Review: biologically active pyrazole derivativesszolcsanyi/education/files... · 16 | New J. Chem., 201, 41,16--41 This journal is ' The Royal Society of Chemistry and the Centre

16 | New J. Chem., 2017, 41, 16--41 This journal is©The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2017

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Review: biologically active pyrazole derivatives

Anam Ansari,† Abad Ali,† Mohd Asif and Shamsuzzaman*

Nitrogen-containing heterocyclic compounds and their derivatives have historically been invaluable as a

source of therapeutic agents. Pyrazole, which has two nitrogen atoms and aromatic character, provides

diverse functionality and stereochemical complexity in a five-membered ring structure. In the past

decade, studies have reported a growing body of data on different pyrazole derivatives and their

innumerable physiological and pharmacological activities. In part, such studies attempted to reveal the

wide range of drug-like properties of pyrazole derivatives along with their structure–activity relationships

in order to create opportunities to harness the full potentials of these compounds. Here, we summarize

strategies to synthesize pyrazole derivatives and demonstrate that this class of compounds can be tar-

geted for the discovery of new drugs and can be readily prepared owing to recent advances in synthetic

medicinal chemistry.

Introduction

Heterocycles are an extraordinarily important and unique class ofcompounds; they make up more than half of all known organiccompounds and have a wide range of physical, chemical andbiological properties spanning a broad spectrum of reactivity andstability.1 Heterocycles are widely distributed in nature and play avital role in metabolism because their structural subunits existin many natural products, including vitamins, hormones, anti-biotics, and alkaloids as well as pharmaceuticals, agrochemicals,dyes, and many others.2 In addition to naturally occurring

compounds, a large number of synthetic heterocyclic compoundswith important physiological and pharmacological propertiesare also known.3 These compounds provide scaffolds on whichpharmacophores can arrange to yield potent and selective drugs.4

Moreover, compounds having heterocyclic moieties displayenhanced solubility and salt-formation properties that enable theiroral absorption and bioavalability.5 Among heterocyclic com-pounds, nitrogen-containing heterocycles are the core structuresof numerous biologically active compounds and exhibit numerousapplication in chemistry, biology and other sciences.6 They are thebuilding blocks of life due to their wide occurrence in nature andcentral roles in the chemical reactions that occur in all organisms.7

Furthermore, nitrogen-containing heterocycles play an importantrole in coordination chemistry.8 Pyrazoles are well-known examplesof aromatic heterocycles containing two nitrogen atoms in theirfive-membered rings.9 They constitute an important heterocyclic

Steroid Research Laboratory, Department of Chemistry, Aligarh Muslim University,

Aligarh 202 002, India. E-mail: [email protected],

[email protected], [email protected]; Tel: +91 9411003465

Anam Ansari

Anam Ansari was born in UttarPradesh (India) in 1992. Shereceived her BSc in Chemistry in2012 and MSc with a specializationin Organic Chemistry in 2014 fromAligarh Muslim University, Aligarh.At present, she is pursuing a PhD asa Junior Research Fellow under thesupervision of Prof. Shamsuzzamanin the Department of Chemistry,AMU, Aligarh. Her research interestfocuses on steroidal derivativesincorporated within heterocyclicsystems.

Abad Ali

Abad Ali received his BSc (Hons.)degree in Chemistry from AligarhMuslim University in 2009. Heobtained his MSc degree inOrganic Chemistry from the sameinstitution in 2011. He has alreadysubmitted a PhD thesis under thesupervision of Prof. Shamsuzzamanentitled ‘‘Synthesis, Characteriza-tion and Biological Evaluation ofSteroidal Heterocyclic Compounds.’’

† These authors contributed equally.

Received (in Montpellier, France)10th October 2016,Accepted 16th November 2016

DOI: 10.1039/c6nj03181a

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family covering a broad range of synthetic as well as naturalproducts that display innumerable chemical, biological, agro-chemical and pharmacological properties.10 Pyrazole derivativesrepresent one of the most active classes of compounds and possessa wide spectrum of biological activities.11–22 In recent years, severaldrugs have been developed from pyrazole derivatives. For example,celecoxib demonstrates anti-inflammatory effects and inhibitsCOX-2; rimonabant functions as a cannabinoid receptor and isutilized to treat obesity; fomepizole inhibits alcohol dehydrogenase;and sildenafil inhibits phosphodiesterase23 (Fig. 1). Some of thesecompounds have important applications in material chemistry24

and as brightening agents,25 and some exhibit significantsolvatochromic26 and electroluminescence27 properties. More-over, they act as semiconductors,28 liquid crystals,29 andorganic light-emitting diodes.30 Heterocycles having pyrazolerings are also of considerable interest because of their syntheticutility as synthetic reagents in multicomponent reactions,31

chiral auxillaries32 and guanylating agents.33 It has also beenfound that various substituted pyrazoles are used as chelationand extraction reagents for many metal ions.34 In addition,there are well-known natural products containing pyrazolemoieties that have various physiological, pharmacological andtoxic properties35 (Table 1). In light of the significance ofpyrazoles in countless areas, particularly medicinal chemistry,the present review focuses on the synthesis of diverse pyrazolederivatives and their biological activities.

Chemistry

The pyrazole ring is a prominent structural motif found innumerous pharmaceutically active compounds. This is mainlydue to its ease of preparation and pharmacological activity. Ithas also been found that the selective functionalization ofpyrazole with diverse substituents improves their range ofaction in various fields. As a part of the continuing interest in

pyrazole derivatives, numerous compounds with pyrazole ringshave been reported. Chimenti et al.36 put forward a synthetic routefor a series of N1-thiocarbamoyl-3,5-di(hetero)aryl-4,5-dihydro-(1H)-pyrazole derivatives that act as monoamine oxidase inhibitors(Scheme 1). In this protocol, the starting 1,3-di(hetero)aryl-2-propen-1-ones (3) have been synthesized by Claisen-Schmidtcondensation under reflux between substituted aryl or hetero-aryl aldehyde (1) and an appropriate substituted aryl or hetero-aryl ketone (2).37 The intermediates were treated withthiosemicarbazide in KOH/EtOH to afford the desired productsin good yields without further purification (Table 2).

Liu et al.38 reported the synthesis of 4,5-dihydro-2H-pyrazole-2-hydroxyphenyl derivatives as BRAF inhibitors with hydrazinehydrate and chalcones (Scheme 2). The chalcones (7a–7t) were

Fig. 1 Drug molecules containing pyrazole scaffolds.

Mohd Asif

Mohd Asif was born in 1986 inAligarh (U.P.). He obtained hisBSc degree in chemistry fromAligarh Muslim University andreceived his MSc from the sameuniversity. Presently, he isworking as a research scholarunder the supervision of Prof.Shamsuzzaman at AMU, Aligarh.

Shamsuzzaman

Prof. Shamsuzzaman obtained aPhD in 1983 in synthetic organicchemistry from AMU. In 1985, hejoined Queen’s University, Belfast(UK) as a Leverhulme Common-wealth/USA Visiting Fellow. InJan. 1989, he joined JMI, NewDelhi as Assistant Professor.Later, in 1998, he joined AMU,Aligarh as Associate Professor.Presently, he is working asProfessor of Chemistry in theDepartment of Chemistry, AligarhMuslim University, Aligarh. He

has published about 100 research papers in reputed internationaljournals. His research interests are mainly steroids and theirsynthetic and biological evaluation.

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obtained from substituted salicylaldehydes (6) and substitutedacetophenones (5) using 40% KOH as catalyst. The N-acetyl groupin the final products (9a–9t) was introduced by treating a solutionof compounds 8a–8t with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) and hydroxybenzotriazole (HOBT) (Table 3).They further reported a slightly modified synthetic route to4,5-dihydro-1H-pyrazole derivatives (13a–13t) as DNA gyraseinhibitors39 (Scheme 3). The chalcones (10a–10t) were first

allowed to react with 1-chloro-2,6-dinitro-4-trifluoromethyl-benzene in the presence of potassium tert-butoxide to furnish11a–11t, which were then reacted with hydrazine hydrate inrefluxing ethanol for 8 h. Subsequently, the desired products(13a–13t) were obtained by the treatment of solutions ofcompounds 12a–12t with EDC (I) and HOBT (II) (Table 4).

Khalilullah et al.40 put forward a slightly altered route to synthe-size a series of pyrazole derivatives (19a–19o) as antihepatotoxic

Table 1 Natural products containing pyrazole moieties

Name Isolated from Structure Applications

L-a-Amino-b (pyrazolyl-N)-propanoic acid– First natural product containing pyrazole Citrullus vulgaris – Antidiabetic

Withasomnine40-Hydroxywithasomnine40-Methoxywithasomnine

Withania somnifera Dun

– Analgesic– Anti-inflammatoryDepressant to

– CNS (CentralNervous System)

– Circulatory system

PyrazofurinPyrazofurin B Streptomyces candidus

– Antitumor– Antiviral

Formycin Streptomyces candidus, Streptomyces lavendulaeand Nocardia interforma

– Antiviral– Antitumor

Formycin B Streptomyces lavendulae and Nocardia interforma– Antiviral– Antitumor

Oxoformycin B– A metabolite of Formycinand Formycin B

Streptomyces lavendulae and Nocardia interforma – Antiviral– Antitumor

Nostacine A Nostoc spongiaeforme – Cytotoxic

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agents from chalcones and hydrazine hydrate (Scheme 4). Thestarting material 2,3-dihydro-1,4-benzodioxane-6-carbaldehyde (16)was prepared by the reaction of 3,4-dihydroxybenzaldehyde (14)and ethylenedibromide (15) in the presence of anhydrous K2CO3.On condensation with substituted acetophenone (17), 15 affordedcorresponding chalcones (18a–18o), which was treated with hydra-zine to obtain pyrazole derivatives (19a–19o) (Table 5).

