Recently reported biological activities of pyrazole compounds

Bioorganic & Medicinal Chemistry 25 (2017) 5891–5903

Contents lists available at ScienceDirect

Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc

Review article

Recently reported biological activities of pyrazole compounds Jéssica Venância Faria a,b, Percilene Fazolin Vegi a, Ana Gabriella Carvalho Miguita c, Maurício Silva dos Santos c,⇑, Nubia Boechat b, Alice Maria Rolim Bernardino a a

Programa de Pós-Graduação em Química,Instituto de Química, Universidade Federal Fluminense, Niterói, RJ, Brazil Fundação Oswaldo Cruz – Fiocruz, Instituto de Tecnologia em Fármacos – Farmanguinhos, Manguinhos, RJ, Brazil c Laboratório de Síntese Orgânica (LABSINTO), Instituto de Física e Química, Universidade Federal de Itajubá, Itajubá, MG, Brazil b

a r t i c l e

i n f o

Article history: Received 9 June 2017 Revised 21 September 2017 Accepted 22 September 2017 Available online 23 September 2017

a b s t r a c t The pyrazole nucleus is an aromatic azole heterocycle with two adjacent nitrogen atoms. Pyrazole derivatives have exhibited a broad spectrum of biological activities, and approved pyrazole-containing drugs include celecoxib, antipyrine, phenylbutazone, rimonabant, and dipyrone. Many research groups have synthesized and evaluated pyrazoles against several biological agents. This review examines recent publications relating the structures of pyrazoles with their corresponding biological activities. Ó 2017 Elsevier Ltd. All rights reserved.

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biological activities of pyrazole derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Analgesic and anti-inflammatory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Antibacterial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Antifungal activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Antitumoral activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Antiviral activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Antileishmanial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Pyrazole 1 is an aromatic heterocyclic system that belongs to the azole class. It is a five-membered ring with two nitrogen atoms bound to each other and three carbon atoms. Nitrogen atom 1 (N1) is ‘‘pyrrole-like” because its unshared electrons are conjugated with the aromatic system. Nitrogen atom 2 (N2) is ‘‘pyridine-like” since the unshared electrons are not compromised with resonance, similar to pyridine systems. Due to the differences between the nitrogen atoms, pyrazoles react with both acids and basis (Fig. 1).1 Another important structural characteristic of pyrazole is prototropic tautomerism. Three tautomers are possible in unsubstituted pyrazoles (Fig. 2), while five tautomers can exist in

⇑ Corresponding author. E-mail address: [email protected] (M.S. dos Santos). https://doi.org/10.1016/j.bmc.2017.09.035 0968-0896/Ó 2017 Elsevier Ltd. All rights reserved.

5891 5892 5892 5894 5896 5896 5899 5900 5900 5901 5901 5901

monosubstituted pyrazoles (Fig. 3). The structures 1a, 2a, and 2b are the most relevant because they preserve aromaticity.2,3 B-

H 30+

+ H N N H

N

N N H

N-

(1) Fig. 1. Cations and anions produced from pyrazole.

N

N N H (1a)

N (1b)

N

N (1c)

Fig. 2. Tautomers of unsubstituted pyrazole.

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R

R

N

R

HN

R

N

N H

N

(2a)

(2b)

compounds that shows high affinity for the CB1 cannabinoid receptor and used for the treatment of obesity (Fig. 5).10,11 In medicinal chemistry, several compounds containing pyrazole rings have exhibited biological activity, including antimicrobial,12,13 antifungal,12 leishmanicidal,14–17 antiviral,13 antichagasic,14 pesticidal,18 antihyperglycemic,19 anti-inflammatory,20 and antitumoral activities.13 Consequently, many works have been published on the development of new pyrazole-based drugs.

R

N

N

N

N

N

(2c )

(2d )

(2e)

Fig. 3. Tautomers of 3(5)-monosubstituted pyrazoles.

H 3C(H 2C) 8

N

N

N

2. Biological activities of pyrazole derivatives

HO2C

N H

NH2

(3)

2.1. Analgesic and anti-inflammatory activity

(4)

Non-steroidal anti-inflammatory drugs (NSAIDs) provide analgesic and antipyretic effects and are commonly used to treat inflammatory diseases, including rheumatoid arthritis. This anti-inflammatory class inhibits cyclooxygenases enzymes COX1, COX-2, and COX-3, which are responsible for the production of prostaglandins. NSAIDs have presented a series of side effects, such as gastrointestinal bleeding and stroke. Additionally, an increased cardiovascular risk during treatment with NSAIDs has been reported in patients with a history of myocardial infarction.21 Dipyrone, celecoxib and lonazolac are pyrazole derivatives used as anti-inflammatory agents. El-Sehemi and colleagues replaced the carboxylic acid group of naproxene, a NSAID, with additional heterocycles. Several compounds were obtained and evaluated with regard to anti-inflammatory, analgesic, and ulcerogenic activities. The derivative 12 showed significant analgesic activity and exhibited no ulcerogenic effect (Fig. 6).22 Hassan et al. synthesized celecoxib analogs with benzofuran moieties and evaluated them for COX-2 inhibitory activity

Fig. 4. Pyrazoles extracted from natural products.

