studies on clinically important nitrogen and sulphur...

Studies on clinically important nitrogen and sulphur containing heterocyclic compounds

DECEMBER 2013 Page 60

Part 2

In part-II, we have installed three medicinally important heterocycles i.e.

pyrazole, 1,3,4-oxadiazole and pyridine. It is our ongoing process to search for

novel bio-active molecules.

Introductory features of pyrazoles

Pyrazoles belong to the family of azoles, i.e. five-member ring containing only

nitrogen and carbon atoms, ranging from pyrrole to pentazole. According to

Albert’s classification, they are �-excessive, N-heteroaromatic derivatives and

according to Kauffmann’s arenology principle, as a substituted carbon, they are

analogues of amines and as substituted nitrogen they are analogues of halogens,

i.e. pseudohalogens. Synthesis of pyrazole and its N-aryl analogues has been

subject of consistent interest because of the wide applications of such

heterocycles in pharmaceutical as well as in agrochemical industry.1,2 Numerous

compounds containing pyrazole moiety have been shown to exhibit anti-

inflammatory,3 analgesic,4 antihyperglycemic,5 antibacterial,6 anticancer7 and

anti-HIV8 activity, as well as useful activities in conditions like schizophrenia9

and hypertension.10

1-Phenylpyrazole moiety is present in several drug candidates for treatment of

various diseases such as cyclooxygenase-2 (Cox-2) selective inhibitors, IL-1

synthesis inhibitors and protein kinase inhibitors etc.11-14 Similarly, few of 1,5-

diarylpyrazole derivatives exhibit non-nucleoside HIV-1 reverse transcriptase

inhibitor activity15 along with Cox-2 inhibitor.13,14 The corresponding 1,3,5-

triaryl-4-alkylpyrazoles have been recently identified as efficient ligands for

estrogen receptor displaying high binding affinities and selective transcriptional

efficacy for ERI subtype.16-19

In the last 20 years pyrazole ring has attracted much attention as it has become

fairly accessible and shows diverse properties. Besides traditional interest in

pyrazole derivatives, pyrazoles containing sulfonic group at N position have

exhibited promising antimicrobial activity.20 They are also studied as

antioxidants, as interesting complexing agents for analysis and separation of

cations. They are also reported for significant bacteriostatic, bactericidal and

fungicidal action.21



Commercially available pyrazole based analogues



Synthetic study of pyrazoles

Most of the methods for the synthesis of pyrazoles involve approaches based on

either

(i) Cyclocondensation of 1,3-dicarbonyl compounds and their equivalent 1,3-

dienophilic synthons such as propargylic ketones,

dialkylamino/alkoxy/chloro ketones with arylhydrazines.

(ii) Intermolecular [2+3] cycloadditions of 1,3-dipoles to alkynes22-30.

However, the appealing generality of these methods is somewhat vitiated due to

the frequent formation of regioisomeric mixtures of unsymmetrical pyrazoles in

these reactions. Therefore, several elegant methods for the synthesis of

unsymmetrical substituted pyrazoles are reported in literature. Before presenting

the results of our work, a brief literature survey on some of the recent synthesis

of pyrazoles and their derivatives have been discussed. Among these methods,

few selected recent examples have been highlighted in the following.

Mikulskiene G et al31 have synthesized some new 1-aryl-4-[(3,5–dimethylpyrazole-

1-yl)carbonyl]-2-pyrrolidinones (3a,b) by condensation of hydrazides (2a,b) with

2,4-pentanedione in 2-propanol in presence of a catalytic amount of hydrochloric

acid.

Giacomelli G et al32 have developed synthesis of 1,4,5-trisubstituted pyrazoles (8) from meldrum acid (4) under microwave conditions. The meldrum’s acid (4) was

acylated with acid chlorides and the resulting products (5) were reacted with

amines affording the substituted β-ketoamides (6) in good yields. Subsequent



reaction of β-ketocarbonyl compounds (7) with N,N-dimethylformamide

dimethylacetal (DMF-DMA) followed by cyclization with substituted

monohydrazines furnished the corresponding 1,4,5-trisubstituted pyrazoles (8) in

good yields.

Recently Lee K Y et al33 have reported the synthesis of 1,3,4,5-tetrasubstituted

pyrazoles (10) involving the reaction of Baylis-Hillman adducts (9) and hydrazine

hydrochloride in dichloroethane at 50-70 °C.