An efficient synthetic route for 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (23a–23g) and 5-amino-1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (24a–24g) as antileishmanial agents(Scheme 5) was reported by Santos et al.41 The intermediates(21a–21g) were obtained from arylhydrazine hydrochlorides(20a–20g) and ethoxymethylene malononitrile42 and were con-verted to pyrazole carbonitriles (22a–22g) by aprotic deaminationusing t-butyl nitrite. Finally, the targets were obtained usingcarbon disulphide and ethylenediamine. Huang et al.43 reportedan expeditious, straight-forward, one-pot methodology for thesynthesis of pyrazolo[3,4-d]pyrimidines (26a–26o) showing anti-proliferative activity (Scheme 6). The procedure involved the

Table 1 (continued )

Name Isolated from Structure Applications

Fluviols (A–E) Pseudomonas fluoresences – Antimicrobial

Scheme 1 Synthesis of N1-thiocarbamoyl-3,5-di(hetero)aryl-4,5-dihydro-(1H)-pyrazole derivatives (4a–4t) as monoamine oxidase inhibitors.

Table 2 N1-Thiocarbamoyl-3,5-di(hetero)aryl-4,5-dihydro-(1H)-pyrazolederivatives (4a–4t)

Entry Compound Ar Ar0

1 4a Ph Ph2 4b Ph 40-CH3-Ph3 4c Ph 40-Cl-Ph4 4d Ph Fur-20-yl5 4e 40-CH3-Ph 40-F-Ph6 4f 40-CH3-Ph Thiophen-20-yl7 4g 40-F-Ph Thiophen-20-yl8 4h 40-Cl-Ph 40-CH3-Ph9 4i 40-Cl-Ph 40-F-Ph10 4j 40-Cl-Ph 40-Cl-Ph11 4k 40-Cl-Ph Pyrrol-20-yl12 4l Fur-20-yl 40-CH3-Ph13 4m Fur-20-yl 40-F-Ph14 4n Fur-20-yl Thiophen-20-yl15 4o Thiophen-20-yl Pyrrol-20-yl16 4p Pyrrol-20-yl Ph17 4q Pyrrol-20-yl 40-F-Ph18 4r Pyrrol-20-yl 40-Cl-Ph19 4s Pyrrol-20-yl Fur-20-yl20 4t Pyrrol-20-yl Thiophen-20-yl

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treatment of 5-aminopyrazoles (25a–25o) with PBr3 in formamide(Table 6).

Some new 1H-pyrazole derivatives containing aryl sulfonatemoieties acting as COX-2 inhibitors were synthesized byKendre et al.44 (Scheme 7). In this synthetic route, the inter-mediate (29a–29e) was prepared by the reaction of 2-hydroxyacetophenone45,46 (27a–27e) with N,N-dimethyl formamidedimethyl acetal (DMF-DMA) (28) under microwave irradiation,which furnished 30a–30e when reacted with p-toluene sulfonylchloride in the presence of anhydrous K2CO3 as catalyst. Thedesired product (31a–31f) was obtained by the action of hydra-zine hydrate (Table 7). Another microwave-assisted syntheticroute to synthesize pyrazole-4-carbaldehyde with analgesic andanti-inflammatory activity was reported by Selvam et al.47

(Scheme 8). In this approach, acetophenone (32) and substitutedaryl hydrazine (33) were exposed to microwave to give 1-substitutedphenyl-2-(1-phenylethylidene) hydrazine (34a–34l), which undergoVilsmeier–Haack reactions to furnish the target compounds

Scheme 2 Synthesis of 4,5-dihydro-2H-pyrazole-2-hydroxyphenyl derivatives (9a–9t) as BRAF inhibitors.

Table 3 4,5-Dihydro-2H-pyrazole-2-hydroxyphenyl derivatives (9a–9t)

Entry Compound R1 R2 R3

1 9a CH3 Br Br2 9b CH3 Cl Cl3 9c CH3 H Br4 9d CH3 H Cl5 9e OCH3 Br Br6 9f OCH3 Cl Cl7 9g OCH3 H Br8 9h OCH3 H Cl9 9i F Br Br10 9j F Cl Cl11 9k F H Br12 9l F H Cl13 9m Cl Br Br14 9n Cl Cl Cl15 9o Cl H Br16 9p Cl H Cl17 9q Br Br Br18 9r Br Cl Cl19 9s Br H Br20 9t Br H Cl

Scheme 3 Synthesis of 4,5-dihydro-1H-pyrazole derivatives (13a–13t) as DNA gyrase inhibitors.

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(35a–35l) (Table 8). A similar synthetic strategy involving thecondensation and cyclization of phenylhydrazine with varioussubstituted acetophenones followed by Vilsmeier–Haack reac-tion was reported by Sun et al.48 (Scheme 9). In this synthetic

route, a series of 1,3-diphenyl-N-(phenylcarbamothioyl)-1H-pyrazole-4-carboxamide derivatives (36a–40d) were synthesized via the inter-action of substituted cyanic 1,3-diphenyl-1H-pyrazole-4-carboxylicthioanhydride (36–40) and substituted anilines (Table 9).

Sidique et al.49 reported the synthesis of pyrazole amides (45) asselective inhibitors of tissue-nonspecific alkaline phosphatasesfrom pyrazole acids (Scheme 10). These acids were obtained bythe reaction of acetophenone derivatives with sodium methoxideand dimethyl oxalate to furnish 1,3-diketone. Diketone derivatives(42) were then reacted with hydrazine to give pyrazole esters (43),which gave pyrazole acids (44) upon saponification (Table 10).A multistep synthetic strategy was put forward by Ma et al.50

to synthesize trifluoroethylpyrazole derivatives (51a–51c) withherbicidal activity (Scheme 11). The intermediates 46 wereobtained starting from glyoxalic acid and hydroxylamine hydro-chloride and was then reacted with trifluoroethylpyrazoleethanethioate (49) followed by treatment with mCPBA to furnishthe desired products.

Starting from pyrazole aldehyde,52 Wang et al.51 reported asynthetic route for oxazole ring-containing pyrazole derivatives(57a–57r) that show acaricidal, insecticidal and fungicidalactivities (Scheme 12). Aldehyde 52 was directly converted tothe key intermediate 53 by treatment with hydroxylamine.Intermediate 4-chloromethyl-2-aryloxazole (56) was successivelyprepared from substituted benzoic acid (54). Further reaction of53 with 56 promoted by Cs2CO3 produced the target compound(Table 11).

A highly regioselective approach for the synthesis of cis-restricted 3-aminopyrazole has been reported by Tsyganov et al.53

(Scheme 13). Polyalkoxybenzoic acids (58) and aromatic aceto-nitriles (59) underwent base-mediated condensation to furnisha-ketonitriles 60 and 62, which subsequently cyclized into pyrazoles61 and 63 with hydrazine hydrochloride. McElroy et al.54 reportedthe convenient synthesis of amidopyrazoles utilizing ketonitriles(Scheme 14). The a-ketonitriles 64 were condensed with 4-methyl-phenylhydrazine to form 65.55 Aminopyrazole (65) was then allowedto react with acid chloride to produce the desired product, whichshows inhibitory activity against IRAK4 (Table 12).

Inceler et al.56 reported a novel synthetic approach to synthesizeester and amide derivatives of 1-phenyl-3-(thiophen-3-yl)-1H-pyrazole-4-carboxylic acid as anticancer agents (Scheme 15).Carboxylic acid derivatives (68) were obtained from hydrazonederivatives (67) when reacted with POCl3 and DMF followed byoxidation. Treatment of 69 with appropriate amines or phenolsin the presence of Et3N/CH2Cl2 provides access to the targetproduct (Table 13). An interesting synthesis of pyrazolylbenzyl-triazole derivatives (72, 73) as cyclooxygenase inhibitors wasdeveloped by Chandna et al.57 using 1-[(4-hydrazinophen-1-yl)methyl]-1H-1,2,4-triazole hydrochloride (Scheme 16). The triazoleintermediate was obtained via the condensation of 4-nitrobenzylbromide and 4-aminotriazole in ethyl acetate followed by diazotiza-tion and reduction. The intermediate was then treated withtrifluoromethyl-b-diketones (71) to afford the target compounds.

A multicomponent and green synthetic route for the synthesisof pyrano pyrazole derivatives as antioxidants and antimicrobialagents was reported by Ambethkar et al.58 (Scheme 17). The target

Table 4 4,5-Dihydro-1H-pyrazole derivatives (13a–13t)


1 13a CH3 Br Br2 13b CH3 Cl Cl3 13c CH3 Br H4 13d CH3 Cl H5 13e OCH3 Br Br6 13f OCH3 Cl Cl7 13g OCH3 Br H8 13h OCH3 Cl H9 13i F Br Br10 13j F Cl Cl11 13k F Br H12 13l F Cl H13 13m Cl Br Br14 13n Cl Cl Cl15 13o Cl Br H16 13p Cl Cl H17 13q Br Br Br18 13r Br Cl Cl19 13s Br Br H20 13t Br Cl H

Scheme 4 Synthetic route for the preparation of 5-(2,3-dihydro-1,4-(benzodioxane-6-yl)-3-phenyl)-4,5-dihydro-1H-pyrazole derivatives (19a–19o).

