1

Chapter 1

INTRODUCTION

The chemistry of heterocyclic compounds is one of the most complex branches of

organic chemistry. It is equally interesting for its theoretical implications, for the

diversity of its synthetic procedures, and for the physiological and industrial

significance of heterocyclic compounds [Wiley et al., 1967]. In particular, the

heterocyclic compounds have been extensively studied not only for their intrinsic

interest, but also because many natural products, many drugs and medicines, and

many dyestuffs belong to this group [Badger, 1961].

Heterocyclic compounds are cyclic organic substances which contain in the ring

system at least one atom other than carbon. Many alkaloids, vitamins, antibiotics and

many synthetic medicines and dyestuffs are heterocyclic, and so also are many

substances (such as the nucleic acids) which are most intimately connected with the

processes of life [Wiley et al., 1967; and Badger, 1961].

Presumably any atom which can form two covalent bonds is capable of forming

a heterocyclic compound. However, with a few exceptions (e.g., mercury, iodine), all

the known heterocyclic compounds involve an element from group IVB, VB or group

VIB of the periodic table [Badger, 1961]. The most important “heteroatoms” are

nitrogen, oxygen and sulfur.

Pyrazoles are characterized by a basic molecular architecture composed of

three carbons and two nitrogens in adjacent positions of a five membered ring.

2

Pyrazoles have attracted much attention in last decades as their synthesis has become

more accessible and their diverse properties appreciated. Pyrazole was described for

the first time by Buchner, who obtained it by decarboxylation of pyrazole-3,4,5-

tricarboxylic acid 1 in 1889 (Figure 1) [Wiley et al., 1967].

Figure 1. First synthesis of pyrazole by the decarboxylation of pyrazole-3,4,5-

tricarboxylic acid (1)

Until recently, the pyrazole ring was believed to be unknown in nature. In 1954,

however, the first natural pyrazole derivative was isolated by Japanese workers who

isolated 3-n-nonylpyrazole 2 from Houttuynia Cordata which is a plant of the

“piperaceae” family from tropical Asia. They observed its antimicrobal activity. Another

naturally occurring pyrazole derivative is levo-β-(1-pyrazolyl)alanine 3 (Figure 2). This

pyrazolic amino acid has been isolated from watermelon seeds (Citrullus Vulgaris).

These are the only naturally occurring pyrazole derivatives known at present.

Figure 2. Examples of naturally occurring pyrazoles

3

Pyrazoles are unique in their chemical behaviour not only among heterocyclic

compounds in general, but also among related azoles. This is because pyrazole

possesses the typical properties of the aromatic system, which are in fact rather

pronounced in these derivatives, together with the high lability of the ring under

certain condition. Although pyrazole derivatives have been known for more than 80

years, the investigation of their chemistry commenced rather slowly. Pyrazole

derivatives have a long history of application in agrochemicals as herbicides and

insecticides and in pharmaceutical industry as antipyretic and anti-inflammatory.

The chemistry of pyrazoles has been extensively investigated in the past and

the chemical reactivity of pyrazole molecule can be explained by the effect of

individual atoms. The N-atom at position 2 with two electrons is basic and therefore

reacts with electrophiles. The N-atom at position 1 is unreactive, but loses its proton in

the presence of base. The combined two N-atoms reduce the charge density at C3 and

C5, making C4 available for electrophile attack. Deprotonation at C3 can occur in

presence of strong base, leading to ring opening. Protonation of pyrazoles leads to

pyrazolium cations that are less likely to undergo electrophilic attack at C4, but attack

at C3 is facilitated. The pyrazole anion is much less reactive toward nucleophiles, but

the reactivity to electrophiles is increased [Bansal, 2007].

Much of the basic information obtained about the chemistry of the pyrazole

moiety was its aromatic properties compared to those of benzene derivatives. Since

then the studies of the pyrazoles have centered principally about structural problems

arising from the tautomerism existing in the N-substituted types and the isomerism of

the N-substituted derivatives. To illustrate, pyrazole ring, like other nitrogen containing

4

heterocycles, can be represented by different tautomeric structures. Three tautomeric

forms can be written for unsubstituted pyrazole (Figure 3).

Figure 3. Tautomeric structures of the unsubstituted pyrazole ring

Among the many five-membered heterocycles, considerable interest has been

focussed on the pyrazole nucleus which is a part of the popular drugs Celebrex

[Penning et al., 1997] and Sildenafil [Terrett et al., 1996]. Pyrazole, a five-membered,

two-nitrogen-containing heterocycles ring, is widely found as the core structure in a

large variety of compounds that possess important agrochemical [Gandhale et al.,

1982] and pharmaceutical activities [Elguero et al., 2002]. Pyrazole derivatives are also

known to possess a broad spectrum of biological properties such as hypoglycaemic

[Vazquez et al., 2013], cytotoxic [Puthiyapurayil et al., 2012], anti-malarial [Kalaria et

al., 2014], anticonvulsant [Aziz et al., 2009], anti-depressant [Palaska et al., 2001;

Bailey et al., 1985], antitumor [Park et al., 2005], antipsychotic [Markourtz et al.,

1999], antibacterial [Kane et al., 2003], anti-inflammatory [Trilok et al., 2010; Nagarapu

et al., 2011] and antimicrobial activity [Bondock et al., 2011].

Pyrazoles display a range of bioactive properties [Penning et al., 1997; Bhat et

al., 1981; Petrie III et al., 1985], and are widely utilized in the agricultural and

pharmaceutical sectors. Among the several FDA approved pharmaceutical drugs, the

pyrazole core is found in Rimonabant and Celebrex (Figure 4) [Elguero et al., 1996].

Numerous compounds containing the pyrazole moiety were found to exhibit wide

range of biological activities such as analgesic [Saad et al., 2011], antitubercular

5

[Pathak et al., 2012], antipyretic [Eissa et al., 2009], anti-HIV [Mizuhara et al., 2013],

anticancer [Koca et al., 2013], antioxidant [Burguete et al., 2007], antiproliferative

[Pirol et al., 2014], leishmanicidal [Bernardino et al., 2006], anti-angiogenic

[Christodoulou et al., 2010] and sedative-hypnotic activities [Stauffer et al., 2001].

Recent studies have shown the incorporation of a pyrazole core in A2A receptor

antagonists, CB1 receptor antagonists, DNA intercalating agents, and estrogen

receptor ligands [Slee et al., 2008; Baraldi et al., 2002]. The structural resemblance of

pyrazole with isoxazole offer the feasibility to construct useful analogs associated with

potential biological properties.