Alinezhad H et al34 have reported an efficient protocol for the one pot

regioselective synthesis of 4-bromopyrazole derivatives (13) and (14) from 1,3-

diketones (11), arylhydrazines (12) and N-bromosaccharin, in the presence of

silica gel supported sulfuric acid as heterogeneous catalyst, under solvent free

conditions.


DECEMBER 2013 4

Sharma P K et al35 synthesized a novel series of pyrazolylpyrazolines (17) by the

reaction of appropriate chalcones (16) derived from different pyrazole aldehydes

(15) and acetophenone derivatives with 4-hydrazinobenzene- sulfonamide

hydrochloride in ethanol. All the newly synthesized target compounds (5a–k)

were screened for their anti-inflammatory activity using carrageenan-induced rat

paw edema assay. Additionally, the synthesized compounds were evaluated for

their in vitro antimicrobial activity against two Gram-positive bacteria and two

Gram-negative bacteria.

Mohamed S et al36 have reported a novel one-pot synthesis of pyrazoles. In this

method four component coupling of a terminal alkyne (18), hydrazine, carbon

monoxide and an aryl iodide (19) furnishes pyrazole derivatives (20) in presence



of palladium catalyst. The reaction proceeds at room temperature and an

ambient pressure of carbon monoxide in an aqueous solvent system.

Pharmalogical profile of pyrazoles

Fadda A A et al37 have synthesized (3-methyl-5-(phenylamino)-1H-pyrazol-4-

yl)(phenyl)methanone (21). These compounds showed significant molluscicidal

activity to Biomphalaria alexandrina snails. Ming L et al38 have reported the

formation of ethyl 5-amino-1-(5’-methyl-1’-t-butyl-4’-pyrazolyl)carbonyl-3-

methylthio-1H-pyrazole-4-carboxylate (22) by treatment of ethyl 2-cyano-3,3-

dimethylthioacrylate with 1-t-butyl-5-methyl-4-hydrazinocarbonylpyrazole. These

compounds showed fungicidal and plant growth regulation activities. Farag A M

et al39 have reported the formation of 3-(3-acetyl-1-phenyl-1H-pyrazole-4-

carbonyl)-1,5-diphenyl-1H-pyrazole-4-carbonitrile (23) and compounds showed a

significant cytotoxic activity in a nano molar range against certain types of

breast and ovarian tumors with tolerable toxicity.

Chovatia P T et al40 have synthesized 1-acetyl-3-aryl-5-{1-phenyl-3-[p-

(methylthio)phenyl]-pyrazol-4-yl}-4,5-dihydro-(1H)-pyrazoles (24) by the reaction



of 1-aryl-3-{1-phenyl-3-[p-(methylthio)phenyl]pyrazol-4-yl}-2-propen-1-ones with

hydrazine hydrate in glacial acetic acid. These synthesized compounds were

tested in vitro for their antitubercular, antibacterial and antifungal activities.

Badawey EI-S A et al41 have reported novel 1-[6-amino-5-cyano-4-(aryl)pyrimidin-

2-yl]-4-(2-hydroxyethyl)-3-methylpyrazoline-5-ones (25) and 2-[6-amino-5-cyano-

4-(aryl)pyrimidin-2-yl]-1,2,4,5,6,7-hexahydro-3H-indazol-3-ones (26). These

compounds were shown to possess anti-inflammatory, analgesic and antipyretic

activities.

Banoglu E et al42 have synthesized some new amide derivatives of 3-[1-(3-

pyridazinyl)-5-phenyl-1H-pyrazole-3-yl]propanoic acid (27). These compounds

exhibited potent analgesic activity. Karthikeyan M S et al43 have reported the

synthesis of 1-aryloxy-3-aryl-5-hydroxy-5-arylpyrazolines (28) by the reaction of

chalcone dibromides with aryloxy acid hydrazides in the presence of triethyl-

amine and ethanol. These synthesized compounds showed very good

antibacterial and antifungal activities. Perali R S et al44 were synthesized a series

of 1,3-diarylpyrazole ligated DHPMs possessing lipophilic carbamoyl moiety (29) by utilizing Biginelli reaction and displayed good in vitro anticancer activity

against MCF-7 human breast cancer (HBC) cell line using sulforhodamine B

(SRB) assay and antitubercular activity against Mycobacterium tuberculosis

(MTB) H37Rv using Microplate Alamar Blue Assay (MABA).