The first pyrazole isolated from natural sources was 3-n-nonyl1H-pyrazole 3, extracted from Houttuynia cordata, a common plant from tropical Asia. b-(1-pyrazolyl)alanine 4 can be found in watermelon seeds (Fig. 4).2 Classical methods for the synthesis of pyrazoles involve approaches based either on the condensation of hydrazines with 1,3-dicarbonyl compounds or 1,3-dielectrophiles, such as the Knorr synthesis, and [3 + 2] cycloadditions involving 1,3-dipole compounds and alkynes, e.g., the Pechmann synthesis.3–5 A large number synthetic pyrazoles have been synthesized and approved for use, including fipronil 5, an insecticide; tartrazine 6, an azo dye employed as food coloring; sildenafil 7, used to treat erectile dysfunction;6 dipyrone 8, a potent analgesic and antipyretic agent;3 celecoxib 9 and tepoxalin 10 a COX-2 selectivies nonsteroidal anti-inflammatory drugs (NSAID’s);7–9 rimonabant 11,

+

CN Cl

N N

F3C

Cl

O

Na-O3 S

N

CF3 S O

N

N

O

H O O S N

N

SO3- Na+

N

NH2

N

N

OH

O

N

N

O- Na+

Fipronil (5)

Tartrazine (6)

Sildenafil (7)

HON O NH 2 S O

O N N

N

N N

N N

SO3- Na+

O

F3 C MeO Dipyrone (8)

Celecoxib (9)

O

N Cl

Tepoxalin (10)

N N H

N Cl

Cl Rimonabant (11) Fig. 5. Examples of commercial substances containing a pyrazole ring.

Cl

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N H N MeO

OMe

N

OMe

NH

O

N

N

N

N O

N O

OH

OH OMe

OMe

(12)

O O S NH2

O O S NH2

(13a ) IC50= 0.40 mM

(13b) IC 50= 0.36 mM

R1

R O

N

N HN

N

HN N N

OCH3

O S O NH2 O S O NH2

(15)

( 14a ) R= H, R1 = OCH 3 (14b) R= OCH 3, R 1= OCH3

O

HN N N

O

N N

O N

R1

S

NO2 N

O

N N

O

N

N

N

R

(16a) R= H IC 50 = 0.51 mM (16b ) R= CH3 IC 50 = 0.44 mM

(17a) R 1 = OH ( 17b ) R 1= NO2

(18) IC 50= 0.31 mM COX-2 Celecoxib IC50 = 0.28 mM COX-2

Fig. 6. Pyrazoles with analgesic and anti-inflammatory activity.

in vitro (Fig. 6). The compounds 13a and 13b showed the highest anti-inflammatory activity, with IC50 values of 0.40 lM and 0.36 lM, respectively, compared to 0.28 lM for celecoxib.23 Kumar et al. described the anti-inflammatory activity of two novel series of pyrazolylpyrazolines bearing benzenesulfonamide at position-1 of the pyrazole ring (Fig. 6). The 18 novel compounds were screened for in vivo anti-inflammatory activity. The compounds 14a and 14b exhibited the same degree of anti-inflammatory effects as that of the reference drug indomethacin (78% inhibition) 3 h after carrageenan injection.24 Mohammed and Nissan evaluated the anti-inflammatory activity of hybrid sulfonamide-pyrazoles. Many compounds were less ulcerogenic than the reference drug indometacine (Fig. 6). Derivative 15 showed 81% inhibition of edema, which is better than that of diclofenac, and a selectivity index (SI) of 11.1, which was the best among all compounds synthesized. The ulcer selectivity index of derivative 15 was 2.79, while the value found for indomethacin was 12.82.25

Tewari and colleagues synthesized a novel series of 1,3,5trisubstituted pyrazoles and evaluated the in vivo anti-inflammatory activity in a carrageenan-induced rat paw edema model (Fig. 6). The maximum percentage of paw edema growth in control group after 90 min was 38.7%, which was lowest than found for compounds 16a and 16b: 13.4% and 19.4%, respectively, compared to reference drug Nimesulide where it was found 23.4%. All compounds were also assayed for their anti-inflammatory activity by biochemical COX-1 and COX-2 tests. The ratios of IC50 COX-2 to IC50 COX-1 (SI) for the compounds were 0.51 lM and 0.44 lM, respectively, compared to 0.0028 lM for celecoxib.26 Alegaon et al. synthesized twenty-two 1,3,4-trisubstituted pyrazole derivatives and screened them for anti-inflammatory activity in a carrageenan-induced rat paw edema model (Fig. 6). The most successful pyrazoles were compounds 17a and 17b (>84.2% inhibition) compared to the reference drug diclofenac (86.72%).27

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51.43%, 63.11%, and 42.64%, respectively (Fig. 7). All compounds evaluated were almost ten times more active than reference drug aceclofenac (5.50%).30

Among several 1,3,4-oxadiazoles containing a pyrazole ring synthesized by Bansal and colleagues, compound 18 was the most potent inhibitor of COX-2 with an IC50 value of 0.31 lM (Fig. 6). With regard to ED50, the value found was 74.3 mg/kg, while the values obtained for reference drugs celecoxib and diclofenac were 81.7 mg/kg and 110.4 mg/kg, respectively. The compound 18 presented a low ulcer-index of 22.8 when compared to aspirin.28 The synthesis and evaluation of a series of pyrazole-oxadiazole derivatives as anti-inflammatory agents were described by Cidade’s research group. Compounds 19a, 19b, and 20 (Fig. 6) reduced the edema in a carrageenan-induced rat paw edema model and decreased the levels of the cytokine TNF-a, which is an important pro-inflammatory cytokine involved in cellular chemotaxis and inflammatory hypernociception.29 Among many coumarins containing pyrazole moiety synthesized by Chougala and coworkers, compounds 21, 22a, and 22b showed good inhibition of heat induced protein denaturation: H N

O

2.2. Antibacterial activity The rising prevalence of multi-drug resistant microbial infections has become a global health problem. There is a continuous need to develop new antimicrobials with higher activity and lower toxicity.31 Several pyrazoles containing trifluoromethyl (CF3) group have presented remarkable antibacterial properties. Fifteen compounds were synthesized by Aggarwal et al. and screened for their in vitro antibacterial activity against several bacterial strains (Fig. 8). Compound 23 was the most potent against Pseudomonas aeruginosa, with an MIC of 0.022 lM. The values for ampicillin and chloramphenicol were 0.004 lM and 0.003 lM, respectively.32 Bhavanarushi and colleagues designed a series of bispyrazoles 24a–m containing two trifluoromethyl (CF3) groups (Fig. 8). All compounds synthesized were evaluated in vitro for their antibacterial effect against Pseudomonas aeruginosa, Xanthomonas protophormiae, Bacillus licheniformis, and Staphylococcus aureus. The MIC values were 25–50 mg/mL for many compounds, compared to the ciprofloxacin control (12 mg/mL).33 Nimbarte et al. synthesized a series of novel compounds containing piperidine and pyrazole rings for the inhibition of soluble epoxide hydrolases (sEH), a group of enzymes that can be found in bacteria (Fig. 8). Compounds 25 and 26 exhibited values of

H N N

NH2

N

CO2H

CO2 Et O

R O (21)

O

O

O

heat induced protein denaturation (22a) R= OMe: 63.11% (22b) R= Cl: 42.64%

Fig. 7. Coumarins containing pyrazole ring with anti-inflammatory activity.