Table 5 5-(2,3-Dihydro-1,4-(benzodioxane-6-yl)-3-phenyl)-4,5-dihydro-1H-pyrazole derivatives (19a–19o) as antihepatotoxic agents

Entry Compound R

1 18a, 19a H2 18b, 19b 2-OH3 18c, 19c 4-OH4 18d, 19d 2,4-Dihydroxy5 18e, 19e 2-Cl6 18f, 19f 4-Cl7 18g, 19g 4-F8 18h, 19h 4-Br9 18i, 19i 4-OMe10 18j, 19j 3,4-Dimethoxy11 18k, 19k 2-CH312 18l, 19l 3-CH313 18m, 19m 4-CH3

14 18n, 19n 4-NO2

15 18o, 19o N(CH3)2

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compounds (74a–74i) were obtained from aryl aldehyde,malononitril, hydrazine hydrate and diethyl acetylenedi-carboxylate by a grinding method. The synthesis of somesteroidal pyrazolines and pyrazoles was also reported byBanday et al.59 In this synthetic strategy (Scheme 18),pyrazolines (77) were synthesized by the reaction of pre-gnenolone (75) with aryl aldehyde to obtain 76, which wasfurther treated with hydrazine hydrate in the presence of

acetic acid. In the synthetic protocol for pyrazoles (79), priorto treatment with hydrazine, pregnenolones were first con-verted to 78 (Table 14).60

Scheme 5 Synthetic path for the preparation of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (23a–23g) and 5-amino-1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (24a–24g).

Scheme 6 One-pot synthesis of pyrazolo[3,4-d]pyrimidines derivatives(26a–26o).

Table 6 Cytotoxic pyrazolo[3,4-d]pyrimidines derivatives (26a–26o)43

Entry Compounds X(N-1) R(C-3)

1 a Ph Ph2 b o-Cl-Ph Ph3 c p-Cl-Ph Ph4 d p-Br-Ph Ph5 e p-OMe-Ph Ph6 f Ph Me7 g Ph t-Bu8 h Ph p-Cl-Ph9 i p-Cl-Ph p-Cl-Ph10 j 2-Pyridinyl Me11 k 2-Pyridinyl Ph12 l 2-Quinolinyl Me13 m 2-Quinolinyl t-Bu14 n 2-Quinolinyl p-Me-Ph15 o 2-Quinolinyl p-OMe-Ph

Scheme 7 Synthesis of 1H-pyrazole derivatives (31a–31f) containing arylsulphonate moieties acting as COX-2 inhibitors.

Table 7 1H-Pyrazole derivatives (31a–31f)


1 a H H H2 b I H I3 c Br H Br4 d I Me Me5 e H H Cl6 f H H H7 g I H I8 h Br H Br9 i I Me Me10 j H H Cl

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BiologyMonoamine oxidase inhibitors

Monoamine oxidase (MAO) is a flavoprotein located at the outermembrane of the mitochondria in neuronal, glial, and othercells. MAO is widely distributed among mammals, plants,prokaryotic and eukaryotic microorganisms and catalyzes theoxidative deamination of monoamine; thus, MAO is a target

enzyme for antidepressant drugs. In addition, it is also responsiblefor the biotransformation of 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) into 1-methyl-4-phenylpyridinium, a Parkinsonian-producing neurotoxin. MAO exists in two forms, MAO-A and MAO-B,which are characterized by specific substrates and inhibitors. MAO-Aoxidizes norepinephrine and serotonin [5-hydroxytrypamine, 5-HT],whereas MAO-B preferentially deaminates 2-phenylethylamine(2-PEA) and benzylamine. These properties determine the clinicalimportance of MAO inhibitors.61,62 Several N1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-(1H)-pyrazoles (80a–80j) have been synthesizedby Palaska et al.63 and assayed as MAO inhibitors against mono-amine oxidases isolated and purified from the mitochondrialextracts of rat liver homogenates and human platelets (Fig. 2).

They suggested that these compounds were time-dependentinhibitors of MAO since their inhibitory activities were significantlyincreased with incubation time, and the inhibition of liver MAOby these compounds was found to be non-competitive andirreversible. However, the N1-thiocarbamoyl-3,5-di(hetero)aryl-4,5-dihydro-(1H)-pyrazole derivatives (4a–4t) synthesized byChimenti et al.36 (Scheme 1) exhibit inhibitory activity againstA and B isoforms of human MAO (hMAO). The authors sug-gested that the presence of a fluorine atom in the 40-position of

Scheme 8 Microwave-assisted synthetic route for the preparation of pyrazole-4-carbaldehyde derivatives (35a–35l) via Vilsmeier–Haack reagent.

Table 8 Pyrazole-4-carbaldehyde derivatives (35a–35l)

Entry Compound R1 R2

1 a H H2 b CH3 H3 c H CH3

4 d OCH3 H5 e H OCH36 f F H7 g H F8 h Br H9 i H Br10 j Cl H11 k H Cl12 l H NHCOCH3

Scheme 9 Schematic representation of the preparation of a series of 1,3-diphenyl-N-(phenylcarbamothioyl)-1H-pyrazole-4-carboxamide derivatives(36a–40d).

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the 5-phenyl substituent on the pyrazoline ring is important foractivity. The most active compound of the series is compound4m (IC50 = 2.75 � 0.81 mM and selectivity ratio is 25), which hasa 40-fluorophenyl substituent in the 5-position and a fur-20-ylgroup in the 3-position of the pyrazoline ring (Table 2). Thesecompounds also show irreversible inhibitory effects.

BRAF inhibitors

BRAF is a human gene that makes a protein called B-Raf,formally known as serine/threonine protein kinase B-Raf,which is mutated in some human cancers. BRAF belongs tothe RAS/RAF/MEK/ERK/MAP kinase pathway, which mediatescellular responses to growth signals. This mitogen-activatedprotein kinase pathway plays an important role in the transductionof mitogenic signals from the cell membrane to the nucleus toregulate cell growth, survival, differentiation and proliferation inresponse to external stimuli.64 Various mutations occur in BRAF,and the substitution of valine for glutamic acid at position 600

(V600E; formally identified as V599E) has been identified as themost common mutation in human cancer.65 Targeting theprotein kinase pathway through the inhibition of BRAFV600E isimportant in cancer therapeutics, particularly melanoma. The4,5-dihydro-2H-pyrazole-2-hydroxyphenyl derivatives synthesizedfrom hydrazine hydrate and chalcones by Liu et al.38 (Scheme 2)showed remarkable antiproliferative effects against BRAFV600E,WM266.5 (human melanoma cell line) and MCF-7 (humanbreast cancer cell line). Among them, compounds 9d and 9mdisplayed the strongest inhibitory activity (9d: IC50 = 1.31 mM forMCF-7 and IC50 = 0.45 mM for WM266.5; 9m: IC50 = 0.97 mMfor MCF-7 and IC50 = 0.72 mM for WM266.5) (Table 3). Thestructure–activity relationships (SARs) of these dihydropyrazolederivatives indicate that compounds with para electron-donatingsubstituents (9a–9h) show more potent activities than those withpara electron-withdrawing substituents (9i–9t). A series of novel5-phenyl-1H-pyrazole derivatives with niacinamide moieties(81a–81u) were reported by Wang et al.66 as potential BRAFV600E

inhibitors. Among them, compound 81o displayed the strongestinhibitory activity (IC50 = 2.63 mM for WM266.4 and IC50 =3.16 mM for A375). The authors also suggested that paraelectron-donating substituents showed more potent inhibitoryactivity. Zhao et al.67 reported 4,5-dihydro-1H-pyrazole thiazolederivatives (82a–82t) as BRAFV600E inhibitors. The compoundcontaining R1 = Cl and R2 = CF3 (82t) showed the most potentinhibitory activities against BRAFV600E kinase (IC50 = 0.05 mM)and two cancer cell lines, WM266.4 (IC50 = 0.12 mM) and MCF-7(IC50 = 0.16 mM). In contrast to above, the authors observed thatcompounds with para electron-withdrawing groups are more

Table 9 Structure of 1,3-diphenyl-N-(phenylcarbamothioyl)-1H-pyrazole-4-carboxamide derivatives (36a–40d)


1 36a H Me2 36b H OMe3 36c H F4 36d H Cl5 37a Me Me6 37b Me OMe7 37c Me F8 37d Me Cl9 38a Cl Me10 38b Cl OMe11 38c Cl F12 38d Cl Cl13 39a F Me14 39b F OMe15 39c F F16 39d F Cl17 40a OMe Me18 40b OMe OMe19 40c OMe F20 40d OMe Cl

Scheme 10 Synthesis of pyrazole amides (45) as selective inhibitors.