Moreover, pyrazoles are reported to possess anticancer, germicidal, antidiretic,

antihistamine, antidiabitic, antirheumatic, antineoplastic, anti HIV and

antifertility activities. The pharmaceutical importance of these compounds lies in

the fact that they can be effectively utilized as antibacterial, antifungal, antiviral,

antiparasitic, and antitubercular agents. As evident from the literature, in recent

years significant research work in heterocyclic chemistry has been devoted to

pyrazole containing different aryl groups as substituents.

Introductory features of pyridines

Pyridine is a simple and important heterocyclic aromatic organic compound with

the formula C5H5N (30). This colourless liquid with a distinctive fish-like odour is

structurally related to benzene, wherein one CH group in the six-membered ring

is replaced by a nitrogen atom. Pyridines came to prominence in the 1930s with

the recognition of the importance of niacin (31) for the prevention of dermatitis

and dementia. In the 1940s a new major application was discovered for 2-

vinylpyridine (32) as a constituent in latex that promoted the binding of rubber to

tyre cord. Demand for 2-picoline (33) for latex production outstretched its

availability from coal tar sources and so industries developed an industrial

synthesis of 2-picolines and 4-picolines (34).



Since the middle of the last century, pyridine has assumed an important role in

our understanding of the chemistry of biological systems. It plays a key role

catalyzing both biological and chemical systems. In many enzymes of living

organisms, it is the prosthetic pyridine nucleotide (NADP) that is involved in

various oxidation–reduction processes.45 Other evidence of the potent activity of

pyridine in biological systems is its presence in the important vitamins niacin

and pyridoxine (vitamin B6) and also in highly toxic alkaloids such as nicotine.46

The pyridine ring is also ubiquitous in agrochemicals.47

In addition to these important biological applications, pyridine is also of great

utility in preparative organic chemistry (Scheme 6), for example, DMAP (35), which is used in demanding process-scale acylation reactions and in the

activation of carboxylic acids without racemization of a sensitive chiral

α-functionality. An axially chiral analogue of DMAP (36) is developed to carry out

enantioselective acylation, a reaction formerly dependent on the use of

enzymes.48 Within synthetic organic chemistry, pyridines are extensively utilized

in coordination chemistry: bipyridines such as (37) and terpyridines such as (38)

have an excellent ability to complex various metal ions, including ruthenium,

zinc and copper. These functional ligands have found a multitude of applications

in highly sensitive analytical reagents, sensor systems, enantioselective

synthesis, luminescent agents for labelled peptide synthesis and building blocks

for supramolecular chemistry.49



Commercially available pyridine based analogues

Synthetic study of pyridines

Joshi H S et al50 have synthesized some new cyanopyridines (40) from 1-[p-(3’-

chloro-2’-benzo(b)thiophenoylamino)-phenyl]-3-aryl-2-propen-1-ones (39) and

malononitrile in the presence of ammonium acetate and also reported their

antitubercular and antimicrobial properties. Xiong X et al51 have synthesized

some polysubstituted pyridines (43) by the one-pot reaction of 1,3-dicarbonyl

compound (41), alkynone (42) and ammonium acetate in alcoholic solvents. This

new three-component heteroannulation reaction proceeds under mild conditions

in the absence of an additional acid catalyst.



Andersson H et al52 have reported that addition of Grignard reagents to pyridine

N-oxides (44) in THF at room temperature and subsequent treatment with acetic

anhydride at 120°C yields 2-substituted pyridines (45) in good yields. Trost B M

et al53 have synthesized substituted pyridine (47) derivatives from unsaturated

ketones and aldehydes (46) with excellent regiocontrol.



Fathalla O E M et al54 have synthesized iminopyridines (49) and pyridones (50) from 3-(4-acetylphenyl)-2-[(E)-2-(2-furyl)vinyl]-(3H)-quinazolin-4-one (48) with

good yield and evaluated their antimicrobial and anti-inflammatory properties. They used Escherichia coli as Gram negative and Staphylococcus aureus as Gram

positive bacteria, Candida albicans as yeast and Aspergillus niger as fungi in

antimicrobial activity. Anti-inflammatory activity was checked with respect to

Indomethacin.

Thirumurugan P and Perumal P T55 have prepared 2-(1H-Indol-3-yl)-6-methoxy-

4-(aryl)pyridine-3,5-dicarbonitrile derivatives (53) through one-pot multi-

component reaction using indium chloride as catalyst under reflux condition.