CH 3 N N

N

N

Br

HN F3 C

N

F3C CF3

R1

N N

N

N N

R1

OH H2 NO2S

R2

N

OH

O

O

N H

(23) MIC= 0.022 µM Ampicillin MIC= 0.004 µM Chloramphenicol MIC= 0.003 µM

(25) IC50= 0.220 µM AUDA IC50= 0.0065 µM

(24 a-m )

R

CH3

R1

N N

OMe OMe

N N N

H 3CO2 S

N

N N H

N

O

OMe

N

NH N

O

N N

Cl

Cl

N

N

OMe OMe OMe

(26) IC 50= 0.224 µM AUDA IC50= 0.0065 µM

(28) MIC= 20 mg/mL Tetracycline MIC= 12 mg/mL

(27a) R= H, R 1= 4-SO 3H MIC= 60.5 µg/mL (27b) R= Cl, R1 = 4-SO 3H MIC= 61.5 µg/mL Ampicillin MIC= 62.5 µg/mL

H 3CO

O O

R NH N

H N

N N N O (29a) R= thiometyl MIC= 0.25 µg/mL (29b) R= isopropyl MIC= 0.25 µg/mL Gentamycin MIC= 1.00 µg/mL

O S O

N H

O

NH2

(30) MIC = 19.6 µg/mL (P. vulgaris ) and 17.1 µg/mL (K. pneumonia) Sulfisoxazole MIC = 18.2 µg/mL (K. pneumonia) Gentamycin MIC = 23.4 (P. vulgaris ), 26.3 µg/mL (K. pneumonia)

Fig. 8. Pyrazoles with antibacterial activity.

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0.220 lM and 0.224 lM, respectively, compared to that of the standard, 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), which has a value of 0.0065 lM.34 Rizk et al. synthesized new pyrazole-containing derivatives that were assayed for their antibacterial activity (Fig. 8). Compounds 27a and 27b showed the most potent activity against five bacterial species: Enterobacter cloacae, Shigella dysenteriae, Serratia marcescens, Escherichia coli, and Staphylococcus aureus.35 Novel pyrazole-1,3,4-dioxazole hybrids were synthetized and evaluated against Bacillus cereus, Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae. Compound 28 showed a wide spectrum of activity in a preliminary inhibitory zone (diameter) test. The results were better than that of the reference drug tetracycline (Fig. 8). The MIC values for that compound were 20 lg/mL for those four bacteria.36 Benzo[1,3-d]dioxoles containing pyrazole rings synthesized by Umesha and Basavaraju were assayed against Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli and Bacillus subtilis (Fig. 8). The best results were observed for compounds 29a and 29b against E. coli, and gentamycin was used as reference drug.37 Nasr et al. prepared various pyrazoles containing a sulfisoxazole group; this functionality has been applied in antibiotics used in the treatment of infections caused by bacteria, such as ear infections and meningitis (Fig. 8). Many of synthesized compounds were more potent than sulfisoxazole, gentamycin, and ampicillin against six bacteria strains: Streptococcus pneumoniae, Bacillus subtilis,

Staphylococcus epidermidis, Escherichia coli, Proteus vulgaris, and Klebsiella pneumonia. For example, the pyrazole derivative 30 was more potent than sulfisoxazole and gentamycin against Klebsiella pneumonia and more potent than gentamycin against Pneumocystis vulgaris.38 Malladi et al. synthesized a series of novel 2,5-disubstituted1,3,4-oxadiazole derivatives containing pyrazole ring, which were tested against Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. Compound 31 showed equipotent activity to that of streptomycin (500 mg/mL) against Escherichia coli and Staphylococcus aureus (Fig. 9). Therefore, none of the compounds showed good results against Pseudomonas aeruginosa.39 Kalaria, Satasia and Raval synthesized pyrano[2,3-d]thiazole compounds containing a pyrazole nucleus and evaluated them against Mycobacterium tuberculosis H37Rv, Bacillus subtilis, Clostridium tetani, Escherichia coli, Salmonella typhi, and Vibrio cholerae (Fig. 9). Among several results, compounds 32a–c have emerged as potent inhibitors of the gram-positive bacteria Bacillus subtilis with IC50 62.5 mg/mL, lowest than ampicillin and norfloxacin, 250 mg/mL and 100 mg/mL, respectively. Compound 32c also showed 95% inhibition against Mycobacterium tuberculosis H37Rv while the reference drugs rifampicin and isoniazid presented 98% and 99% inhibition, respectively.40 A series of novel pyrazole-hydrazine carboxamide derivatives were evaluated for their antibacterial activities by Kumar and coworkers. Compound 33 presented the best result against Escherichia coli (MIC 0.25 lg/mL), compared to standard ciprofloxacin (MIC 0.50 lg/ mL) (Fig. 10). The results against Streptococcus epidermidis, Pseudomonas aeruginosa and Staphylococcus aureus weren’t promising.41 A new sequence of fifteen 3-(pyridin-4-yl)-1H-pyrazole-5-carboxamide chalcones were synthesized by Sribalan and colleagues. All compounds were active against Pseudomonas aeruginosa which 34a, 34b, and 34c derivatives showed the highest zone of inhibition, 12.1 mm, 12.5 mm, and 12.2 mm, respectively. They were also evaluated against Klebsiella pneumoniae. The best results were obtained for the compounds 34d (7.5 mm) and 34c (6.8 mm) (Fig. 10).42 B’Bhatt and Sharma obtained eight novel pyrazol-thiazolidin-4one derivatives (Fig. 10). These compounds were evaluated against four different kinds of bacteria: Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pyogenes. Compound 35a presented good activity against E. coli (approx. 100 lg/mL) as compared to the standard ampicillin (approx. 100 lg/mL). Compounds 35a and 35b were moderately active against P. aeruginosa (approx. 200 lg/mL) while 35b showed good