Celebrex Rimonabant

Figure 4

The pyrazole scaffold has drawn a great deal of attention due to its

contributions in biological and pharmacological fields regardless of scarcity in nature

[Parameswaran et al., 1997]. N-substituted pyrazoles such as pirazolac is known as

non-steroidal anti-inflammatory drugs (NSAIDs) [Biere et al., 1983]. N-substituted

pyrazoles have also been developed as inhibitors of p38 mitogen-activated protein

kinase, SERMs (selective estrogen receptor modulators) for the treatment of cancer

cells [Zhou et al., 2009]. Also, pyrazoles have found applications as intermediates in

6

the synthesis of some new azo dye derivatives having pyrazole moieties [Rizk et al.,

2015] and were evaluated as reactive dyes for the exhaust dyeing of cotton fibre.

Microorganisms are becoming resistant more quickly than new drugs are being

found. Research in the field of antimicrobial agent is of significant interest for

medicinal chemist aiming to synthesize more potent compounds. In view of these

facts, it was contemplated to synthesise some novel pyrazole derivatives with potent

biological activity.

The chemistry of pyrazole until 1995 has been reviewed extensively by, in

Comprehensive Heterocyclic Chemistry vol.5, [Elguero, 1984] and Comprehensive

Heterocyclic Chemistry II vol.3 [Elguero et al., 1996] edited by A.R. Katritzky. The review

by [Fustero et al., 2009 ] on Recent Advances in the Synthesis of Pyrazoles published in

Organic Preparations and Procedures International summarises the most relevant

advances in construction of pyrazole ring reported in the literature from 1995-2008.

Subsequent review by [Kumar et al., 2009] in Recent Patents on Anti-Infective Drug

Discovery describes the recent developments in biological activities of pyrazoline

derivatives. A recent review on pyrazole as promising scaffold for synthesis of anti-

inflammatory and antimicrobial agents was published in Mini review in Medicinal

Chemistry by [Bekhit et al., 2010]. A very recent review on Chemistry and

Pharmacological potential of pyrazole published by [Dewangan et al., 2011] in Current

Pharma Research summarises the pharmacological activities of pyrazoles and its

derivatives. A review on functionalised tetra substituted pyrazolyl heterocycles by

[Dadiboyena et al., 2011] summarizes recent advances in synthesis of tetra substituted

pyrazoles. A very recent review by [Baumstark et al., 2013] describes the synthesis and

chemistry of hexasubstituted pyrazolines.

7

The general and classical methods of pyrazole synthesis involve approaches

based either on the condensations of hydrazines with 1,3-dicarbonyl compounds and

their 1,3-dielectrophile equivalents, or on intermolecular [3+2] cycloadditions of 1,3-

dipoles to alkynes. During the past few years, however, more and efficient and broadly

applicable methodologies have been developed with the aim of increasing the

regioselectivity in the preparation of pyrazoles. Synthesis of pyrazole derivatives and

their biological studies is briefly reviewed below:

1.1 Pyrazolyl-2-pyrimidinamines

[Reddy et. al., 2011] have reported the synthesis of a new series of 4-

(aryl/hetaryl)-6-(3,5-dimethyl-1-phenyl-1H-pyrazolyl)-2-pyrimidinamine. Cyclo-

condensation of diketone with phenyl hydrazine resulted in the formation of 3,5-

dimethyl-1-phenyl-1H-pyrazole (Scheme 1.1). The pyrazole on formylation with

DMF/POCl3 and subsequent Claisen condensation with methyl ketone resulted in

formation of (E)-3-(3,5-dimethyl-1-phenyl-1-H-4-pyrazolyl)-1-phenyl-2-propen-1-one,

which on reaction with guanidine hydrochloride afforded 4-(aryl/hetaryl)-6-(3,5-

dimethyl-1-phenyl-1H-pyrazolyl)-2-pyrimidinamine. All the synthesized compounds

were tested against bacteria and fungi. The compounds containing 4-nitrophenyl, 2-

furyl and 2-thiazolyl at 6-position on pyrimidine ring are highly active against the entire

organism employed.

8

Scheme 1.1

1.2 1H-Pyrazole-4-carboxylates

[Sridhar et al., 2004] have synthesized 1H-pyrazole carboxylate related

microbicides using Vilsmeier reagent. Hydrazones and semicarbazones of ketones

yielded pyrazoles upon treatment with Vilsmeier reagent. 1H-pyrazole-4-carboxylates

were synthesized from 2,4-dinitro phenyl hydrazones of β-ketoesters upon treatment

with DMF/POCl3 (Scheme 1.2). These compounds were screened for their anti-

microbial activity against four human pathogenic bacteria such as Escherichia coli

(ATCC 25922), Staphylococcus aureus (ATCC 29213), Pseudomonas aeruginosa (ATCC

27853) and Enterobacter faecalis (ATCC 29212). Anti-fungal activity of these

compounds was also tested against plant pathogenic fungi such as Rhizoctonia solani,

Fusarium oxysporum, Altrenaria alternata. Pyrazole-4-carboxylates were found active

against both plant pathogenic fungal growth inhibition and bacterial inhibition for the

select group of strains.

9

Scheme 1.2

1.3 3-(Phenoxathiin-2-yl)-2-pyrazolines

A new series of 3-(phenoxathiin-2-yl)-2-pyrazoline derivatives was synthesized

by [Behalo et al., 2010] from reaction of 1-(phenoxathiin-2-yl)-3-phenyl/(4-

chlorophenyl)propanones with different nitrogen nucleophiles (Scheme 1.3). These

compounds were tested for their anti-microbial activity. Most of the synthesized

compounds demonstrated potent to weak anti-microbial activity.

10

Scheme 1.3

1.4 Thiazolylhydrazinomethylidene pyrazoles

The synthesis of novel series of thiosemicarbazones and

thiazolylhydrazinomethylidene pyrazoles (Scheme 1.4) has been reported by [Kumar et

al., 2012]. All the newly synthesized target compounds were screened for their in vivo

anti-inflammatory activity using carrageenan induced rat paw edema assay and in vitro

antibacterial activity against two Gram-positive and two Gram-negative bacteria. Some

compounds showed consistently excellent activity (C70% inhibition), at 3 and 4 h after

the carrageenan injection, comparable to that of standard drug indomethacin. All the

tested compounds showed moderate antibacterial properties.