Particularly valuable features of this method include high yields of products in

short reaction time and broad substrate scope. It is an efficient and promising

synthetic strategy to build indol-3-yl pyridines. Barluenga J et al56 have

synthesized trisubstituted pyridines are regioselectively through multicomponent

and one-pot processes promoted by a bifunctional Pd catalyst.



Palacios F et al57 have reported the reaction of N-vinylic phosphazenes (58a-c) with α,β-unsaturated ketones (59) leads to the formation of pyridines (61)

derived from β-amino acids in a regioselective fashion through the formation of

dihydropyridines (60) substituted with carboxylate or phosphonate groups.



Pharmalogical profile of pyridines

The pyridine substructure is one of the most important heterocycle found in

natural products, pharmaceuticals, and functional materials.58,59 Pyridines and

its analogues were reported to possess anticonvulsant,60,61 cardiotonic,62

antihypertensive,63 �-adrenergic blocking activity.64 Recent papers have reported

novel 1,4-dihydropyridine derivatives as calcium channel modulators,65 as Ca-

blockers against endothelial cell oxidative injury,66 with vasodilating activity67

and as nonpeptide HIV-1 protease inhibitors.68 Pyridine derivatives containing

multi-functional groups such as streptonigrin, streptonigrone and lavendamycin

are reported as anticancer drugs, and cerivastatin is reported as the HMGCoA

enzyme inhibitors.69 Moreover, substituted pyridines are reported as leukotriene

B-4 antagonists.70,71

Narendar P et al72 have synthesized a series of 2-substituted-pyridines. The

compounds were assayed against seizures induced by the maximal electro shock

(MES) and pentylenetetrazole (scMet). Neurologic deficit was evaluated by the

rotarod test. The decrease in the elevated motor activity by introceptive chemical

stimuli (amphetamine antagonistic activity) was studied at the dose level of 25

and 50 mg/kg, antihistaminic and cardiac activity were also studied. All the

compounds exhibited significant anticonvulsant activity.

Bach P et al73 have described the development of a new series of P2Y12 receptor

antagonists (64) endowed with a sulfonylurea group. The improved affinity

observed in the in vitro binding assay also translated to the potency observed in

the WPA aggregation assay and the observed in vitro ADME properties translates

to the in vivo PK properties observed in rat. In addition, we found that the

chemical stability of the sulfonylureas during prolonged storage in solution was



related to the sulfonyl urea linker and depended on the type of solvent and the

substitution pattern of the sulfonyl urea functionality. Hayashi S et al74 designed

a series of novel [2-{[(4-substituted or 4,5-disubstituted)-pyridin-2-yl]carbonyl}-(5-

or 6-substituted or 5,6-disubstituted)-1H-indol-3-yl]acetic acid (65) analogues

and evaluated to identify potent and selective COX-2 inhibitors as potential

agents against inflammatory diseases. As significant findings, the present study

clarified unique structure activity relationship of the analogues toward potent

and selective COX-2 inhibition in vitro, and identified 2-{6-fluoro-2-[4-methyl-2-

pridinyl)carbonyl]-1H-indol-3-yl}acetic acid as a potent and selective COX-2

inhibitor in vitro that demonstrated orally potent anti-inflammation efficacy

against carrageenan-induced oedema formation in the foot of SPF/VAF male SD

rats as a peripheral inflammation model in vivo.

Prasanthi G et al75 have developed dialkyl 4-(benzo[d][1,3]dioxol-6-yl)-1,4-

dihydro-2,6-dimethyl-1-substituted pyridine-3,5-dicarboxylate derivatives (66) as

isosteric analogues of isradipine and nifedipine, by the replacement of

benzofurazanyl and 2-nitrophenyl groups respectively with benzo[d][1,3]dioxo-6-

yl group, as potential anticonvulsants. All the compounds were tested for

anticonvulsant activity using maximal electroshock and subcutaneous

pentylenetetrazole induced seizure methods. Compound possessing free -NH

group in 1,4-dihydropyridine ring, diethyl ester functionality at the positions 3

and 5 showed significant anticonvulsant and antioxidant activities. This was also

supported by molecular properties prediction data. Selected compounds were

evaluated for antinociceptive activity in capsaicin induced nociception assay at



10 mg/kg body weight, but displayed no significant activity at the tested dose.