Cl N N Cl Cl

N N O

het N

N NH

CN

S N N

O

NH 2

(31) MIC (mg/mL) B. subtilis

R

(32a) R= 4-CF3 Het= triazole (32b) R= 4-CF3 Het= benzimidazole (32c) R= 2-CF3 Het= triazole Ampicillin Norfloxacin Ciprofloxacin

62.5 62.5 62.5 250 100 50

Fig. 9. Pyrazole-oxadiazoles and pyrazole-thiazoles with antibacterial activity.

HO N

H N N H N N H

NH 2

O

O

N

OH

(33) MIC 0.25 mg/mL Ciprofloxacin MIC 0.50 mg/mL

H N N H

R

O

P. aeruginosa (mm) K. pneumoniae (mm) (34a) R= 4-FC6H 4 12.1 (34d) R=thiophen-2-yl 7.5 12.5 (34b) R= 4-OMeC 6H4 6.8 (34c) R= 2,4-diClC6H3 (34c) R= 2,4-diClC6H3 12.2

R O NH S S N

N

Cl

N

(35a) R= Cl; (35b) R= Br

Fig. 10. Pyrazole-hydrazine carboxamides, pyrazole-pyridines and pyrazole-thiazolidinones with antibacterial activity.

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activity against S. aureus and S. pyogenes (approx. 100 lg/mL) compared also to ampicillin (approx. 200 lg/mL).43

H 3 CO N

2.3. Antifungal activity

N

N

N O

Fungi are ubiquitous eukaryotic microorganisms. Most are not dangerous, but some varieties are harmful to humans. Fungi are responsible for a large number of diseases, such as candidiasis, pneumocystis pneumonia (PCP), coccidioidomycosis, and aspergillosis. Novel pyrazole-3-carboxylic acid and pyrazole-3,4-dicarboxylic acid derivatives were synthesized by Mert et al. and screened for their antifungal activity (Fig. 11). The values found were within the range of 25–50 mg/mL against Candida albicans (ESOGÜ-Eskisehir Osmangazi University). Compounds 36a–b and 37a–c exhibited MICs of 25 mg/mL compared to nystatin (19 mg/mL). Compounds 36a–b and 37a–b were highlighted as the most potent against strains of C. albicans.44 Nagamallu and colleagues synthesized several coumarin derivatives (Fig. 11). The compounds showed good activity against three fungal species: Aspergillus niger, Aspergillus flavus, and Candida albicans. Compound 38 was identified as the most potent against the three species.45 In their search for new antifungal drugs for the treatment of candidiasis, Oliveira and colleagues reported the notable antifungal activity of eleven 3,5-diaryl-4,5-dihydro-1H-pyrazole-1-carboximidamides. Most of the compounds exhibited similar effects at 125– 250 lg/mL against Candida albicans, Candida parapsilosis, Candida famata, Candida glabrate, Candida lipolytica, and Rhodotorula mucilaginosa. However, compound 39 was the most active, with an MIC of 15.6 lg/mL against strains of C. albicans and C. lipolytica (Fig. 12). It was suggested that a methoxy group at the ortho position acts as a hydrogen bond acceptor group; this feature might be important for the improved activity of compound 39.46 Radi et al. described a novel class of b-keto-enols linked to heterocycle moieties and their evaluation for in vitro antifungal activity (Fig. 12). Among the synthesized compounds, derivative 40 R1 O

O

HN

X O

NH N

N

N

NO2

NO2 mg/mL) MIC (m C. albicans (36a) R1= 3-NO2 (36b) R1= 4-NO2 Nystatin

MIC (mg/mL) C. albicans

25 25 19

(37a) X= O, R= methyl (37b) X= O, R= ethyl (37c) X= S, R= ethyl Nystatin

S H 2N N N

CH3

OHC HO

O N N

O

CHO

S NH 2 MIC (mg/mL) A. niger (38) Fluconazole

R NH

O

HN

NH N

X

R HN

R1

12.5 25

MIC (mg/mL) A. flavus

MIC ( mg/mL) C. albicans

25 25

50 50

Fig. 11. Pyrazoles with fungicide activities.

25 25 25 19

HN

OH

NH2 (40)

(39) MIC (mg/mL) C. albicans 62.5

MIC (mg/mL) C. lipolytica

MIC (mM) F. oxysporum

62.5

0.055

Fig. 12. Pyrazole-carboximidamides and pyrazole-b-keto-enol with fungicide activities.