Table 10 Pyrazole amide derivatives (45)

Entry Compound R1 R2 R

1 45a H H NH2CH2CH2OH2 45b H F NH2CH2CH2OH3 45c H H NH2CH(CH3)24 45d H H NH(CH3)25 45e H H NH2CH2CH2CH2OH6 45f H H NH2CH2CH2OMe7 45g H H NH2(CH2CH2OH)2

8 45h Cl H NH2CH2CH2OH

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active than compounds with para electron-donating groups(Fig. 3).

DNA gyrase inhibitor

DNA gyrase is an essential bacterial enzyme involved in the vitalprocesses of DNA replication, transcription and recombination.It belongs to a class of enzymes known as topoisomerases,which are involved in the control of topological transitions ofDNA. This enzyme possesses a unique ability to catalyze theATP-dependent negative supercoiling of double-stranded closed-circular DNA.68 The mechanism by which gyrase influences the

topological state of DNA molecules is of inherent interest from anenzymological standpoint; hence, gyrase hence receives much atten-tion as a selected target for antibacterial agents.69 Many pyrazolederivatives are acknowledged to possess a wide range of antibacterialbioactivities70 and act as DNA gyrase inhibitors. Gomez et al.71

synthesized a series of novel pyrazole derivatives as DNA gyraseinhibitors that exhibit antibacterial activities against Gram-negative(E. coli) and Gram-positive (S. aureus and S. pneumoniae) bacterialstrains. Compound 83 was described as one of the most activecompounds, with potent antibacterial activities against bothGram-positive and Gram-negative bacterial strains. The authors

Scheme 11 Multistep synthetic strategy for the synthesis of trifluoroethylpyrazole derivatives (51a–51c).

Scheme 12 Multistep synthetic approach for the synthesis of pyrazole derivatives (57a–57r).

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highlighted the importance of the linker length and the orienta-tions of the moieties on the right- and left-hand sides in theantibacterial activity (Fig. 4).

The compound synthesized by Liu et al.39 exhibited antibacter-ial activity (Scheme 3) against two Gram-negative bacterial strains(E. coli and P. aeruginosa) and two Gram-positive bacterial strains(B. subtilis and S. aureus). The compounds were examined againstDNA gyrase isolated from B. subtilis and S. aureus; compounds13b, 13l, and 13r showed poor inhibitory activities, whereas 13a,13d, 13g, 13h, 13o, 13p, 13s and 13t displayed potent inhibitoryactivities (Table 4). Among all derivatives, compound 13t dis-played broad-spectrum antimicrobial activity against all testedbacterial strains, compound 13d showed the most potent activity(MIC = 0.39 mg mL�1) against both B. subtilis and S. aureus, andcompounds 13h and 13t showed the most potent activities

(MIC = 0.39 mg mL�1) against P. aeruginosa and E. coli. Thisdemonstrated that the potent anti-Gram-positive bacterial activitiesof the synthetic compounds were probably correlated to their relatedDNA gyrase inhibitory activities. The SARs of these dihydro-pyrazolederivatives indicated that compounds with para electron-donatingsubstituents (13a–13h) on the A-ring showed more potent activitiesthan those with electron-withdrawing substituents (13i–13t) on theA-ring. Compounds with F (13i–13l), Cl (13m–13p) and Br (13q–13t)substituents had mostly moderate effects compared to compoundswith OCH3 (13e–13h). Moreover, keeping the substituent constanton the A-ring and changing the substituent of the B-ring also affectedthe activities of these compounds. Compounds with halogen atomsat the 5-position display higher activities than compounds with twohalogen atoms at both the 3- and 5-positions, and the activity isgenerally greater when the substituent at the 5-position is Clcompared to Br. Thus, compounds 13d and 13h, which have a paraelectron-donating group in the A-ring and Cl in the B-ring, bothshowed wonderful antibacterial activity. Furthermore, a bioassay ofGram-positive bacteria showed that the order of strength is CH3 4OCH3 (13a–13h) and Cl 4 Br 4 F (13i–13t) for para-substitutedA-ring compounds. On the other hand, for Gram-negative bacteria,the strength order is OCH3 4 CH3 (13a–13h) and Br 4 Cl 4 F(13i–13t) for para-substituted A-ring compounds. Thus, com-pound 13d, which has a para-CH3 group on the A-ring and Clon the B-ring, showed the best anti-Gram-positive activity. Thecompounds 13h, with a para-OCH3 group on the A-ring and Clon the B-ring, and 13t, with Br on the A-ring and Cl on the B-ring,both showed the best anti-Gram-negative activities.

Antihepatotoxicity

The liver is a vital organ and plays a major role in metabolism.The liver has numerous functions in the human body, includingthe regulation of glycogen storage, decomposition of red blood

Table 11 Pyrazole derivatives (57a–57r)


1 57a 4-CH3 4-F2 57b 4-OCH3 4-F3 57c 4-F 4-F4 57d 4-Cl 4-F5 57e 2,4-F2 4-F6 57f 2,4-Cl2 4-F7 57g 4-F 4-Cl8 57h 4-Cl 4-Cl9 57i 4-Br 4-Cl10 57j 3-F 4-Cl11 57k 3-CF3 4-Cl12 57l 2,4-Cl2 4-Cl13 57m 4-F 2,4-Cl2

14 57n 4-Cl 2,4-Cl2

15 57o 4-Br 2,4-Cl2

16 57p 3-CF3 2,4-Cl217 57q 4-OCF3 2,4-Cl218 57r 2,4-F2 2,4-Cl2

Scheme 13 Synthesis of 4,5-polyalkoxydiaryl-3-aminopyrazoles 61 and 63.

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cells, hormone production and detoxification. The liver is involvedin the transformation and clearing of chemicals from the body

and therefore is susceptible to toxicity from these agents. Thistype of liver damage driven by certain chemicals and drugs isknown as hepatotoxicity. Although hepatotoxicity can be pre-vented or treated, if not, it can lead to progressive liver injury andliver fibrosis and ultimately cirrhosis, portal hypertension, liverfailure, and in some instances, cancer. Silymarin isolated from

Scheme 14 Synthetic path for the preparation of amidopyrazoles (66).

Table 12 Amidopyrazoles derivatives (66a–66h and 66i–66p)

Entry Compound R1(a–h) R2(a–h) R3(i–p)

1

2

3

4

5

6

7

8

Scheme 15 Synthesis of 1-phenyl-3-(thiophen-3-yl)-1H-pyrazole-4-carboxylic acid derivatives (70a–70l).

Table 13 1-Phenyl-3-(thiophen-3-yl)-1H-pyrazole-4-carboxylic acidderivatives (70a–70l)

Entry R Entry R

1 7

2 8

3 9

4 10

5 11

6 12

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seeds of S. marianum, which is commonly known as milkthistle, has been found to be a potent antihepatotoxic agentagainst a variety of toxicants. Silymarin has been recognized asa mixture of three isomers: silybin, silychristin and silydianin.The main component of silymarin is silybin, which contains a1,4-benzodioxane ring system and possesses significant anti-hepatotoxic activity.72 Khalilullah et al.40 synthesized pyrazolederivatives containing 1,4-benzodioxane rings as antihepatotoxicagents (Scheme 4). These compounds were evaluated against CCl4-induced hepatic damage in rats and shown to possess significantantihepatotoxic activity. Among all compounds reported, com-pounds 19d and 19j demonstrated significant antihepatotoxicactivities compared to the standard drug silymarin. Othercompounds in the series showed moderate antihepatotoxicactivity. Upon administration, the synthesized compoundsprovided significant protection against hepatocyte injury and

promoted normal tissues as neither fatty accumulation nornecrosis was observed.

Antileishmanial

Leishmaniasis is a tropical vector-borne disease caused byprotozoan parasites of the genus Leishmania and spread bythe bites of infected female Phlebotomine sand flies.73 Theinsect vector injects promastigotes into the host’s skin, and soonafter, the parasite transforms to an amastigote. Leishmaniasisrepresents a complex disease and may be divided into differenttypes: visceral leishmaniasis or kala azar (black fever) is potentiallyfatal if untreated; cutaneous leishmaniasis is the most serious andmost common form, is long-lasting, and causes open sores;diffuse cutaneous leishmaniasis includes disseminated lesionsthat resemble leprosy and occurs in individuals with defective cell-mediated immune response; and mucocutaneous leishmaniasis

Scheme 16 Synthesis of pyrazolylbenzyltriazole derivatives (72 and 73).

Scheme 17 One-pot multicomponent and green synthetic route for the preparation of pyrano pyrazole derivatives (74a–74i).

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produces lesions that can lead to the extensive and disfiguringdestruction of the mucous membranes of the nose, mouth andthroat cavities.74 The 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazole derivatives reported by Santos et al.41 (Scheme 5) weretested against the promastigote stages of L. amazonensis,L. infantum and L. braziliensis parasites and established thatamong them, six derivatives (23a, 23b, 23e, 23g, 24d, and 24f)were more effective against L. amazonensis compared to the otherspecies. The relationship between structure and antileishmanialactivity against L. amazonensis revealed that compound 24d,which has chlorine substituents at both meta-positions of the

aryl nucleus, was the most active, while a similar structurewithout the amino group (23d) presented unsatisfactory activity.On the other hand, the pyrazole derivatives 23b (without amino

Scheme 18 Synthetic protocol for the preparation of steroidal pyrazolines and pyrazoles.

Table 14 Nature of the aryl group (Ar-) in steroidal pyrazole derivatives(77a–d and 79a–d)

Entry Ar Entry Ar

1 5

2 6

3 7

4 8

Fig. 2 Pyrazole derivatives as monoamine oxidase inhibitors.