Khidre R E et al76 have synthesized a new series of 1-substituted amino-4,6-

dimethyl-2-oxo-pyridine-3-carbonitrile such as ethane-1,2-diaminopyridine (67) using 1-amino-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile as a key

intermediate. The antibacterial and antifungal activities of the synthesized

compounds were evaluated. The obtained data indicated that the majority of the

tested compounds exhibited both antibacterial and antifungal activities.

Acharya B N et al77 have reported a series of 1,3,5-trisubstituted pyrazolines (68) and evaluated for in vitro antimalarial efficacy against chloroquine sensitive

(MRC-02) as well as chloroquine resistant (RKL9) strains of Plasmodium

falciparum. The activity was at nano molar concentration. β-hematin formation

inhibition activity (BHIA50) of the pyrazolines were determined and correlated with

antimalarial activity. A reasonably good correlation (r = 0.62) was observed

between antimalarial activity (IC50) and BHIA50. This suggests that antimalarial

mode of action of this class of compounds appears to be similar to that of

chloroquine and involves the inhibition of hemozoin formation. Xia Y et al78 have

synthesized a series of novel hydrazone derivatives of pyrazole containing

pyridines (69) and the effects of all the compounds on A549 cell growth were

investigated. The results showed that all compounds had almost inhibitory effects

on the growth of A549 cells. The study on structure activity relationships and

prediction of lipophilicities of compounds showed that compounds with Lo values

in the range of 4.12-6.80 had inhibitory effects on the growth of A549 cells.



Desai N C and Dodiya A79 have synthesized a series of 3-chloro-1-(aryl)-4-(2-(2-

chloro-6-methylquinolin-3-yl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)-4-ethyl-

azetidin-2-ones (70) and were screened for their antibacterial activity against four

different strains like Escherichia coli, Pseudomonas aeruginosa, Staphylococcus

aureus and Streptococcus pyogenes, while antifungal activity was determined

against three different strains like Candida albicans, Aspergillus niger and

Aspergillus clavatus. On the basis of statistical analysis, it has been observed

that compounds gave significant co-relation. Kumar R S et al80 have reported the

2,2’-{[4-(aryl)-2,6-dimethyl-1,4-dihydropyridine-3,5-diyl]dicarbonyl}dihydrazine-

carbothioamides (71) prepared from condensation between corresponding

diethylacetate and thiosemicarbazide. All the synthesized derivatives were

screened for anticoagulant properties.



Plausible mechanistic pathway of 3-(4-aryl)-1-phenyl-1H-pyrazole-4-carbaldehyde:

Plausible mechanistic pathway (sections 6-9):



Looking to the literature survey and pharmacological importance of pyrazole,

pyridine and 1,3,4-oxadiazole, we have synthesized the following hybrid

heterocyclic compounds.

Section 6: 1-(2-(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-(pyridin-4-yl)-

1,3,4-oxadiazol-3(2H)-yl)-3-(aryl)prop-2-en-1-ones.

Section 7: 1-(2-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-(pyridin-4-yl)-


Section 8: 1-(2-(3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-5-(pyridin-4-

yl)-1,3,4-oxadiazol-3(2H)-yl)-3-(aryl)prop-2-en-1-ones.

Section 9: 1-(2-(3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-(pyridin-4-yl)-




EXPERIMENTAL PROCEDURE

PREPARATION OF 3-(4-ARYL)-1-PHENYL-1H-PYRAZOLE-4-CARBALDEHYDES (IIa-d) BY VILSMEIER-HAACK REACTION

Preparation of 1-(1-(4-chlorophenyl)ethylidene)-2-phenylhydrazine (Ia)

Glacial acetic acid (1mL) and phenyl hydrazine (0.01 mol) was added to a solution

of 4-chloroacetophenone (0.01 mol) in 30 mL of ethanol (95%). Then, reaction

mixture was warmed for 1 hr. The precipitates were filtered and washed with

ethanol (95%), then it was dried in vacuum over P2O5 and recrystallized from

methanol.

Preparation of 3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (IIa)

Dimethylformamide (0.35 mol) and phosphorus oxychloride (0.35) were

separately cooled at 0 °C before being stirred at same temperature. A solution of

compound Ia (0.11 mol) in dimethylformamide was added dropwise to the

reaction mixture which was then allowed to attain room temperature and

refluxed at 70-80 °C for 5 hrs. After cooling at room temperature, the mixture

was treated with a cold saturated K2CO3 solution. The precipitates were filtered,

strongly washed with water and recrystallized from ethanol (95%).