showed a potent IC50 value against Fusarium oxysporum f. sp. albedinis: 0.055 mM.47 2.4. Antitumoral activity Cancer is caused by uncontrolled growth of abnormal cells. According to the World Health Organization (WHO), 8.2 million people die from cancer each year, which corresponds to approximately 13% of all deaths around the world. There are three main types of treatment for cancer: surgery, radiation therapy and chemotherapy. With regard to chemotherapy, many research groups have synthesized and evaluated a diverse array of compounds, including substances containing pyrazole rings.48,49 Mohareb and colleagues synthesized a series of thiophenepyrazole derivatives that were evaluated against three types of tumor cells: breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460), and CNS cancer (SF-268), also known as glioblastoma (Fig. 13). For example, compounds 41a and 41b showed good cell growth inhibition when compared to reference drug doxorubicin.50 A series of 1-aryl-3,4-substituted-1H-pyrazol-5-ol derivatives were obtained and assayed against cancer antigen-1 (PCA-1 ALKBH3). The best results were obtained for compound 42 (Fig. 13), which exhibited high inhibition against the proliferation of DU145 (human hormone-independent prostate cancer cells), with no apparent side effects, when administered in a xenografted mouse model.51 Xing and colleagues synthesized a series of twenty pyrazoles containing an acylhydrazone group. The compounds were evaluated for inhibition of MCF-7 and B16-F10 cancer cell lines. Compound 43 showed the most potent activity against both cell lines (Fig. 13).52 Derivative 44 has been described by Aydin and colleagues as a potent inhibitor of K-562 myeloid leukemia cells, showing 70% inhibition at 10
5 mol.L
1 (Fig. 13). This compound induced apoptosis of the cells.53 Pirol et al. synthesized novel 5-(p-tolyl)-1-(quinolin-2-yl)pyrazole-3-carboxylic acid derivatives and evaluated their antiproliferative activity. The hybrid pyrazole-quinoline 45 (Fig. 14) exhibited good activity against three human cancer cell lines: Huh7, MCF-7, and HCT116. Additionally, this compound was able to induce apoptosis. The pharmacological inhibition of apoptosis shows promise for the treatment of cancer, a condition in which disequilibrium occurs in the natural process of cell death.54 Li et al. synthesized 4-pyrazolyl-1,8-naphthalimide derivatives and evaluated their biological activity as antitumor agents, revealing a relevant toxicological profile against MCF-7, HeLa and A549 cells. The best results were observed for compounds 46a and 46b (Fig. 14) against MCF-7 cells, IC50 0.79 mM, and 0.51 mM, respectively, which showed more activity than amonafide (1.68 mM). With regard to evaluation against HeLa and A549 cells IC50 values were higher than 3.0 mM for all compounds assayed.55 Zhang and coworkers prepared twelve pyrazoles containing hydroxamic acid groups 47 (Fig. 14) and evaluated their activity against the A459 cell line (lung cancer). All derivatives

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H N

NC H N

R

N

O

N

HO

Cl

N

N

S

N

N N H

HO

NH2

(42)

(41a) R= CN (41b) R= CO2Et Doxorubicin

GI 50 (mM) NCI-H460 MCF-7 0.01 0.02 0.07 0.02 0.04 0.09

IC50 (mM) (PCA-1)

SF-268 0.01 0.01 0.09

0.67

OH O

O

HN N

N

N OH

F

N

F (44)

IC50 (mM) (MCF-7) (B16-F-10) (43) 0.57 5-Fluorouracil 2.75

N

0.49 0.46

Fig. 13. Pyrazoles with antitumoral activities.

O N N

N

N

O

N(CH 3) 2 O

N

Cl

N N

N N Ar (45)

(46) IC50 ( mM)

(45) Camptothecin

MCF-7

HUh7

3.3 0.006

1.6 0.004

R2

HCT116 1.1 0.00015

IC50 (mM) (MCF-7) (46a) Ar= 3,4-(H3 CO) 2-Ph (46b) Ar= 3,4,5-(H3CO) 3 -Ph Amonafide

0.79 0.51 1.68

X NH2 H 2NOC N N

O NHOH

R1 (47a) R1= H, R2= t-Bu X= CH (47b) R1= Cl, R2= t-Bu X= CH 5-Fluorouracil

IC50 (mM) 1.72 1.82 1.65

N N

Br

9

Cl (48) IC50=2.5 mM (MCF-7 cell)

Fig. 14. Other pyrazoles with antitumoral activities.

showed potential inhibition, with IC50 values from 1.72 to 8.56 mM. Compounds 47a and 47b displayed activity similar to a reference drug 5-fluorouracil against A549 human lung cancer cells.56 Yang’s research group prepared thirteen 5-amino-1H-pyrazole4-carboxamide derivatives to investigate their antitumor activities as adenosine deaminase inhibitors. Compound 48 exhibited strong growth inhibition effects and showed selectivity toward estrogen receptor-positive breast cancer cells (Fig. 14) (MCF-7).57 Yao and colleagues described a series of 1,3-disubstituted pyrazoles with activity against various cancer cell lines, such as MCF-7

(breast cancer), BGC823 (stomach cancer), K562 (myeloid leukemia), HT1080 (sarcoma), and A549 (lung cancer). Furthermore, a few of these compounds, especially compound 49, which contained a biphenyl group, were able to inhibit histone deacetylase enzymes (iHDAC) with higher potency than the drug suberoylanilide hydroxamic acid (SAHA) (Fig. 15). These iHDAC inhibitors have emerged as a new class of antitumor agents that demonstrate activity against various types of cancer and have notable effects on the proliferation, programmed cell death, differentiation and angiogenesis of tumor cells in vitro and in vivo.58

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N

N

N O

N

O

CF3

HN OH Fe

IC 50(µM) (HDAC1)

IC 50 (µg/ mL) (Smmc7721) (SGC7901) (50) 10.04 9.84 5-Fluorouracil 19.25 16.03

(49) 0.033 SAHA 0.131

Cl Cl N N

N N O

O

O

HN N

Cl

O

HN N

O

O O (51a)

(51b) IC 50 (µM) (A549)

(HeLa) (MCF-7) (IMR32)

(51a)

1.5

2.3

1.8

3.2

(51b) Nocodazole

2.3 0.9

2.8 1.2

3.9 1.25

4.1 1.3

O Br O

N

O

CF3

N

MeO

HN N

NH

MeO IC50(µM) (MCF-7) (B16-F10) (52) 0.30 Erlotinib 0.08

IC50 (µM) (MCF-7) (53) 0.35 Colchicine 0.39

0,44 0.12

Br

H3 CO

N NH

R

HN N

O

N H IC50 mM HeLa A549 (54a) R= 5-Cl 5.0 6.0 (54b) R= 6-Cl 2.4 3.0 (54c) R= 5-OMe 7.1 8.0 Nocodazole 1.1 0.89

NH O

N F

MCF-7 9.3 3.6 6.0 1.7

IC 50 (µM) BRAFV600E (55) 0.33 Vemurafenib 0.03

Fig. 15. Other pyrazoles with antitumoral properties.