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Scheme 1.4

1.5 4-Pyrazolyl-4H-pyrazolopyran

[Thumar et al., 2009] have synthesized a new series of 4-pyrazolyl-4H-

pyrazolopyran, benzopyran and derivatives of naphthopyran by one-pot base-

catalyzed cyclocondensation reactions of 1-phenyl-3-(het)aryl-pyrazole-4-

carbaldehyde, malononitrile and substituted pyrazolin-5-ones in the presence of

piperidine as catalyst (Scheme 1.5). All the synthesized compounds were subjected to

in vitro antimicrobial screening against a panel of pathogenic strains of bacteria and

fungi. Some of the compounds were found to be equipotent or more potent than

commercial antibiotics against most of employed strains.

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Scheme 1.5

1.6 1-Phenylpyrazol-4-yl)-3-(1,3-dimethyl-2,4,6-pyrimidinetrione-5-

yl)pyrazoline

A novel approach by [Siddiqui et al., 2011] for the synthesis of series of new

pyrazolyl chalcones under thermal solvent-free condition is reported. The chalcones

were then converted to the corresponding pyrazolines under the same condition in

excellent yields (Scheme 1.6). The synthesized compounds were tested for their

antimicrobial activity against Gram-positive, Gram-negative strains of bacteria as well

as fungal strains. The investigation of antimicrobial screening revealed that compounds

showed good antibacterial and antifungal activities, respectively. Among these some

compounds showed more potent inhibitory activity (MIC = 12.5 µg/ml) nearly to that

of standard antibiotics ciprofloxacin, griseofulvin and fluconazole.

13

Scheme 1.6

1.7 Bipyrazole and Isoxazole

Novel N-arylpyrazole-containing enaminones were synthesized as key

Intermediates by [Riyadh, 2011]. Enaminones reacted with hydrazine hydrate and

hydroxylamine hydrochloride to give bipyrazoles and pyrazolylisoxazoles respectively

(Scheme 1.7). The cytotoxic effects of compounds against human breast cell line (MCF-

7) and liver carcinoma cell line (HEPG2) were screened and in both lines they showed

inhibition effects comparable to those of 5-fluorouracil, used as a standard. The

antimicrobial activity of some products chosen as representative examples was also

evaluated.

14

Scheme 1.7

1.8 Hexahydro-2H-indazole derivatives

[Minu et al., 2009] have accomplished the synthesis of sulfonyl indazoles

(Scheme 1.8). The synthesized hexahydro indazole derivatives were evaluated for their

in vitro antimicrobial activity using ciprofloxacin and fluconazole as reference

compounds for antibacterial and antifungal activities, respectively. Indazole derivatives

3-(4-chlorophenyl)-2-(4-nitrophenylsulfonyl)-3,3a,4,5,6,7-hexahydro-2H-indazole and

3-(4-fluorophenyl)-2-(4-nitrophenylsulfonyl)-3,3a,4,5,6,7-hexahydro-2H-indazole were

the most active compounds.

15

Scheme1.8

1.9 Pyrimido[1,2-b]indazoles

[Yakaiah et al., 2008] have reported that Indazole regioisomers such as 3-

amino-4-(trifluoromethyl)-6-phenyl-1H-indazole-7-carbonitrile and 3-amino-6-

(trifluoromethyl)-4-phenyl-1H-indazole-7-carbonitrile on reaction with formaldehyde

followed by unsymmetrical, symmetrical and cyclic electron rich olefins in presence of

GdCl3 as catalyst furnished pyrimidine fused indazole derivatives (Scheme 1.9).

Representative compounds were screened against Gram-positive, Gram-negative

bacteria and fungal species such as yeast and filamentous fungi in vitro. Some

compounds showed significant activity against all species of Gram-positive and Gram-

negative bacteria, whereas some compounds showed the least activity with reference

to penicillin as well as streptomycin. Similarly other compounds showed promising

activity against yeast and filamentous fungi whereas some compound is inactive at the

maximum concentration of 150 μg/ml.

Scheme 1.9

16

1.10 Pyrazolothiazol-4(5H)-ones and pyrazolothiazoles

[Sabbagh et al., 2009] have reported the synthesis of new N-acetyl and N-

thiocarbamoyl derivatives of 4,5-dihydropyrazole from α, β-unsaturated ketones under

the effect of hydrazine hydrate and thiosemicarbazide respectively. N-

Thiocarbamoylpyrazole derivatives were cyclized using either ethyl bromoacetate or

phenacyl bromides to afford the novel pyrazolothiazol-4(5H)-ones or pyrazolothiazoles

(Scheme 1.10). The antiviral activity for such novel compounds against a broad panel

of viruses in different cell cultures revealed that N-acetyl-4,5-dihydropyrazole was the

only active one at sub toxic concentrations against vaccinia virus (Lederle strain) in

HeLa cell cultures with a 50% effective concentration (EC50) value of 7 µg/ml.

Scheme 1.10

17

1.11 1,3,4,5-Tetrasubstituted pyrazoles

[Lee et al., 2003] have achieved the regioselective synthesis of tetra substituted

pyrazole derivatives in good yields from the reaction of Baylis–Hillman adducts and

hydrazine hydrochlorides in 1,2-dichloroethane (Scheme 1.11). The reaction proceeds

through conversion of Baylis–Hillman adduct in to corresponding hydrazone derivative,

acid catalyzed cyclization and subsequent 1,3-hydrogen transfer to afford the

pyrazoles.

Scheme 1.11

1.12 Pyrazoles from 1,3-diketones

An expeditious room temperature synthesis of pyrazoles and diazepines by

condensation of hydrazines/hydrazides and diamines with various 1,3-diketones is

described by [Polshettiwar et al., 2008]. This greener protocol was catalyzed by

polystyrene supported sulfonic acid (PSSA) and proceeded efficiently in water in the

absence of any organic solvent within 1–2 min. 1,2-Diaminobenzene reacted efficiently

18

with various 1,3-diketones to yield diazepines in a single step (Scheme 1.12). The

reaction proceeded at room temperature delivering excellent yields within 1-2 min.

Scheme 1.12

1.13 5-Hydroxy-5-trifluoromethyl-∆2-isoxazolines

[Kumar et al., 2006] have reported that reaction of hydroxylamine

hydrochloride with aryl trifluoromethyl-β-diketones affords 5-hydroxy-5-

trifluoromethyl-∆2-isoxazolines rather than the reported 3-trifluoromethylisoxazoles.