The progress of reaction and purity of compounds (IIa-d) were checked on TLC

[Aluminium sheet silica gel 60 F245 (E. Merck)] plates using n-hexane:ethyl

acetate (7:3) as an irrigator and plates were visualized with ultraviolet (UV) light,

or iodine vapour. All compounds were prepared by using the same method and

their physical constants are recorded in TABLE A.



PHYSICAL CONSTANTS OF OF 3-(4-ARYL)-1-PHENYL-1H-PYRAZOLE-4-CARBALDEHYDES

TABLE A

Sr.No. -R Molecular Formula

% Yield

M.P. °C

Elemental Analysis

% Carbon % Hydrogen % Nitrogen

Calcd (Found)

Calcd (Found)

Calcd (Found)

IIa -4-Cl C16H11ClN2O 72 111 67.97 (67.85)

3.92 (4.05)

9.91 (10.02)

IIb -4-F C16H11FN2O 65 183 72.17 (72.02)

4.16 (4.03)

10.52 (10.67)

IIc -4-OCH3 C17H14N2O2 68 102 73.37 (73.53)

5.07 (5.20)

10.07 (9.94)

IId -4-NO2 C16H11N3O3 58 165 65.53 (65.64)

3.78 (3.64)

14.33 (14.46)



SECTION 6

PREPARATION OF 1-(2-(3-(4-CHLOROPHENYL)-1-PHENYL-1H-PYRAZOL-4-YL)-5-(PYRIDIN-4-YL)-1,3,4-OXADIAZOL-3(2H)-YL)-3-(ARYL)PROP-2-EN-1-

ONES

SYNTHETIC SCHEME 6



PHYSICAL CONSTANTS OF 1-(2-(3-(4-CHLOROPHENYL)-1-PHENYL-1H-PYRA- ZOL-4-YL)-5-(PYRIDIN-4-YL)-1,3,4-OXADIAZOL-3(2H)-YL)-3(ARYL)PROP-2-EN-

1-ONES

TABLE 6

Sr.No. -R Molecular

Formula %

Yield M.P. °C

Elemental Analysis % Carbon % Hydrogen % Nitrogen

Calcd (Found)

Calcd (Found)

Calcd (Found)

GK6-1 -H C31H22ClN5O2 57 220 69.99 (69.90)

4.17 (4.24)

13.16 (13.24)

GK6-2 -2-Cl C31H21Cl2N5O2 61 189 65.73 (65.81)

3.74 (3.65)

12.36 (12.43)

GK6-3 -3-Cl C31H21Cl2N5O2 62 178 65.73 (65.79)

3.74 (3.66)

12.36 (12.43)

GK6-4 -4-Cl C31H21Cl2N5O2 58 212 65.73 (65.82)

3.74 (3.67)

12.36 (12.44)

GK6-5 -4-F C31H21ClFN5O2 56 180 67.70 (67.84)

3.85 (3.76)

12.73 (12.79)

GK6-6 -2-CH3 C32H24ClN5O2 59 232 70.39 (70.48)

4.43 (4.53)

12.83 (12.76)

GK6-7 -4-CH3 C32H24ClN5O2 60 241 70.39 (70.49)

4.43 (4.52)

12.83 (12.74)

GK6-8 -3-NO2 C31H21ClN6O4 64 195 64.53 (64.40)

3.67 (3.74)

14.57 (14.65)

GK6-9 -4-NO2 C31H21ClN6O4 61 218 64.53 (64.40)

3.67 (3.75)

14.57 (14.64)

GK6-10 -4-OH C31H22ClN5O3 58 201 67.94 (67.81)

4.05 (4.12)

12.78 (12.89)

GK6-11 -3-OCH3 C32H24ClN5O3 55 221 68.39 (68.50)

4.30 (4.22)

12.46 (12.55)

GK6-12 -4-OCH3 C32H24ClN5O3 59 244 68.39 (68.51)

4.30 (4.38)

12.46 (12.54)

GK6-13 -4-Br C31H21BrClN5O2 64 184 60.95 (60.80)

3.46 (3.54)

11.46 (11.56)




N'-((3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)isonicotino-hydrazide (IV)

Compound 3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde IIa (0.01

mol) and isoniazide III (0.01 mol) were dissolved in 1,4-dioxane (20 mL) and the

reaction mixture were refluxed for 8 h at 90 ºC. After cooling, the crystals formed

were filtered and recrystallized from absolute alcohol to give compound IV. Yield:

78%; m.p.: 148 ºC; Anal. calcd. for C22H16ClN5O: C-65.76, H-4.01, N-17.43;

Found: C-65.63, H-4.09, N-17.53%.

