2 N N H2N O S N O S H2N O O N N F N N F H F F F F F OH F F F E-6087 O S O H N N F F F E-6231 F F E-6232 Fig (17) Compound 12b O S 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 E-6087, E-6232, E-6231, E-6036 and E6259 (Fig 20) [63] as well as the chemically related COX-2 inhibitor Celecoxib Their findings suggest that 4,5-dihydro3-trifluoromethyl pyrazole NSAIDs display COXindependent immunomodulatory and anti-inflammatory actions through the inhibition of NF-B and NFATdependent transcription, leading to down-regulation of T cell activation The result of western blotting of compounds E6087, E-6232, E-6231, E-6036 and E-6259 have been showed in Fig 21 [63] C HN CH3 O F H3C O S O F F NH2 S O N F E-6036 N F N N N F E-6259 N F F CH3 celecoxib Fig (20) Compound E-6087, E-6232, E-6231, E-6036 and E-6259 O C HN S COOC2H5 SCH3 N N Fig (18) Compound 4C Fig (21) The result of western blotting of compound E-6087, E-6232, E-6231, E-6036 and E-6259. Mini-Reviews in Medicinal Chemistry, 2013, Vol 13, No 13 Pyrazole Derivatives as Antitumor, Anti-inflammatory and Antibacterial Agents 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 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)-4,5dihydropyrazol-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-(substitutedphenyl)-5-methyloxazol-4-yl)-3-(2-substitued-phenyl)-4,5dihydro-1H-pyrazol-5-yl)-7-substitued-1,2,3,4-tetrahydroisoquinoline 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 O NH2 S F F H3C O N O N N C CH ROCON N F CH3 celecoxib H N N HN O H3C N N C O H3C Fig (24) Recently disclosed pyrazole as antibacterial inhibitors 1963 O 1964 Mini-Reviews in Medicinal Chemistry, 2013, Vol 13, No 13 Liu et al F F O2N N OC O N OC O N N N Cl N OC O N N N Cl Cl Cl Cl Cl 7c Cl Cl 7d 7f Cl Fig (25) Compound 7c, 7d and 7f F F O F F N N N O O N N N O N N 9q OCH3 10q Fig (26) Compound 9q and 10q H3CO H3CO N N O F N N Cl 12 O 13 Fig (27) Compound 12 and 13 (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-diphenyl4,5-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 REFERENCES [1] [2] [3] Menozzi, G.; 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