Acid catalyzed dehydration of isoxazoline generated corresponding 5-

trifluoromethylisoxazoles (Scheme 1.13).

19

Scheme 1.13

1.14 1,4-Dihydroindeno[1,2-c]pyrazole-3-carboxamides

[Mussinu et al., 2003] have described the synthesis of 1-aryl-1,4-

dihydroindeno[1,2-c]pyrazole-3-carboxamide derivatives from substituted 1-aryl-1,4-

dihydroindeno[1,2-c]pyrazole-3-carboxylic acids and requisite amines (Scheme 1.14).

The various analogues were assayed for binding both to the brain and peripheral

cannabinoid receptors (CB1 and CB2). Some new compounds displayed very high in

vitro CB2 binding affinities and the highest selectivity for CB2 receptor.

20

Scheme 1.14

1.15 3,5-Diaryl-1H-pyrazole

[Shaw et al., 2010] selected the scaffold of 3,5-diaryl-1H-pyrazole as a

molecular template to synthesize novel growth-inhibitory agents. The findings

suggested that analogs bearing electron withdrawing groups on one ring while

electron-donating groups on another reveal significant activities. In particular, some

compounds bearing a 1,10-biphenyl moiety displayed the most potent activity against

OVCA, SW620, H460 and AGS cells with GI50 values of 0.67, 0.89, 0.73 and 0.79 μM,

respectively. The mechanistic study revealed that 26-mediated apoptosis-inducing

effect on OVCA cells was, in part, attributed to the inhibition of protein kinase B/Akt

activity, accompanied by the mitochondrial apoptotic pathway through the activation

of caspase-9, caspase-3, as well as the cleavage of protein poly(ADP-ribose)

polymerase (PARP) and DNA fragmentation. Further structure–activity relationship

21

study employed by Comparative Molecular Field Analysis (CoMFA) was carried out

with q2 and R2 values of 0.671 and 0.846, respectively (Scheme 1.15).

Scheme 1.15

1.16 5-Methyl-1-aryl-1H-pyrazole-4-carboxylate

[Zhao et al., 2008] have synthesized six pyrazole derivatives (Scheme 1.16) and

characterized the structure of the compounds by IR, 1H NMR, mass spectroscopy, and

element analysis. The biology assay showed that a novel pyrazole derivative, ethyl 3-

(o-chlorophenyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxylate (MPD) at low

concentration (25 µM) increased VECs viability and inhibited VECs apoptosis induced

by deprivation of serum and FGF-2. During this process, the levels of integrin β4,

reactive oxygen species (ROS), and p53 were depressed obviously. The data suggested

that MPD was a potential inhibitor of apoptosis associated with the signal pathway

mediated by integrin β4, ROS, and p53 in VECs.

22

Scheme1.16

1.17 Ethyl 5-(4-aminophenyl)-1H-pyrazole-3-carboxylate derivatives

[Qi et al., 2011] have designed and synthesised a series of novel ethyl 5-(4-

aminophenyl)-1H-pyrazole-3-carboxylate derivatives (Scheme 1.17) and their in vitro

acrosin inhibitory activities were evaluated. Most of the compounds exhibited acrosin

inhibitory activities. Among them, some compounds were more potent. These provide

a new structural type for the development of novel contraceptive acrosin inhibitory

agents.

23

Scheme 1.17

1.18 Pyrazolo[3,4-b]quinolines and pyrazolo[3,4-c]pyrazoles

[Paul et al., 2001] described the synthesis of Pyrazolo[3,4-b]quinolines and

pyrazolo[3,4-c]pyrazoles from β-chlorovinylaldehydes and hydrazine

hydrate/phenylhydrazine using p-TsOH under microwave irradiation. These conditions

were extended to the synthesis of pyrazolo[3,4-b]quinolines and pyrazolo[3,4-

c]pyrazoles (Scheme 1.18) with very satisfactory results (78-97%).

Scheme 1.18

24

1.19 Tricyclic pyrazoles: 4,5-dihydro-1H-benzo[g]indazole

[Murineddu et al., 2005] have synthesized a series of 4,5-dihydro-1H-

benzo[g]indazole-3-carboxamides in good yield (Scheme 1.19) and their affinity and

selectivity towards cannabinoid CB1 and CB2 receptors were evaluated. Several of

these compounds exhibited CB1 affinity in the nano molar range with moderate or

negligible affinity towards CB2 receptors. Consequently, in vivo CB1 antagonistic activity

was highlighted for these compounds.

Scheme 1.19

1.20 Thiocarbamoyl-3,3a,4,5,6,7-hexahydro-2H-indazoles derivatives

[Kelekci et al., 2009] have reported the synthesis of a novel series of 2-

thiocarbamoyl-2,3,4,5,6,7-hexahydro-1H-indazoles and 2-substituted thiocarbamoyl-

3,3a,4,5,6,7-hexahydro-2H-indazole derivatives (Scheme 1.20) and investigated their

ability to inhibit the activity of monoamine oxidase (MAO). Synthesized compounds

showed high activity against both the MAO-A and the MAO-B isoforms. The rest of the

compounds, carrying N-allyl and N-phenyl, appeared to select the MAO-A isoform. The

25

inhibition profile was found to be competitive and reversible for all compounds. A

series of experimentally tested compounds was docked computationally to the active

site of the MAO-A and MAO-B isoenzyme. The differences in the intermolecular

hydrophobic and H-bonding of ligands to the active site of each MAO isoform were

correlated to their biological data. Excellent to good correlations between the

calculated and experimental Ki values were obtained.

Scheme 1.20

1.21 N1-propanoyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazoles

A series of N1-propanoyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives

were obtained by reaction of α,β-unsaturated ketones (chalcones) and hydrazine

monohydrate in propionic acid (Scheme 1.21). The inhibitory activities of compounds

were evaluated against both MAO-A and MAO-B isoforms [Chimenti et al., 2008]. Most

of the compounds showed inhibitory activity with micromolar values and MAO-A

selectivity.

26

Scheme 1.21

1.22 1,8-Disubstituted 5,5-dimethyl-4,5-dihydro-1H-benzo[g]indazoles

A number of novel 1,8-disubstituted 5,5-dimethyl-4,5-dihydro-1H-

benzo[g]indazoles based on a conformationally restricted pyrazole framework have

been designed as potential inhibitors of PDE4 [Reddy et al., 2012]. Treatment of 7-

substituted-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one with dimethylformamide

dimethyl acetal (DMFDMA) afforded the corresponding enaminoketone, which on

condensation with a variety of hydrazines in ethanol provided the target compound

(Scheme 1.22). The in vitro PDE4B inhibitory properties and molecular modelling

studies of the compounds synthesised along with X-ray single crystal data of a

representative compound is presented.