Ren et al. synthesized a series of compounds with pyrazole cores containing a ferrocene moiety that presented good antitumor activity. Derivative 50 (Fig. 15) showed potent activity against hepatoma Smmc7721 and gastric SGC7901 cancer cells.59 Kamal and coworkers prepared several hybrid pyrazol-oxadiazole conjugates to assay antiproliferative activity against various human cancer cell lines, such as HeLa and MCF-7, derived from cervical and breast cancer, respectively. Compounds 51a and 51b displayed potent IC50 values ranging from 1.5 to 4.1 mM when compared to nocodazole (Fig. 15). Molecular docking studies revealed that a monochloro or dichloro group in the aryl ring was essential for high antitubulin activity.60

A series of new pyrazole derivatives were synthesized and their biological activities were evaluated for the inhibition of epidermal growth factor receptor (EGFR) kinase and HER-2 as well as the antiproliferation of MCF-7 and B16-F10 tumor cells (Fig. 15). Among the thirty substances investigated, Compound 52 exhibited excellent inhibition of EGFR and HER-2. Furthermore, compound 52 also showed the best results against the growth of MCF-7 and B16-F10 cell lines.61 Wang and collaborators synthesized a series of new pyrazole derivatives that were tested for inhibition of tubulin polymerization in tumor cells (Fig. 15). Compound 53 exhibited the best inhibitory activity against MCF-7 breast cancer cells.62

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R1

Wang et al. synthesized and evaluated new (3)5-phenyl-1Hpyrazole derivatives containing a nicotinamide group for their inhibitory activity of BRAFV600E, a mutant gene present in papilliferous thyroid carcinomas (Fig. 15). Compound 55 showed potential inhibitory activity of BRAFV600E with an IC50 equal to 0.33 mM.64 Dai et al. prepared twenty novel 1,2,3-thiadiazoles bearing pyrazole ring. Compounds 56a, 56b, 56c, and 56d presented better inhibitory activities than the standard 5-fluorouracil against HCT116 cells (Fig. 16). All compounds were also evaluated against SGC-7901 cells and 56e, 56c, and 56d showed higher inhibitory activities than 5-fluorouracil.65

N N S

O H 3C N

N N CH3 R2

(56a) R1 = Me, R 2= 4-Br IC50= 7.19mM HCT-116 (56b) R 1= Me, R 2= 2,3-diF IC50= 6.56mM HCT-116 (56c) R1 = Me, R 2= 3,5-diF IC50= 8.12mM HCT-116 and 9.41mM SGC-7901 IC50= 7.06mM HCT-116 and 8.64mM SGC-7901 (56d) R 1= n-Pr, R2 = 4-F (56e) R1 = Me, R 2= 4-OCF 3 IC 50= 11.46mM SGC-7901 5- Fluorouracil IC 50= 29.50mM HCT-116 and 56.12mM SGC-7901

2.5. Antiviral activity

Fig. 16. Pyrazole-thiadiazoles with antitumoral properties.

Viruses are organisms responsible for a great number of infections; many viruses present worldwide public health problems. Hepatitis B, hepatitis C and HIV are three examples of viruses that cause chronic infections with high rates of morbidity and mortality. Molecules containing a pyrazole core have been highlighted in the search for new antiviral agents. Pyrazole derivatives with activity against HIV, hepatitis C, HSV-1, RSV, and H1N1 have been reported in the literature.66

Kamal and collaborators synthesized a series of compounds containing pyrazole and oxindole rings and evaluated them for their antiproliferative activity on different cancer cell lines, such as cervical carcinoma (HeLa), lung cancer non-small cells (A549) and breast cancer (MCF-7). Derivatives 54a, 54b, and 54c demonstrated promising antitumor activity against the three cell lines (Fig. 15).63

OH

S N N

H2N

Cl

H2N

N

Cl

OH

S

N N

N N

N N

H N N

N

O OH

N

N

Cl NO2

NO2

(59)

(58)

(57)

IC 50= 0.32 mM

N N H N N

O OH

N H

N

H N

N

N

Cl Cl Cl

(60)

(61)

IC 50= 0.047 mM

R N N

Mechanistic Assays PBMC-HIV HIV-RT IC50= 10 mM HIV-1 IC50= 2.3 mM CCR5 Fusion IC 50= 36 mM HIV-2 IC 50= 31 mM CXCR4 Fusion IC50= 52 mM

H N

N O

NHSO 2Me N S O O

O

N N

(62)

(63)

Cell-based replication assay EC50 (mM) CC50 (mM) (62a) R= (4-Cl)Ph (62b) R= (4-Me)Ph

8.1 4.8

>224 >186

IC50 (mM) (63) Acyclovir

0.1 0.002

Fig. 17. Pyrazoles with antiviral activity.