Fig. 3 Pyrazole derivatives as BRAF inhibitors.

Fig. 4 Pyrazole derivatives as DNA gyrase inhibitors.

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group) and 24b (with amino group) having only one chlorineatom at meta-position of the aryl nucleus shows moderateantileishmanial activity against L. amazonensis. The authorsalso synthesized 1-aryl-1H-pyrazole-4-carboxamides (84a–84e)that showed antileishmanial activity when tested againstL. amazonensis.75 They reported that the compound containinga pyrazole ring with a slightly different substituent than 23 and24 displayed impressive antileishmanial activity. Dardari et al.76

synthesized 4-[2-(1-(ethylamino)-2-methyl-propyl)phenyl]-3-(4-methylphenyl)-1-phenylpyrazole (84), which showed antileish-manial activity against L. tropica, L. major, and L. infantum. TheIC50 values of 85 for the promastigote growth of L. tropica,L. major, and L. infantum were 0.48, 0.63 and 0.40 mg ml�1,respectively. They also indicated that L. infantum was the mostsensitive strain. The growth of L. infantum promastigotes wasinhibited by 50% after 24 h at a concentration of 0.75 mg mL�1

of 85, whereas the growths of L. major and L. tropica promastigoteswere only inhibited by 8% and 9.3%, respectively, at the sameconcentration. It is also interesting to note that L. infantum causeslethal visceral leishmaniasis in humans and canines and isreported more and more frequently in association with thehuman immunodeficiency virus (HIV) (Fig. 5).

Antiproliferative

Cell proliferation is a process that results in an increase of thenumber of cells and is one of the significant processes in theoverall growth of an individual. Abnormal cell growth and over-proliferation can cause various health problems. Cancers andtumors are some of the most fatal and fast-growing diseases.This group of diseases is characterized by the loss of controlover cellular growth and is not easy to combat. Severalpyrazolo[3,4-d]pyrimidine derivatives possessing antiprolifera-tive activity were reported by Huang et al.43 (Scheme 6). Thesecompounds show antiproliferative activity against a panel ofhuman cancer cell lines, including lung carcinoma (NCl-H226),nasopharyngeal (NPC-TW01), and T-cell leukemia (Jurkat)cells. SAR studies indicated that the introduction of o-Cl-Phor p-Br-Ph groups at the N-1 position and p-Me-Ph or p-Cl-Phgroups at the C-3 position in the pyrazole ring enhancesbioactivity. Furthermore, the SARs indicated that 1-(quinolin-2-yl)-1H-pyrazolo[3,4-d]pyrimidines are more potent than 1-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidines. Among all derivatives (Table 6),compound 26h was found to possess the best efficacy against NCl-H226 (IC50 = 18 mM) and NPC-TW01 (IC50 = 23 mM) cancer cells.

Mert et al.77 reported a novel series of pyrazole–sulfonamidederivatives (86a–86e) synthesized from 1-(4-aminophenyl)-4-benzoyl-5-phenyl-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)-1H-pyrazole-3-carboxamide. The reported compound showed antiproliferativeactivity against HeLa and C6 cell lines and selective effects againstC6 cell lines. According to the test results, compound 86d inparticular has considerable antiproliferative activity against HeLaand C6 cell lines compared to reference drugs cis-platin and 5-FU.Compounds 86a and 86e have good antiproliferative activitiesagainst the C6 cell line at high concentrations, and SAR studiesshowed that presence of phenolic hydroxyl and iodine in 86a and86e, respectively, may be responsible for the enhancement ininhibitory activity. Compound 86b also includes a carboxylategroup next to the hydroxyl group, and carboxylate groups havebeen suggested to reduce the antiproliferative activity. A set ofnovel benzothiopyranopyrazole derivatives (87a–87f) with antipro-liferative activity was reported by Via et al.78 These compoundsshowed antiproliferative activity when tested against HeLa andHL-60 cells; the activities were characterized by the presence of amethoxy substituent at the 7-position and a pendant phenyl,p-chlorophenyl, or p-methoxyphenyl in the 1-position of theheterocyclic moiety, respectively. Compound 87b appeared to bethe most active compound against both cell lines (Fig. 6). Theinvestigation of the mechanism of action of this compoundhighlighted the absence of interaction with DNA, and HeLa cellstreated with 87b showed an evident depolarization of the mito-chondrial membrane. These findings suggest that the reportedcompounds activate the apoptotic pathway to damage mitochondrialfunctions, and this mechanism accounts for the antiproliferativeeffects on tumor cell lines.

Anti-inflammatory

Inflammation is a multifactorial process that reflects theresponses of the organisms to various stimuli and is related

Fig. 5 Pyrazole derivatives as antileishmanial agents.

Fig. 6 Pyrazole derivatives as antiproliferative agents.

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to many disorders such as pain, redness of skin, swelling, andloss of function in the case of acute inflammation; chronicinflammation may lead to arthritis, asthma, and psoriasis.79

Cyclooxygenases (COXs) are key enzymes in the biosynthesis ofprostanoids, thromboxanes, and prostacyclins, and are involvedin several physiological processes, including inflammation.80

COXs exist in two isoforms: COX-1 is constitutively expressedand is critical for the protection of gastric mucosa, plateletaggregation, and renal blood flow; COX-2 is inducible andexpressed during inflammation, pain, and oncogenesis.81 Theassociation of COX-2 with induced inflammation has led to thehypothesis that the selective inhibition of COX-2 over COX-1might provide a good anti-inflammatory effect with fewer sideeffects compared to classical non-steroidal anti-inflammatorydrugs (NSAIDs). Therefore, selective COX-2 inhibitors with bettersafety profiles have been marketed and termed as coxibs,including Celecoxib, Rofecoxib, Valdecoxib, and Etoricoxib.82

Numerous pyrazole derivatives have found clinical applicationsas NSAIDs, and Celecoxib is one bearing a pyrazole moiety.Other examples of pyrazole derivatives as NSAIDs include Mefo-butazone, Ramifenazone, and Famprofazone. A series of novelpyrazole derivatives (88–90) were synthesized by Tewari et al.,83

and their anti-inflammatory activities were determined usingcarrageenan rat paw edema bioassay. Among the reportedcompounds, 88b, 88c and 89b showed maximum inhibitoryeffects, while compounds 89c and 89d showed intermediateeffects. Molecular modeling showed that pyrazole analoguesinteract with the COX-2 active site through classical hydrogenbonds, p–p interactions and cation–p interactions, therebyaugmenting the anti-inflammatory activities of the reportedcompounds (Fig. 7).

Kendre et al.44 reported some new 1H-pyrazole derivativescontaining aryl sulfonate moieties (Scheme 7) with anti-inflammatory effects. The authors suggested that minor changesin the aromatic ring by halogen substitutions profoundly influencedthe activity, and 31b was found to show maximum activity (Table 7).Malladi et al.84 synthesized 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles bearing pyrazole moieties (91a–91i) withanti-inflammatory activities. Among the reported compounds,

91i showed the most significant anti-inflammatory activity(64.7% inhibition) compared to the standard drug Diclofenacsodium, and compounds 91d and 91f showed 56.9% inhibition.The presence of propyl and p-chlorophenyl substituents accountedfor the significant activity of 91i. Compound 91d has ethyl andp-chlorophenyl moieties, and 91f has propyl and phenyl moieties,accounting for their moderate activities. El-Sayed et al.85 alsosynthesized pyrazole derivatives (92 and 93) having anti-inflammatory activities, and compounds 92a and 92d werethe most selective among the tested compounds with reason-able inhibitory profiles against COX-2. Based on SAR studies,the authors concluded that the anti-inflammatory activities of92a–92d were higher than those of 93a and 93b (Fig. 8).

The pyrazole-4-carbaldehyde derivatives synthesized bySelvam et al.47 (Scheme 8) also possess anti-inflammatory activitiesin addition to being analgesic in nature. Among the synthesisedcompounds, the para-substituted derivatives (35c, 35e, 35g, 35i, 35kand 35l) showed excellent activities, and 35g, 35i, and 35k showedhigher activities compared to other para derivatives (Table 8). Thiswas attributed to the presence of para position halogen moieties.The pyrazolylbenzyltriazoles synthesized (Scheme 16) by Chandnaet al.57 exhibited anti-inflammatory activities in addition to actingas antimicrobial agents. Four compounds (72b, 72e, 72g and 72h)were found to be the most potent COX-2 inhibitors, with 72hshowing the best COX-2 profile (IC50 = 5.01 mM) followed by 72b(IC50 = 5.25 mM) and 72e (IC50 = 6.69 mM); 72b is a directanalogue of Celecoxib with a benzyltriazole moiety in the placeof sulfonamide.

Analgesic

Pain is an unpleasant sensation and it is widely accepted to beone of the most important determinants of quality of life.Individuals with persistent pain suffer four times more fromdepression and anxiety than healthy persons. The identifi-cation of compounds able to treat both acute and chronic painwith limited side effects is one of the most prominent goals inFig. 7 Pyrazole derivatives as anti-inflammatory agents.

Fig. 8 Pyrazole derivatives as anti-inflammatory agents.