27

Scheme 1.22

1.23 Tetrahydro-4H-indazol-4-ones

1,3-Cyclohexanedione and 5,5-dimethyl-1,3-cyclohexanedione were converted

in to dimethylaminomethylene derivatives by reaction with DMF-DMA. The

dimethylaminomethylene derivatives on condensation with hydrazine furnished

tetrahydroindazol-4-ones [Claramunt et al., 2006]. In another step 2-acetyl-1,3-

cyclohexanedione and 2-acetyl- 5,5-dimethyl- 1,3 cyclohexanedione were treated with

hydrazine in THF to obtain tetrahydroindazoles (Scheme 1.23) with satisfactory yields.

These compounds have rich reactivity with not less than four reactive positions that

make them interesting scaffold in medicinal chemistry.

28

Scheme 1.23

1.24 3,5- Diphenyl-1H-Pyrazoles

A convenient route was established [Bhat et al., 2005] for the synthesis of 3,5-

diphenyl-1H-pyrazoles. Chalcones, obtained from condensation of acetophenone with

aromatic aldehydes, was subjected to epoxidation by using hydrogen peroxide in

alkaline media at 0 0C (Scheme 1.24). The epoxy chalcone was subjected to Wharton

reaction using hydrazine hydrate as nucleophilic reagent without the addition of acetic

acid. As expected, it did not form allylic alcohol, but a heterocyclic compound, which

was identified as 3,5-diphenyl-1H-pyrazole. In case of Wharton reaction, a large excess

of hydrazine is used along with catalytic amount of acetic acid. The hydroxypyrazole

formed was subjected to acid-catalyzed dehydration to give the desired 3,5-diphenyl-

1H-pyrazoles in excellent yield.

29

Scheme 1.24

1.25 4,5-Dihydro-1H-1-pyrazolyl-2-toluidinomethane thiones

A series of 5-(-4-(substituted)phenyl)-3-(4-hydroxy-3-methylphenyl)-4,5-

dihydro-1H-1-pyrazolyl-2-toluidino methane thione and 5-(substituted) phenyl-3-(4-

hydroxy-3-methylphenyl)-4,5-dihydro-1H-pyrazolyl-2-methoxyanilino methane thione

were synthesized [Ali et al., 2007] by the reaction between hydrazine hydrate and

chalcones followed by condensation with appropriate aryl isothiocyanate which

yielded N-substituted pyrazoline derivatives (Scheme 1.25). Newly synthesized

compounds were tested for their anti-tubercular activity against Mycobacterium

tuberculosis H37Rv using the BACTEC 460 radiometric system. The structure activity

relationship and cytotoxicity (IC50) in VERO cells is reported. Some of the newly

synthesised compounds have displayed relatively higher inhibitory activity.

30

Scheme 1.25

1.26 1-Alkyl-1H-indazoles

[Liu et al., 2013] have established method for regioselective synthesis of 3-

unsubstituted 1-alkyl-1H-indazoles starting from 2-halobenzonitrile and N-

alkylhydrazines. The two step reaction path way proceeds through intermediacy of 1-

alkyl-3-amino-1H-indazoles followed by reductive deamination. In this case 2-

halobenzonitriles, containing either electron donating or electron withdrawing groups

reacted with methylhydrazine in ethanol efficiently to produce the corresponding 3-

amino-1-methyl-1H indazoles. Reductive deamination of indazoles with tert-butyl

nitrile in either CHCl3, DMF or THF generated 3-substituted-1-methyl-1H-indazole in

high yield (Scheme 1.26).

Scheme 1.26

31

1.27 1,4-Dihydrobenzothiopyrano[4,3-c]pyrazoles

[Via et al., 2009] have reported the synthesis of number of 1- and 2-phenyl

derivatives of the 1,4-dihydrobenzothiopyrano[4,3-c]pyrazole nucleus, which were

obtained by the reaction of the versatile 7-substituted 2,3-dihydro-3-

hydroxymethylene-4H-1-benzothiopyran-4-ones with hydrazine and substituted

phenylhydrazines. The antiproliferative activity of the synthesized compounds was

evaluated by an in vitro assay on human tumor cell lines (HL-60 and HeLa) and showed

a significant capacity of the 7-methoxy-substituted benzothiopyrano[4,3-c]pyrazoles to

inhibit cell growth. The condensation of compounds containing the reactive methine

group adjacent to the C=O function, with hydrazine or the appropriate

phenylhydrazine hydrochlorides afforded the target series (Scheme 1.27).

Scheme 1.27

1.28 Fluorine containing pyrazole based thiazole derivatives

[Desai et al., 2012] have synthesised a series of 2-(5-(3-(4-fluorophenyl)-1-

phenyl-1H-pyrazol-4-yl)-3-(aryl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-ones

32

(Scheme 1.28) and screened for in vitro antibacterial activity against the representative

panel of Gram-positive (Staphylococcus aureus, Streptococcus pyogenes) and Gram-

negative (Escherichia coli, Pseudomonas aeruginosa) bacteria. These compounds were

also tested for their inhibitory action against strains of fungi (Candida albicans,

Aspergillus niger, Aspergillus clavatus). The synthesized compounds showed potent

inhibitory action against the test organisms.

Scheme 1.28

1.29 1-(6-Chloro-pyridin-2-yl)-5-hydroxy-1H-pyrazole-3-carboxylic acid

[Shen et al., 2012] have reported the synthesis of two new pyrazole derivatives

of 1-(6-chloro-pyridin-2-yl)-5-hydroxy-1H-pyrazole-3-carboxylic acid methyl ester and

33

5-acetoxy-1-(6-chloro-pyridin-2-yl)-1H-pyrazole-3-carboxylic acid methyl ester. The

cyclization of the hydrazones prepared from 6-chloro-2-hydrazionopyridine derivatives

and (DMADC), could have occurred either on the hydrazine nitrogen atom with the

formation of a 5-membered pyrazole ring or on the nitrogen atom of pyridine with the

formation of 1,2,4-triazine-5-ones (Scheme 1.29).