% Reduction in the n° of plaques 53 100

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N F3C N O Ph

NH

S

N N

N

N

N

O

Ph N N

O S

S

N N Ph

NO2 HCV IC50 (mM)

(64)

(65) INFa-2b

Anti-HCVcc Cytotoxicity IC50 (mM) CC50 (mM) 0.11

0,56 0,1

ited the best IC50 (Fig. 18), but the high cytotoxicity of the majority of the compounds resulted in poor selective index values.72 Dawood et al. synthesized pyrazoles with 1,3-bisthiazole groups and investigated their antiviral profile. The most potent compound, 65 (Fig. 18), is a HCV inhibitor comparable to the reference drug INFa-2b.73 The human respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections, such as pneumonia and bronchiolitis. A new class of anti-RSV agents, N-((1,3-diphenyl-1H-pyrazol-4-yl)methyl)anilines, was described by the Fioravant research group. The most potent compounds, 66a and 66b, are illustrated in Fig. 18.74 2.6. Antileishmanial activity

3.2 R1 R HN

N

N

RSV viruses IC50 (m M) (66a) R= CF3, R 1= Br (66b) R= H, R 1= Cl

5 6

Fig. 18. Other pyrazoles with antiviral activity.

Iyer et al. synthesized the compound 57, a potent inhibitor of the negative regulatory factor (Nef), which is a multifunctional protein essential to the virulence of HIV-1. Compound 58 showed activity equipotent to that of 57 and structure-activity studies suggest that pyrazole ring is important for activity (Fig. 17).67 Mizuhara et al. synthesized a series of phenylpyrazole derivatives for the development of novel anti-HIV agents. The substituents on the right-side phenol and left-side pyrazole aryl ring were essential for potent anti-HIV activity. An optimization study starting from N-phenylpyrazole 59 led to analog 30 ,40 -dichlorophenyl 60, which exhibited anti-HIV activity six times greater than compound 59 (Fig. 17).68 The synthesis and evaluation of a series of pyrazole derivatives as a potential anti-HIV-1 multitarget agents was reported by Cox’s research group. A mechanism of action study confirmed the ability of the pyrazole-piperidine core to block viral entry by binding to the host protein CCR5 and CXCR4 receptors as well as inhibiting viral reverse transcriptase. Compound 61 (Fig. 17) was the most potent among the eleven compounds evaluated.69 Manfroni and colleagues synthesized a new class of pyrazolobenzothiazines to investigate activity against HCV. Most of the derivatives exhibited IC50 values lower than 15 lM against HCV in the cell-based replicon assay. Compounds 62a and 62b (Fig. 17) were identified as successful anti-HCV agents that did not display any anti-metabolic effects or alterations of cell morphology.70 A novel series of 4-substituted-3-methyl-1,5-diphenyl-1H-pyrazoles has been synthesized and assayed for their in vitro cytotoxicity and antiviral activity against herpes simplex virus type-1 (HSV-1). These compounds act via inhibition of the reverse transcriptase enzyme. Compound 63 (Fig. 17) was the most potent with regard to the reduction in the number of plaques and was less cytotoxic than acyclovir.71 Hwang et al. described novel 1,3,4-trisubstituted pyrazoles as potent hepatitis C virus (HCV) entry inhibitors. The pyrazoles interfered with viral entry, as determined by experiments with HCV replicons and HCV pseudo particles. Compound 64 exhib-

Leishmaniasis is a parasitic disease with severe morbidity and mortality rates. It is caused by Leishmania sp., which is transmitted to humans and others mammals through the bite of an infected female Phlebotomine sandfly. According to the World Health Organization (WHO), leishmaniasis is a neglected disease and the treatment presents many disadvantages including serious clinical side effects such as nephrotoxicity, hepatotoxicity, and cardiac arrhythmia, in addition to emerging resistance to available drugs.75 Various compounds containing the pyrazole nucleus have been evaluated for their antileishmanial activity. Bernardino’s research group synthesized a series of pyrazole derivatives with remarkable antileishmanial activities. Fourteen compounds were synthesized and assayed against L. amazonensis, L. braziliensis, and L. infantum. Compound 67 (Fig. 19) was the most potent against L. amazonensis.76 Bernardino and colleagues assayed several pyrazole-tetrazole hybrids against L. amazonensis and L. braziliensis. Compound 68 was the most potent against L. braziliensis.77 In another work, compound 69 showed potent activity, and in vivo tests displayed that the parasite load in infection mice was significantly reduced.78 Bekhit et al. synthesized pyrazoles substituted with five-membered heterocycles. All compounds were evaluated for their in vitro antileishmanial activity against Leishmania aethiopica promastigotes and amastigotes, leading to the identification of thiadiazole derivative 70 (Fig. 19) as the most potent compound.79 Marra et al. investigated the biological effects of 4-(1H-pyrazol1-yl)benzenesulfonamide derivatives against the L. infantum (L. chagasi syn.) and L. amazonensis promastigote forms. The biological data showed the almost equipotent potential of substances 71a and 71b (Fig. 19) compared to pentamidine. The pyrazole structures containing sulfonamide groups were active for treating infections caused by these two Leishmania strains.80 Borges and colleagues prepared novel pyrazolyl benzenesulfonamide derivatives with potential antileishmanial activity. These compounds were evaluated for their in vitro activity against Leishmania amazonensis and showed no murine macrophage toxicity. Derivative 72 (Fig. 19) showed activity higher than ketoconazole.81 Mowbray et al. identified three series of active compounds to investigate the activity of the pyrazole core against L. infantum and L. donovani, the two species of Leishmania parasites that cause visceral leishmaniasis (VL) in humans. Among the eleven pyrazolearylpiperazine derivatives assayed, compound 73 (Fig. 19) demonstrated good potency against both L. infantum and L. donovani and high levels of efficacy in an in vivo hamster model of VL.82 3. Conclusion Pyrazole is a five membered heterocyclic system capable of inhibiting distinct pathogens. It is a moiety that has been exploited for the synthesis of several compounds that have biological activities and can be further examined for prospective use against many diseases.