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biomedical research. Abd-El Gawad et al.86 designed pyrazolederivatives with analgesic activities (94 and 95) and suggestedthat the substitution of the pyrazole ring with at least one arylmoiety is essential for activity. All the reported compoundsshowed analgesic activity except 95d (Fig. 9).

Selvam et al.47 (Scheme 8) reported that compounds 35g, 35i and35k containing –F, –Br and –Cl substituents at the para position,respectively, showed significant analgesic activities, whereascompounds 35c, 35e and 35l containing –CH3, –OCH3 and–NHCOCH3 substituents, respectively, exhibited weaker analgesicactivities (Table 8). This indicates that the electronic nature of thesubstituent group at the para position in the phenyl ring played asignificant role in the bioactivity. A novel series of 1-(5,7-dichloro-1,3-benzoxazol-2-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde derivatives(96a–96e) with analgesic properties were synthesized by Jayannaet al.87 Compounds 96b and 96d with para-hydroxyl and para-bromo substituents, respectively, exhibited potent analgesicactivities with 55.78% and 54.63% protection, respectively, com-pared to acetyl salicylic acid as a standard drug (Fig. 10).

Cyclin-dependent kinase inhibitors

Cyclin-dependent kinases (CDKs) are a family of serine-threonineprotein kinases, which govern the initiation, progression andcompletion of cell cycle events. They are also involved in regulatingtranscription, mRNA processing and differentiation of nerve cells.The activities of CDKs are critically dependent on the presence oftheir regulatory partners (cyclins), whose levels of expression aretightly controlled throughout the different phases of the cell cycle.88

Loss of cell cycle control resulting in aberrant cellular proliferationis one of the key characteristics of cancer, and the inhibition ofCDKs is expected to be the most effective strategy for control-ling tumor growth and hence an effective weapon in cancertherapy.89 The 1,3-diphenyl-N-(phenylcarbamothioyl)-1H-pyrazole-4-carboxamide derivatives synthesized by Sun et al.48 (Scheme 9)exhibited anti-proliferative activities against A549 (carcinomichuman alveolar basal epithelial cells) and CDK2,4,6-inhibitoryactivities. Among the synthesized compounds, 40b demonstratedthe most potent inhibitory activity (IC50 = 25, 35 and 25 nM forCDK2, CDK4 and CDK6, respectively) (Table 9). SAR studiesshowed that the compounds with OMe and Me groups aselectron-donating substituents exhibited better activities thanthose with electron-withdrawing substituents. Huang et al.90

synthesized N-((1,3-diphenyl-1H-pyrazole-4-yl) methyl) anilinederivatives (97a–97p) as CDK inhibitors. These compoundsexhibited potent CDK2-inhibitory activities and antiprolifera-tive activities against MCF-7 and B16-F10 cell lines. Among thesynthesized compounds, 97a showed the most potent inhibi-tory activity; 97a inhibited the growths of MCF-7 and B16-F10cell lines with IC50 values of 1.88 � 0.11 and 2.12 � 0.15 mM,respectively, and inhibited CDK2/cyclin E holoenzyme activitywith IC50 = 0.98� 0.06 mM. Another group of pyrazole derivatives(98a–98m) as CDK inhibitors was reported by Krystof et al.91

Among the 4-arylazo-3,5-diamino-1H-pyrazole derivatives, 98a isthe first representative of a novel group of compounds that candiminish the catalytic activity of CDK2-cyclin E. Compounds98c–98e have similar inhibitory activities to 98a, while the non-polar 4-methyl-phenyl derivative 98b showed a slightly loweractivity. Compounds 98h–98m also showed CDK-inhibitoryeffects; however, large substituents were found to be responsiblefor the decrease in CDK-inhibitory effects, probably due to sterichindrance (Fig. 11).

TNAP inhibitor

Alkaline phosphatase is a hydrolase enzyme responsible forremoving phosphate groups from many types of molecules,including nucleotides, proteins and alkaloids. Humans and mostother mammals contain the following alkaline phosphate isozymes:tissue-specific alkaline phosphatases (placental, intestinal and germcell) and tissue-non-specific alkaline phosphatase (TNAP).

TNAP hydrolyzes extracellular inorganic pyrophosphate(PPi), a potent mineralization inhibitor, to enable the physiologicaldeposition of hydroxyapatite in bones and teeth.92 In this way, acontrolled steady-state level of PPi is maintained, therebysustaining normal bone formation and growth. Its lack offunction in hypophosphatasia leads to impaired mineralization,

Fig. 9 Pyrazole derivative as analgesics.

Fig. 10 Pyrazole derivatives as analgesics.

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while its overexpression or increased activity induces ectopiccalcification. Due to its key function in mineralization, TNAP isan obvious target to prevent ectopic calcification, inducing vascularcalcification.93 This has convinced many researchers to search forTNAP inhibitors to be used as a drug to target diseases caused bymedial calcification, such as idiopathic infantile arterial calcifica-tion, end-stage renal disease and diabetes.94 Sidique et al.49 synthe-sized a novel series of pyrazole amide derivatives (Scheme 10) aspotent and selective inhibitors of TNAP. SAR studies showed thatthe incorporation of a hydroxyl group on the amide generallyincreases the potency. The most potent compound in this serieswas the 2,3,4-trichlorophenyl analogue 45h (Table 10). This com-pound showed exceptional activity with an in vitro IC50 of 5 nM.Furthermore, compound 45h was inactive (IC50 4 10 mM) againstboth the related placental alkaline phosphatase (PLAP) isozymeand the housekeeping enzyme glyceraldehyde-3-phosphatedehydrogenase (GAPDH), indicating a selectivity for TNAP ofat least 2000-fold. By performing detailed kinetic studies, theauthors demonstrated that the mechanism of action of 45h iscompetitive with respect to the substrate.

Agrochemicals

Herbicidal. Herbicides (commonly known as weed killers) arepesticides used to remove unwanted plants. These unwantedplants are known as weeds, and they compete with productivecrops or pasture, ultimately converting productive land intounusable scrub. Weeds can be poisonous or distasteful, produce

burrs or thorns, and/or otherwise interfere with the use andmanagement of desirable plants by contaminating harvestsor interfering with livestock. Weeds compete with crops fornutrients, water, and physical space and may harbor insectsand pests; thus, weeds are capable of greatly undermining bothcrop quality and yield. Weed control is the major constraint infood production efficiency. Several herbicides kill specific targetswhile leaving the desired crops relatively unharmed. With con-cerns about environmental pollution and the difficulties faced byfood and agriculture management systems, several new weedcontrol systems and strategies had been put forward. Manypyrazole derivatives with promising properties have beenreported with different principles of action. Among the activeprinciples through which several compounds act as inhibitors ofweed growth include photosynthetic electron transport inhibi-tion as shown by pyrazole derivatives 99 and 100.95 Among thepyrazolo[1,5-a][1,3,5]triazine-2,4-dione derivatives, those includingbutyl (99d) and cyclohexyl (99b) substituents showed maximalactivity. Compounds 100c and 100d were more effective than theirtriazine counterparts. On the other hand, the comparison betweencompounds 99b–99e and 100a–100d, which have the exact samesubstituents, strongly suggested that the thiadiazine ring mayamplify the inhibitory effect (Fig. 12).

Ma et al.50 synthesized N-(2,2,2)-trifluoroethylpyrazole derivatives(Scheme 11) as herbicides that work by inhibiting long-chainfatty acid elongase (VLCFAE). The herbicidal tests showed thatwhen the dihydroisoxazole was attached to the 5-position of the

Fig. 11 Pyrazole derivatives as CDK inhibitors.

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N-(2,2,2)-trifluoroethylpyrazole ring linked by thiomethylene orsulfonylmethylene, the corresponding compounds presentedgood herbicidal activities. It was also found that when thesubstituent at the 4-position of the pyrazole ring was chlorine,the corresponding compound 51a exhibited the best herbicidalactivity. When applied to soil in field trials, compound 51ashowed excellent inhibitory activity against both dicotyledonousand monocotyledonous weeds along with good safety to maizeand rape.

Insecticidal and acaricidal. Insecticides are substances usedto kill insects, and acaricides are specially used to kill membersof the arachnid subclass acari, which includes ticks and mites.Both insecticides and acaricides are used in agriculture andmedicine, although their main use is in the field of agricultureand crop protection. Modern insecticides should have a favorablecombination of properties, including high levels of insecticidalactivity, low application rates, crop tolerance, low levels oftoxicity to mammals, and environmental friendliness. Manypyrazole derivatives have been reported as insecticides andacaricides, including a series of novel pyrazoles containinga-hydroxymethyl-N-benzyl carboxamide, a-chloromethyl-N-benzylcarboxamide, and 4,5-dihydrooxazole moieties designed andsynthesized by Song et al.96 These compounds (101a–101l and102a–102l) possessed good to excellent activities against abroad spectrum of insects such as cotton bollworm (H. armigera),bean aphid (A. craccivora), mosquito (Cx. pipiens pallens), andspider mite (T. cinnabarinus). The compounds containinga-chloromethyl-N-benzyl and 4,5-dihydrooxazole moieties exhibitedhigher activities than the compounds containing a-hydroxymethyl-N-benzyl moieties (Fig. 13).