Scheme 1.29

1.30 2-Pyrazolines bearing benzene sulphonamide moiety

[Bano et al., 2011] have reported the synthesis of novel 2-pyrazolines by the

reaction of appropriate chalcones/flavones with 4-hydrazinobenzenesulfonamide

hydrochloride and tested for anti-inflammatory and anti-cancer activities. The reaction

between synthesized chalcones/flavones and 4-hydrazinobenzenesulfonamide

hydrochloride in ethanol led to the synthesis of pyrazolines (Scheme 1.30). These

compounds showed good anti-inflammatory activity which is comparable to the

34

reference drug celecoxib. Some compounds exhibited antitumor activity against tested

60 human tumor cell lines.

Scheme 1.30

1.31 1,3,5-Triaryl-2-pyrazolines

A new method was established by [Li et al., 2007] for the synthesis of

pyrazolines through the reaction of chalcone and phenylhydrazine hydrochloride in

sodium acetate-acetic acid aqueous solution under ultrasound irradiation within 1.5-2

h (Scheme 1.31) in quantitative yield.

Scheme 1.31

35

1.32 1,3-Disubstituted Indeno[1,2-c]pyrazoles

[Mohil et al., 2014] have described the synthesis of new 3-alkyl indeno[1,2-

c]pyrazoles, possessing 4-substituted thiazole moiety at position-1, from 2-acyl

indane-1,3-dione. Thiosemicarbazone of 2-acylindane-1,3-dione, on treatment with

different 4-substituted phenacyl bromides afforded the corresponding key hydrazones.

The hydrazones on cyclization in boiling absolute ethanol in presence of glacial acetic

acid furnished indenopyrazoles in good yield (Scheme 1.32). All these newly

synthesized compounds were screened for anti-microbial activities against five

microorganisms, two Gram-positive bacteria B.subtilis and S. aureus and one Gram-

negative bacteria E. Coli and two fungi C. albicans and A. niger. Some compounds have

been reported to exhibit significant antimicrobial activities.

Scheme 1.32

36

1.33 1-(3,5-Diaryl-4,5-dihydro-1H-pyrazol-4-yl)-1H-imidazoles

[Zampieri et al., 2008] have reported three step reaction, which involved an N-

alkylation of imidazole with the substituted-2-bromoacetophenone to afford the

corresponding 1-aryl-2-(1H-imidazol-1-yl)-ethanone followed by condensation with

substituted benzaldehyde and final cyclization of the obtained α, β-unsaturated

ketones with hydrazine hydrate, methyl hydrazine sulphate, phenylhydrazine and 4-

fluorophenylhydrazine to yield the imidazolyl-pyrazoles (Scheme 1.33). Newly

synthesised compounds were tested for their in vitro anti-fungal and antimycobacterial

activities. These imidazole derivatives showed an excellent antifungal activity against a

clinical strain of Candida albicans and an interesting antitubercular activity against

Mycobacterium tuberculosis H37Rv reference strain.

Scheme 1.33

37

1.34 Benzopyrano[4,3-c]pyrazoles and benzothiopyrano[4,3-c]pyrazoles

Necrosis is a regulator caspace-independent cell death mechanism that can be

induced in multiple cell types. [Jagtap et al., 2007] have described the synthesis of a

series of tricyclic heterocycles i.e. 3-phenyl-3,3a,4,5-tetrahydro-2H–benz[g]indazoles,

3-phenyl-2,3,3a,4-tetrahydro-[1]benzopyrano[4,3-c]pyrazoles and 5,5-dioxo-3-phenyl-

2,3,3a,4-tetrahydro[1]benzothiopyrano[4,3-c]pyrazoles collectively termed Nec-3, that

can potently inhibit necroptosis (Scheme 1.34). A structure-activity relationship (SAR)

study revealed that the (3R, 3aR)-rel diastereomers were more active than the (3R,

3aS)-rel diastereomers for all four ring systems.

Scheme 1.34

1.35 Isoxazolyl indazoles from Isoxazolyl Schiff base

[Rajanarendar et al., 2008] have described one pot synthesis of isoxazolyl-

indazoles from Isoxazolyl Schiff base. The isoxazolyl Schiff bases have been prepared

from the corresponding amines by reaction with 2-nitrobenzaldehydes. These nitro

38

compounds undergo de-oxygenative cyclization to give indazoles via nitrenes on

heating with triethyl phosphate in acetonitrile (Scheme 1.35).

Scheme 1.35

1.36 1,4,5-trisubstituted 1H-pyrazole-3-carboxylates

[Broz et al., 2013] have reported the conditions for successful synthesis of

polysubstituted pyrazole-3-carboxylates (Scheme 1.36). The methodology consists in

mixing equimolar amounts of diazonium tetrafluoroborates and enaminoesters in

presence of sodium acetate. The advantage of methodology is a simple

implementation without necessity of working under inert atmosphere.

Scheme 1.36

39

1.37 3,5-Biaryl-4,5-dihydro-1H-pyrazole-1-carboxylate derivatives

[Nayak et al., 2013] have reported the synthesis of ethyl and phenyl carbamate

derivatives of pyrazoline (Scheme 1.37). These derivatives were tested for their MAO

inhibitory activity using hMAO-A and hMAO-B. All the compounds were found to be

selective towards MAO-A. Phenyl carbamates were better than ethyl carbamates and

displayed the best selectivity index.

Scheme 1.37

1.38 3-(Pyridin-3-yl) pyrazole derivatives

Novel series of celecoxib analogs endowed with benzofuran moiety were

synthesized and evaluated for COX-1/COX-2 inhibitory activity in vitro by [Hassan et al.,

2014]. The most potent and selective COX-2 inhibitors compounds were assessed for

their anti-inflammatory activity and ulcerogenic liability in vivo. The 3-(pyridin-3-yl)

pyrazole derivatives exhibited the highest anti-inflammatory activity, which is

equipotent to celecoxib. Furthermore, the tested compounds proved to have better

40

gastric safety profile compared to celecoxib. The molecular docking simulation of the

new compounds in COX-2 active site and drug likeness studies showed good

agreement with the obtained pharmaco-biological results.