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N

N

N NH N

N

NH2

N

Cl

N

N NH N

N

N N NH NH2

N

Cl

Cl

OMe L. braziliensis (68) IC 50= 15 mM Pentamidine IC 50= 13 mM

L. amazonensis (67) IC50= 15.5 mM Pentamidine IC50= 10 mM

R1

H 3COC

L. amazonensis (69) IC50 = 22.3 mM Pentamidine IC 50= 10 mM

H3 C N

S

N

Br

N N N COCH 3

N

Cl

N

O S O NH (70)

R2

R

IC 50 (mM) L. i nf antum L. amazonensis

IC 50 (mg/mL) R1

R2

antipromastigote

NO2

Br

(71)

antiamastigote

0.0142

0.28

(71a) R=H 0.059

0.070

Miltefosine

3.192

0.3

(71b) R=Cl 0.065

0.072

Amphotericin B

0.047

0.2

Pentamidine 0.062

0.021

(70)

N

O N S O

O N NH

NH O S O

N NH

N

(72)

N

F

(73)

IC50 24h (mM) Promastigotes Axenic Amastigotes

IC50 (mM) L. i nf antum L. donav ani % inhibition in vi vo

Early log phase Late log phase (72)

6.7

41.3

56.0

Ketoconazole

12.5

29.8

164.1

(73) Miltefosine

2.37 7.26

1.31 n.d

95.0 99.6

Fig. 19. Pyrazoles with antileishmanial activity.

Conflict of interest The authors confirm that the contents of this article present no conflicts of interest. Acknowledgement We acknowledge UFF for the scholarships provided. This work is a collaborative research project between members of the Rede Mineira de Química (RQ-MG) supported by FAPEMIG – Brazil (Project: CEX-APQ-01014-14). References 1. Netto AVG, Frem RCG, Mauro AE. A química supramolecular de complexos pirazólicos. Quim Nova. 2008;31:1208–1217.

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Jéssica Venância Faria was born 03/18/1985, in Niterói, Rio de Janeiro state, Brazil. Currently she works in Farmanguinhos Fiocruz as chemist. In 2017 she obtained her Ph.D at the Universidade Federal Fluminense, Niterói, Rio de Janeiro state, Brazil. Her research fields are organic synthesis and biological evaluation of heterocyclic compounds, such as isatin and imidazole evaluated against HIV-1, Mycobacterium tuberculosis, and Trypanosoma cruzi. She have also worked with pyrazole system with potential antileishmanial activities.

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Percilene Fazolin Vegi was born 11/11/1978, in Muriaé, Minas Gerais state, Brazil. She graduated in Industrial Chemistry (2011) and Master’s Degree in Chemistry (2013) at the Universidade Federal Fluminense. She is currently a PhD student (2013–2017). She has completed a PhD Sandwich in the Chemistry Laboratory (Department of Organic Chemistry) at the Almeria University, Spain (2014–2015). The focus has been synthesis and characterization of pyrazoles and organophosphorus derivatives, including antileishmanial, anticoagulant, anti-inflammatory, and zica activities.

Ana Gabriella Carvalho Miguita was born 07/31/1994, in Conceição do Rio Verde, Minas Gerais state, Brazil. She was an undergraduated student at the Universidade Federal de Itajubá (2016), where she had worked from 2013 to 2015 in the Laboratório de Síntese Orgânica. She carried out organic synthesis, more specifically synthesis, characterization, and antileishmanial evaluation of new pyrazole-tetrahydropyrimidine hybrids. She is currently a master’s degree student at the Universidade Federal de Minas Gerais, Brazil.

Maurício Silva dos Santos was born 07/23/1978, in Bom Jesus do Itabapoana, Rio de Janeiro state, Brazil. He had worked at Bayer MaterialScience from 2005 to 2010 as industrial chemist. He starts his professor career in 2008 and currently is teaching and researching at the Universidade Federal de Itajubá, Brazil. In 2009 he obtained his Ph.D at the Universidade Federal Fluminense, Niterói, Rio de Janeiro state, Brazil. His research fields are organic synthesis and biological evaluation of heterocyclic compounds. The main heterocyclic systems are pyrazole, tetrazole, imidazoline, tetrahydropyrimidine, and thiophene, which are assayed against Leishmania sp. and Trypanosoma cruzi. The anticoagulants and anti-inflammatories properties have been also investigated recently.

Nubia Boechat was born 06/18/1953, in Três Pontas, Minas Gerais state, Brazil. She holds a degree from the Faculty of Pharmacy of the Federal University of Rio de Janeiro (UFRJ), a master’s degree in organic synthesis from the Nucleus of Natural Product Research (NPPN) at UFRJ, a doctorate in Chemistry from the Institute of Chemistry (IQ) at UFRJ. She completed a postdoctoral degree at the London School of Hygiene and Tropical Medicine in London, England. She is a master’s and doctoral advisor at the IQ-UFRJ and ICB-UFRJ permanent staff and a senior technologist at the Oswaldo Cruz Foundation (FIOCRUZ). She is currently head of the Department of Synthesis of Drugs and coordinator of the project to implement the National Reference Center on Drug Synthesis. The main focus is the Pharmaceutical PD & I, having experience in the area of organo-fluorochemicals and heterocycles, with emphasis on Medicinal Chemistry, mainly in the following subjects: AIDS, cancer and neglected diseases, such as: malaria, leishmaniasis, Chagas disease and tuberculosis.

Alice Maria Rolim Bernardino was born 09/01/1951, in Rio de Janeiro state, Brazil. She started her professor career in 1984 and has teaching and researching at Universidade Federal Fluminense, Niterói, Rio de Janeiro state, Brazil. In 1985, she obtained her Ph.D degree at Instituto Militar de Engenharia, Rio de Janeiro, Brazil. In 1994, she obtained her postdoctorate at School of Pharmacy, The University of Mississippi, USA. Currently she is Full Professor at the Department of Organic Chemistry at the Universidade Federal Fluminense. Her research fields are organic synthesis and biological evaluation of heterocyclic compounds. The heterocyclic systems are pyrazole, tetrazole, imidazoline, pyrazolopyridine, quinoline, thienopyridine and other systems with antileishmanial, antimalarial, anti-Trypanosoma cruzi, antiviral, anticoagulant and anti-inflamatory activities.