Wang et al.51 reported a series of pyrazole derivatives con-taining oxazole rings (Scheme 12), as insecticides. Among thesynthesized compounds, 57b–57d and 57f–57j achieved 100%inhibition against A. craccivora and 80% inhibition againstN. lugens (Table 11). In addition, some of the designed compoundsexhibited moderate insecticidal activities against T. cinnabarinus atdosages of 500 mg l�1; in particularly, compounds 57i and 57jexhibited 100% inhibition against T. cinnabarinus. The authors alsoshowed that compound 57c (when R1 and R2 are 4-fluoro atoms)was more potent against N. lugens than other oxime derivatives,and compound 57j (when R1 is a 3-fluoro atom and R2 isthe 4-chloro atom) was more active against A. craccivora andT. cinnabarinus than other oxime compounds. Dai et al.97

synthesized a series of pyrazole oxime derivatives (103a–103e)exhibiting promising insecticidal and acaricidal activities againstT. cinnabarinus and P. xylostella. Particularly, the 4-fluro-substituted compound 103c and 4-chloro-substituted compound103d displayed relatively good acaricidal activities against T.cinnabarinus and potential insecticidal activities against P. xylos-tella compared to other oxime derivatives. Fustero et al.98 synthe-sized fluorinated Tebufenpyrad analogs (104a–104b) withacaricidal activity. Unfortunately, T. urticae is difficult to controlbecause of its ability to quickly develop resistance to acaricides.The authors suggested that the introduction of fluorine intoorganic molecules causes significant physiochemical and bio-logical changes. Interestingly, the compounds 104a and 104bcause complete or nearly complete adult mortality (Fig. 14).

Anticancer

Cancer is a diverse group of diseases characterized by abnormalcell growth with the potential to invade or spread to other partsof the body. There are more than 100 types of cancer, includingbreast cancer, skin cancer, lung cancer, colon cancer, prostatecancer, and lymphoma. Symptoms vary depending on the type

Fig. 12 Pyrazole derivatives as herbicidal agents.

Fig. 13 Pyrazole derivatives as insecticidal and acaricidal agents.

Fig. 14 Pyrazole derivatives as insecticidal and acaricidal agents.

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of cancer. The treatment of cancer may include chemotherapy,radiation therapy, and surgery. Cancer is a worldwide healthproblem and the most frightening disease in humans. Thegreat majority of cancers are caused by environmental factorsand carcinogens. Due to increasing pollution and the use ofcarcinogens, this fatal disease is increasing in prevalence. Themajority of cancers are either resistant to chemotherapy oracquire resistance during treatment. As a result, the design anddiscovery of non-traditional, efficient, and safe chemical classesof agents are the prime targets of contemporary medicinalchemistry. Pyrazoles constitute an important heterocyclicfamily exhibiting anticancer activity, and many studies havebeen done to design new and potent anticancer drugs. A keyfeature of cancerous cells is their uncontrolled proliferation;thus, the inhibition of proliferative pathways is believed to be aneffective strategy to fight cancer. The ester and amide derivatives of1-phenyl-3-(thiophen-3-yl)-1H-pyrazole-4-carboxylic acid (Scheme 15)synthesized by Inceler et al.56 exhibited anticancer activitiesagainst various cancer cell lines. Among all the synthesizedamide derivatives, compounds 70c and 70f possess the bestinhibitory effects on cell growth (Table 13). Compound 70c,which has a benzylpiperidine group in the amide portion,showed significant inhibitory effects with the best results against

Raji and HL60 cell lines. Ester derivatives of 1-phenyl-3-(thiophen-3-yl)-1H-pyrazole-4-carboxylic acid (70g–70l) did notaffect the growth of HeLa, MCF7, MDA-MB-231, Raji, andHL60 cells. A series of functionally substituted pyrazole com-pounds have been synthesized (105–107) and evaluated in vitrofor their antiproliferative effects on a panel of 60 cell linesby Nitulescu et al.99 Promising results were obtained withN-benzoyl-N0-(3-(4-bromophenyl)-1H-pyrazol-5-yl)-thiourea (107a).SAR studies revealed that substituted pyrazolyl thiourea derivativesare more active than the related N-[(1-methyl-1H-pyrazole-4-yl)]-thiourea derivatives. Prasad et al.100 reported novel 4,5-dihydro-pyrazole derivatives (108–110) exhibiting excellent anticanceractivity compared to the reference drug cisplatin. Compound109 having 4-chloro substitution showed excellent anticanceractivity (IC50 = 4.94 mM) against HeLa (human cervix carcinoma celllines), which implied that lipophilic and electron-withdrawinghalobenzyl groups are beneficial for cytotoxic activity against HeLacell lines. Sankappa Rai U. et al.101 synthesized a new series ofpyrazole chalcones (111a–111e) exhibiting anticancer activitiesagainst MCF-7 and HeLa cell lines. Compound 111c showed thehighest inhibition in human MCF-7 and HeLa cell lines; its highestactivity was attributed to the 4-fluoro-phenyl and 5-fluoro-pyridinmoieties (Fig. 15).

Fig. 15 Pyrazole derivatives as anticancer agents.

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The cis-restricted 3-aminopyrazole (Scheme 13) analogues ofcombretastatins synthesized by Tsyganov et al.53 as anticanceragents selectively target microtubules. Microtubules are responsiblefor the formation of the mitotic spindle, which is essential forproper chromosomal separation during cell division. The reportedcompounds possess antiproliferative and microtubule-destabilizingactivities. Molecules 61a and 63a, with 3,4,5-trimethoxy groups onring A, exhibited the highest antimitotic microtubule-destabilizingeffect in sea urchin embryo assay. These compounds also showedconsiderable cytotoxicity against a panel of 60 human cancer celllines. In addition, both 61a and 63b inhibited the growth of multi-drug-resistant, P-glycoprotein-overexpressing ovarian cancer cells,suggestive of their potential as anticancer agents.

IRAK4 inhibitors

Interleukin receptor-associated kinase 4 (IRAK4) is a member ofthe IRAK family of intracellular serine-threonine kinase, whichincludes IRAK1, IRAK2, IRAKM or IRAK3 and IRAK4. IRAK4 isan essential signal transducer downstream of the interleukin-1receptor (IL1R) and toll-like receptor (TLR) superfamily. IRAK4mediates innate immune response by regulating the expression ofinflammatory genes in multiple target cells. The innate immunesystem, also known as the non-specific immune system, comprisesthe cells and mechanism that defend the host from infection byother organisms. IRAK4 signaling is essential in the fundamentalpathogenesis of multiple immune-inflammatory diseases andfor cell survival and proliferation in hematological tumors. Theproximal location of IRAK4 to key immune signaling receptorshas generated significant interest in the therapeutic targetingof IRAK4 for autoimmune and inflammatory diseases. A potentand selective IRAK4 inhibitor would be useful to explore cellmalignancies as well as for autoimmune diseases such asrheumatoid arthritis, psoriasis, inflammatory bowel disease, andgout.102 The degree of selectivity required of IRAK4 inhibitors islikely to vary depending on the targeted disease. A series of potent,selective, and orally bioavailable pyrazole IRAK4 inhibitors weresynthesized by McElroy et al.54 (Scheme 14). SAR studies indicatedthat piperidine and piperazine substituents at the C-3 positionwere well-tolerated, and the identity of the nitrogen substituentcould be used to modulate potency and solubility. In contrast,alkyl-substituted piperidines and piperazines were highly solubleand very potent. Limited SAR studies indicated that o-fluoro andpyridine substituents at the pyrazole N-1 position provided thebest levels of potency (Table 12). A series of 5-amino-N-(1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyrimidine-3-carboxamides (112 and113) as IRAK4 inhibitors was reported by Lim et al.103 The authorsreported that the replacement of the substituents responsible forthe poor permeability and improvement in physical properties ledto the identification of IRAK4 inhibitors with excellent potency,kinase selectivity, and pharmacokinetic properties suitable fororal dosing (Fig. 16).

Antimicrobial

Antimicrobial agents are compounds used to kill micro-organisms or inhibit their growth. They can be grouped accordingto the microorganisms they act primarily against. Many diseases

are indeed caused by these microorganisms, and these microbialinfections pose a tremendous threat to the human race. Theefficacies of many antimicrobial agents are being threatened by aglobal increase in the numbers of resistant microorganisms thatwere once susceptible to some of these agents. In spite of thelarge number of antibiotics and chemotherapeutics available formedicinal use, the emergence of old and new antibiotic-resistantmicrobial strains in the last decades has generated a substantialneed for new classes of antimicrobial agents. Pyrazole and itsderivatives have been found to possess various antibacterial,antifungal and antiviral properties. Chandna et al.57 reportedpyrazolylbenzyltriazoles (Scheme 16) as antimicrobial agents.All the reported compounds possessed variable antibacterialactivities against Gram-positive bacteria (S. aureus and B. subtilis),and some possessed moderate to good activity against Gram-negative bacteria (E. coli and P. aeruginosa). Two compounds(72c and 72e) were found to be the most effective againstS. aureus. However, compounds 72a, 72c and 72f demonstratedcomparable antibacterial activities to that of ciprofloxacinagainst B. subtilis. Vijesh et al.104 synthesized pyrazole-incorporatedimidazole derivatives (114 and 115) that exhibit antimicrobialproperties against various bacterial (E. coli, S. aureus, B. subtilis,S. typhimorium, C. profingens and P. aeruginosa) and fungalstrains (A. flavus, A. niger, C. albicans, M. gypseum, and T. rubrum).Among the reported compounds, compound 114b showed excel-lent antimicrobial activity at concentrations of 1 and 0.5 mg ml�1.Compound 114b has a thioanisyl moiety, which accounted for theenhanced antibacterial activity. The compounds in the secondseries (115a–115j) showed moderate antimicrobial activities. Theimidazole and pyrazole nucleus, which is present in both series, isresponsible for the biological activity. However, the presence ofother substituents is responsible for the varied biological activitiesof the compounds. A novel series of substituted 4-pyrazolyl-N-arylquinoline-2,5-dione (116a–116j) derivatives was synthesizedas antimicrobial agents by Thumar et al.105 Most of the reportedcompounds possess antibacterial and antifungal activitiesagainst B. subtilis, C. tetani, S. pneumoniae, S. typhi, V. cholerae,E. coli, A. fumigatus and C. albicans. Compounds 116g, 116h and116k were found to be highly potent in inhibiting the growth ofmost of the employed strains. A SAR study showed that amongall compounds, that containing a para-bromophenyl ring wasthe most potent against both fungal species (C. albicans andA. fumigatus; Fig. 17).