Scheme 1.38

1.39 3-Hydroxy-2-(1-phenyl-3-aryl-4-pyrazolyl) chromones

New 3-hydroxy-2-(1-phenyl-3-aryl-4-pyrazolyl) chromones have been

synthesized by the oxidation of 2-hydroxychalcone analogues of pyrazole with

hydrogen peroxide (H2O2) in KOH-MeOH by Algar Flynn Oymanda (AFO) reaction by

[Prakash et al., 2008]. The 2-hydroxychalcone analogues of pyrazole were obtained by

the condensation of 2-hydroxyacetophenone with 1-phenyl-3-arylpyrazole-4

carboxaldehydes in KOH-MeOH (Scheme 1.39). All the compounds were tested in vitro

for their antifungal activity against three phytopathogenic fungi, namely

Helminthosporium species, Fusarium oxysporum and Alternaria alternata. Some

compounds were associated with substantially higher antifungal activity than

41

commercial antifungal compound Actidione (cycloheximide) against all three

phytopathogenic fungi.

Scheme 1.39

1.40 4-Functionalized 1,3-diarylpyrazoles bearing benzenesulfonamide

moiety

A library of 4-functionalized 1,3-diarylpyrazoles were designed, synthesized and

evaluated against four human carbonic anhydrase (CA, EC 4.2.1.1) isozymes by [Khloya

et al., 2014] representing two cytosolic isozymes hCA I and hCA II, and two

transmembrane tumor associated ones, hCA IX and hCA XII. All the twenty two tested

compounds exhibited excellent CA activity profile against the four CA isozymes when

compared to the reference drug acetazolamide. Target pyrazole-4-carboxamides were

obtained by the oxidation of 4-cyanopyrazoles with hydrogen peroxide in THF under

basic conditions (Scheme 1.40). The target pyrazole-4-hydrazinocarbonyl compounds

42

were obtained by the condensation of methyl esters with hydrazine hydrate in

MeOH/THF.

Scheme 1.40

1.41 5-Trifluoromethyl-∆2-pyrazoline

[Aggarwal et al., 2013] have prepared a series of potential COX-2 inhibitors, 1-

(4,6-dimethylpyrimidin-2-yl)-5-hydroxy-5-trifluoromethyl-∆2-pyrazolines and 1-(4,6-

dimethylpyrimidin-2-yl)-3-trifluoromethylpyrazoles, by refluxing 2-hydrazino-4,6-

dimethylpyrimidine with a number of trifluoromethyl-β-diketones in ethanol (Scheme

1.41). These compounds were screened for their anti-inflammatory activity using the

carrageenan-induced rat paw edema assay. While all the compounds exhibited

significant anti-inflammatory activity (47-76%) as compared to indomethacin (78%). 3-

Trifluoromethylpyrazoles were found to be the most effective agents (62-76%).

43

Scheme 1.41

1.42 2-Isothiocarbamoyl substituted fused pyrazolines

2-Isothiocarbamoyl substituted fused pyrazolines and their S-alkyl derivatives

were prepared as potentially antimicrobial agents by [Lorand et al., 1999].

Conventional methods were used to synthesize the novel derivatives starting from

cyclic unsaturated ketones and thiosemicarbazide under acidic catalyst. These

cyclizations yielded only one diastereoisomer of 3-H, 3a-H cis. While the reactions with

semicarbazide afforded the mixture of the 3-H, 3a-H cis and trans diastereoisomers,

which have been separated (Scheme 1.42). The alkylations were performed applying

alkyl halides and S-alkyl derivatives were evaluated for activity against Gram-negative

and Gram-positive bacteria and their in vitro toxicity was determined on HeLa cells.

The structure-activity relationship was also studied.

44

Scheme 1.42

1.43 1,4,5-Trisubstituted pyrazoles

A simple efficient and three component one-pot synthesis of 1,4,5-

trisubstituted pyrazoles by condensation of β-dicarbonyls, N,N-dimethylformamide

dimethyl acetal (DMF-DMA) and hydrazine derivatives in 2,2,2-trifluoroethanol

without using any catalyst and activation, is described by [Alinezhad et al., 2011].

Reactions of 3-oxo-butyric acid ethyl ester and N,N-dimethylformamide dimethyl

acetal (DMF-DMA) with various arylhydrazines in TFE at room temperature afforded 4-

carboxylate pyrazoles in excellent yields (Scheme 1.43).

Scheme 1.43

45

1.44 N-Hetaryl-dihydro-pyrazolyl ferrocenes

[Kudar et al., 2005] have reported the cyclocondensation of 1-aryl-3-ferrocenyl-

2-propen-1-ones with hetaryl hydrazines affording N-hetaryl-3-aryl-5-ferrocenyl

pyrazolines. The reaction of aryl-chalcones with 4-hydrazino-phthalazinone led to 3,5-

bis-aryl-N-hetaryl-pyrazolines or to the corresponding ene-hydrazones. In a mixture of

ethanol-acetic acid-water, at reflux temperature the reaction of these compounds with

2-hydrazinopyridine and 4-hydrazino-phthalazinone resulted in N- hetaryl-3-aryl-5-

ferrocenyl-pyrazolines (Scheme 1.44).

Scheme 1.44

1.45 Pyrazolo[3,4-d]-pyrimidine and thiazolo[4,5-d]pyrimidines

[Akbari et al., 2008] have described the synthesis of the desired fused ring

system 3-isopropyl-4-aryl-1,4,5,7-tetrahydropyrazolo[3,4-d] pyrimidin-6-ones by the

reaction of 5-isopropyl-2,4-dihydro-3-pyrazolone, urea and different aromatic

aldehydes (Scheme 1.45). The antibacterial activity of newly synthesized compounds

have been reported against Staphylococcus aureus ATCC 6538, Staphylococcus

epidermidis ATCC 12228, Escherichia coli ATCC 8739 and Pseudomonas aeuginosa

ATCC 1539; antifungal activity against Candida albicans ATCC 10231.

46

Scheme 1.45

1.46 2,3,5,6-Aryl substituted tetrahydro-2H-pyrazolo[3,4-d]-thiazoles

[Turgut et al., 2007] have reported the synthesis of new 2,3,5,6-aryl

substituted tetrahydro-2H-pyrazolo[3,4-d]-thiazoles as potential biologically active

compounds by the condensation of phenyl hydrazine with new 5-arylidene

derivatives of 2,3-disubstituted-1,3-thiazolidin-4-ones (Scheme 1.46).

Scheme 1.46

47

1.47 5-Aryl-5-hydroxy-2-pyrazolines

[Holla et al., 1989] have reported that reaction of 3-(5-nitro-2-furyl)-1-aryl-2-

propyn-1-ones with aroylhydrazines furnished 1-aroyl-3-(5-nitro-2-furyl)-5-aryl-5-

hydroxy-2-pyrazolines rather than expected pyrazoles. On acid-catalyzed hydrolysis

these hydroxypyrazolines are converted into the known 3-(5-nitro-2-furyl)-5-aryl-1H-

pyrazoles (Scheme 1.47). The structural elucidation of products was carried out on the

basis of analytical and spectral data. The newly synthesized nitro-furan derivatives

were screened for their antibacterial properties against Gram-positive and Gram-

negative bacteria. Most of the compounds showed significant activity.

Scheme 1.47

1.48 3-Trifluoromethylpyrazoles

[Singh et al., 2006] have investigated a systematic study on regioselectivity of

reaction of aryl trifluoromethyl-1,3-diketones with aryl and heteroarylhydrazines in

refluxing ethanol under neutral and acidic conditions. From the results, it was

concluded that in going from neutral to acidic conditions, the proportion of 3-

trifluoromethylpyrazole always increases. When the electron-withdrawing effect of the

substituent on the hydrazine increases, so does the percentage of 5-hydroxypyrazoline

48

and when the substituent on phenyl ring of 1,3-diketone has a greater electron-

withdrawing character, the proportion of 5-hydroxypyrazoline is higher (Scheme 1.48).

Scheme 1.48

1.49 Pyrazolo[1,5-a][1,3,5]triazine-2,4-dione and pyrazolo-[1,5-

c][1,3,5]thiadiazine-2-one derivatives

[Vicentini et al., 2004] have reported the synthesis of two series of new

pyrazoles, namely pyrazolo[1,5-a][1,3,5]triazine-2,4-dione and pyrazolo-[1,5-

c][1,3,5]thiadiazine-2-one derivatives (Scheme 1.49), as potential inhibitors of the

photosynthetic electron transport chain at the photosystem II level. Their biological

activity was evaluated in vivo upon both the growth of blue-green algae and the

photosynthetic oxygen evolution by eukaryotic algae and in vitro as the ability to

interfere with light-driven reduction of ferricyanide by isolated spinach chloroplasts.

Some compounds exhibited remarkable inhibitory properties, comparable to those of

the reference commercial herbicides lenacil, diuron, and hexazinone. Results suggest

that the substitution of triazine with thiadiazine ring may act as amplifier for herbicidal

activity described.

49

Scheme 1.49

1.50 5(3)-Hydroxy-3(5)-substituted-1H-pyrazoles

[Khalil et al., 2006] have investigated phase transfer catalyzed acylation of 5(3)-

hydroxy-3(5)-substituted-1H-pyrazoles by different acyl halide reagents at 25 0C in the

presence of tetrabutylammonium bromide as catalyst. (3)-Hydroxy-3(5)-substituted-

1H-pyrazoles have been synthesized by heating a mixture of β-ketoester with

hydrazine hydrate. Acylation of 3-hydroxy-5-methyl-1H-pyrazoles under the optimized

PTC reaction condition in solid/liquid phases by acetyl chloride underwent O-

acetylation, only to give 5-methyl-1H-pyrazole-3-yl-acetate (Scheme 1.50).

50

Scheme 1.50

1.51 1,3,5-Trisubstituted pyrazoles

[Shan et al., 2011] have described a new efficient and convenient approach

toward the synthesis of pyrazoles. Through a Lewis acid catalyzed union of 3-

ethoxycyclobutanones with monosubstituted hydrazines, a variety of pyrazole

derivatives were prepared readily at ambient temperature with complete

regioselectivity. A variety of monosubstituted hydrazines were reacted with 2,2-

dimethyl 3-ethoxycyclobutanone in the presence of either SnCl4 or BF3.OEt2. It was

found that both CbzNHNH2 and BzNHNH2 reacted readily to furnish the corresponding

pyrazole derivatives. Different aryl hydrazines produced the desired pyrazole products

smoothly in good to excellent yields (Scheme 1.51).

51

Scheme 1.51

1.52 4H-Pyrano[2,3-c]pyrazoles

Mg/Al hydrotalcite acts as an efficient heterogeneous basic catalyst for the

synthesis of 4H pyrano[2,3-c]pyrazoles via a multicomponent reaction of aromatic

hydrazine hydrate, ethyl acetoacetate, aldehydes, and malononitrile in ethanol at

ambient temperature [Kshirsagar et al., 2011]. The hydrotalcite catalyst was easily

separated from the reaction mixture and can be reused. Under the optimized

conditions, various substituted aromatic aldehydes were reacted to obtain the

corresponding 4H-pyrano[2,3-c]pyrazoles in good yield (Scheme 1.52). It was observed

that the aldehydes containing electron-withdrawing substituent reacted faster and

gave a better yield of the product as compared to those containing electron-donating

substituent.

Scheme 1.52

52

1.53 Objectives and aim of present work

The thesis is largely based on the synthesis and characterization of various types of

heterocyclic systems containing pyrazole ring namely; indazolyl-hydrazono-thiazolidin-

4-one, indazolyl-hydrazono-1,3-thiazinan-4-one, benzo[g]indazolyl-thiazole,

pyrazolo[3,4-d]thiazole, benzo[e]indazolyl-thiazolidin-4-one, trisubstituted-1H-

pyrazole and thiazolo[3,2-a]pyrimidine-3,7-dione. The present study aimed to

establish best possible procedure and conditions for the synthesis of pyrazole

derivatives and related compounds. The characterization of the products is done on

the basis of elemental analysis, IR, NMR, Mass spectral data and in some cases X-ray

crystallographic studies were carried out. A Density functional theory (DFT) studies

have been carried out to predict the geometry of the cyclised products. The actual and

optimized bond lengths and bond angles, obtained by X-ray crystallographic study as

well as through geometry optimization by DFT method, were compared. 1H and 13C

NMR spectra of cyclised products and their possible isomers have been calculated by

DFT studies and correlated with experimental results. The present work is focused on

the preparation of pyrazole derivatives and related compounds to explore their

antimicrobial activities.

The objectives of present investigations include:

Keeping in view the simplicity, versatility and diverse biological potential of pyrazole

derivatives, the synthesis of new heterocyclic systems containing a pyrazole nucleus

has been accomplished.

53

The characterization of the products is done on the basis of elemental analysis, IR,

NMR and Mass spectra data. The structure of seven compounds is confirmed by X-ray

crystallographic studies.

Newly synthesised pyrazole derivatives have been tested for their antimicrobial

activities.

The molecular modelling studies of the final cyclised products has been carried out

by Density Functional Theory (DFT) method and the predicted properties of the final

compounds have been correlated with the experimental results.