Fig. 16 Pyrazole derivatives as IRAK4 inhibitors.

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The dihydropyrano[2,3-c]pyrazole derivatives synthesized byAmbethkar et al.58 (Scheme 17) using a grinding methodexhibited antimicrobial activities against S. albus, S. pyogenes,K. pneumonia, P. aeruginosa and C. albicans. New N-acetyl(117a–117d) and N-thiocarbamoyl (118a–118d) derivatives of4,5-dihydropyrazole were synthesized by El-Sabbagh et al.13

N-Thiocabamoylpyrazole derivatives were cyclized to afford thenovel pyrazolothiazol-4(5H)-ones (118e–118h) and pyrazolothiazoles

(118i–118p). The reported compounds exhibited antiviral activitiesagainst several viruses like herpes simplex virus type 1 (KOS) [HSV-1KOS], herpes simplex virus type 2 (G) [HSV-2G], vaccinia virus [VV],vesicular stomatitis virus [VSV], Coxsackie virus B4 [CV-B4], respira-tory syncytial virus [RSV] and parainfluenza-3 virus [PI-3V]. A seriesof cycloadducts-pyrazoles formed via 1,3-dipolar cycloadditionreactions has been reported by Zhang et al.106 Most of the targetcompounds (119a–119l) exhibited significant antifungal activitiesagainst C. cassiicola. Among them, compound 119a had goodfungicidal activity against P. syringae pv. Lachrymans. When thebenzene ring is substituted by halogen, the compounds (119band 119g) generally have excellent antifungal activity againstC. cassiicola, whereas the activities decreased for di-halogen,alkane, and H substituents (119a, 119c, and 119k; Fig. 18).

The 2-(1-phenyl-1H-pyrazol-5-yl)-phenyl-4-methylbenzene-sulfonate derivatives synthesized (Scheme 7) by Kendre et al.44

exhibited antimicrobial activities against both Gram-positiveand Gram-negative bacterial and fungal strains, in addition toacting as anti-inflammatory agents (Table 7). Among the synthe-sized compounds, 31e was found to be most active againstvarious pathogens with reference to ampicillin and norcadine.

Antioxidant

Free radicals are highly reactive chemicals that can potentiallyharm cells and are capable of attacking the healthy cells of thebody, potentially damaging molecules. Free radicals can behazardous to the body and damage all major components ofcells, including DNA, proteins and cell membranes. Antioxidants,also known as free radicals scavengers, are chemicals that interactwith and neutralize free radicals, thus preventing them from

Fig. 18 Pyrazole derivatives as antimicrobial agents.

Fig. 17 Pyrazole derivatives as antimicrobial agents.

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causing damage. The body makes some antioxidants, which areknown as endogenous antioxidants. The capacities of endogen-ous antioxidants are affected by the age, diet, and healthstatus of the individual. However, the body relies on external(exogenous) sources, primarily the diet, to obtain the rest of theantioxidants it needs. Cells with damaged DNA stagnate andare prone to developing cancer and growths. This kind ofdamage also accelerates the aging process and diabetes,directly causing wrinkles and age spots and severely taxingthe immune system. Free radicals may also responsible forother diseases such as cardiovascular disease, neural disorders,Alzheimer’s disease, alcohol-induced liver disease. Therefore,the search for new antioxidants has received much attention.Kenchappa et al.107 synthesized coumarin derivatives containingpyrazole rings (120 and 121) as potent antioxidant agents. Theysuggested that the presence of the pyrazole ring endows these

species with important pharmacological and therapeutic properties.SAR studies revealed that compounds containing electron-withdrawing groups/halogens showed good antioxidant properties(Fig. 19).

The dihydropyrano[2,3-c]pyrazole derivatives synthesized byAmbethkar et al.58 (Scheme 17) exhibiting antimicrobial activitywere screened for their antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenger. All the compoundsshowed radical-scavenging activity. Compound 74f showedbetter scavenging capacity, and other compounds 74a–74eand 74g–74i showed moderate scavenging ability. The presenceof a hydroxyl group in the para position of 74f extends thep-conjugation, stabilizing the produced free radicals. Gressleret al.108 synthesized 2-(4,5-dihydro 1H-pyrazol-1-yl)pyrimidineand 1-carboxamidino-1H-pyrazole derivatives (122 and 123) asantioxidant agents. The authors showed that the presence ofthienyl exerts a significant influence on radical stability. On theother hand, the presence of chlorine substituents does notappear to significantly affect the antioxidant properties of thecompounds in this series. Selvam et al.109 reported pyrazolederivatives (124a–124c) as analogues of curcumin, a potentantioxidant agent. Compound 124a was found to be morepotent than curcumin. The authors showed that o-methoxysubstitution enhanced the stability of the radical (Fig. 20).

5a-Reductase inhibitor

5a-Reductases are enzymes that are involved in steroid metabolism.These are also known as 3-oxo-5a-steroid 4-dehydrogenases, whichparticipate in three metabolic pathways: bile acid biosynthesis,androgen/oestrogen metabolism, and prostate cancer. The enzymeis produced in many tissues in both males and females, and there

Fig. 19 Pyrazole derivatives as antioxidants.

Fig. 20 Pyrazole derivatives as antioxidants.

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are three isoenzymes of 5a-reductase that vary in different tissueswith age. The enzyme steroid 5a-reductase (5AR) catalyzes theNADPH-dependent reductive conversion of testosterone todihydrotestosterone. Increased 5AR activity leads to increasedlevels of dihydrotestosterone in the peripheral tissues, which isimplicated in the pathogenesis of prostate cancer, acne andpattern baldness. The inhibition of 5a-reductase is most knownfor preventing the conversion of testosterone to the morepotent dihydrotestosterone (DHT) in androgen-associated dis-orders. The mechanism of 5a-reductase inhibition is complexand involves the binding of NADPH to the enzyme followed bythe substrate. Specific substrates include testosterone, proges-terone, androstenedione, epitestosterone, cortisol, aldosterone,and deoxycorticosterone. Drugs that inhibit 5a-reductase areused to treat benign prostatic hyperplasia, prostate cancer, andpattern baldness and in hormone replacement therapy.Recently, several steroid-based D-ring heterocyclic analogs havebeen evaluated as efficient 5a-reductase inhibitors. Bandayet al.59 synthesized two series of D-ring-substituted pyrazolinyland pyrazolyl pregnenolone derivatives (Scheme 18) exhibiting5a-reductase inhibitory activities. All the compounds reported(Table 14) exhibited promising inhibitory activity, particularlyagainst type-I human 5a-reductase. However, compounds 77b,77c and 79b were found to best inhibit 5a-reductase enzyme.The authors reported that all of the active derivatives arehalogenated, indicating that halogen substitution increases theactivity. They also demonstrated that pyrazolines (77a–77d) aremore active and selective towards type-I reductase.

Conclusions and perspectives

The remarkable chemical diversity of heterocyclic compoundscontinues to be of relevance to drug discovery. Drug developmenthas been a chief component in the rapid maturation of the field ofmedicinal chemistry during the past several decades; during thisperiod, the scientific community has paid significant attentionto the development of intriguing and challenging moleculararchitectures of nitrogen-containing heterocyclic compounds.There is a growing body of evidence that pyrazole and itsderivatives provide a viable and valuable area for drug discovery.Here, we have presented an overview of the many efficient, mild,operationally simple and non-conventional synthetic methods toaccess a library of highly functionalized pyrazole derivatives anda broad range of biological activities displayed by these scaffoldsthat can optimally present a way to capture their intrinsic value.The SARs of the reported compounds reveal that a greaterunderstanding of the pattern of substituents, including electron-donating, electron-withdrawing, and some heterocyclic moieties,on the basic skeleton plays a key role in regulating the biologicalpotentials of the synthesized compounds. Furthermore the target-oriented or focused-library approach seeks to elaborate structuralmodifications onto existing, bioactive pyrazole scaffolds in aparallel, systematic fashion to improve the inherent biologicalactivity or drug-like properties. The ability to predict drug-like andlead-like properties along with recent technological advances

could be sufficient to revitalize the exploitation of the value ofpyrazole derivatives in the quest for new drugs.

Acknowledgements

We sincerely thank Department of Chemistry, Aligarh MuslimUniversity, Aligarh, India, for providing necessary facilities.

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