1-(2-(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-(pyridin-4-yl)-1,3,4-oxa-

diazol-3(2H)-yl)ethanone (V)

Acetic anhydride (0.03 mol) was added to compound N'-((3-(4-chlorophenyl)-1-

phenyl-1H-pyrazol-4-yl)methylene)isonicotinohydrazide IV (0.01 mol) and

refluxed at 90 ºC for 5 h. After cooling, the reaction mixture was poured into ice

cold water. The precipitates were filtered, washed with water, dried and

recrystallized from ethanol (95%) to give compound V. Yield: 72%; m.p.: 168 ºC;

Anal. calcd. for C24H18ClN5O2: C-64.94, H-4.09, N-15.78; Found: C-64.81, H-

4.16, N-15.87%.

1-(2-(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)-3-phenylprop-2-en-1-one (VI) (GK6-1)

A mixture of intermediate compound 1-(2-(3-(4-chlorophenyl)-1-phenyl-1H-

pyrazol-4-yl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)ethanone V (0.01 mol) and

benzaldehyde (0.01 mol) was stirred in ethanolic potassium hydroxide for 20 min.

at room temperature. After stirring, the reaction mixture was refluxed for 8 h and

excess of solvent was distilled out to get final compound VI. Yield: 67%; m.p.: 212

ºC; Anal. calcd. for C31H22ClN5O2: C-69.99, H-4.17, N-13.16; Found: C-69.86, H-

4.24, N-13.25%.

The progress of reaction and purity of compounds IV, V and VI were checked on

TLC [Aluminium sheet silica gel 60 F245 (E. Merck)] plates using

chloroform:methanol (9.5:0.5) as an irrigator and plates were visualized with

ultraviolet (UV) light, or iodine vapour.



SECTION 7

PREPARATION OF 1-(2-(3-(4-FLUOROPHENYL)-1-PHENYL-1H-PYRAZOL-4-YL)-5-(PYRIDIN-4-YL)-1,3,4-OXADIAZOL-3(2H)-YL)-3-(ARYL)PROP-2-EN-1-

ONES

SYNTHETIC SCHEME 7



PHYSICAL CONSTANTS OF 1-(2-(3-(4-FLUOROPHENYL)-1-PHENYL-1H-PYRA- ZOL-4-YL)-5-(PYRIDIN-4-YL)-1,3,4-OXADIAZOL-3(2H)-YL)-3-(ARYL)PROP-2-

EN-1-ONES

TABLE 7


% Yield

M.P. °C


Calcd (Found)

Calcd (Found)

Calcd (Found)

GK7-1 -H C31H22FN5O2 59 214 72.22 (72.31)

4.30 (4.37)

13.58 (13.65)

GK7-2 -2-Cl C31H21ClFN5O2 64 198 67.70 (67.82)

3.85 (3.78)

12.73 (12.81)

GK7-3 -3-Cl C31H21ClFN5O2 61 180 67.70 (67.80)

3.85 (3.77)

12.73 (12.82)

GK7-4 -4-Cl C31H21ClFN5O2 59 218 67.70 (67.79)

3.85 (3.79)

12.73 (12.80)

GK7-5 -4-F C31H21F2N5O2 56 178 69.79 (69.70)

3.97 (3.90)

13.13 (13.21)

GK7-6 -2-CH3 C32H24FN5O2 63 239 72.58 (72.47)

4.57 (4.50)

13.22 (13.29)

GK7-7 -4-CH3 C32H24FN5O2 61 257 72.58 (72.48)

4.57 (4.64)

13.22 (13.30)

GK7-8 -3-NO2 C31H21FN6O4 66 201 66.42 (66.55)

3.78 (3.69)

14.99 (14.89)

GK7-9 -4-NO2 C31H21FN6O4 62 221 66.42 (66.54)

3.78 (3.71)

14.99 (14.90)

GK7-10 -4-OH C31H22FN5O3 59 231 70.05 (70.16)

4.17 (4.25)

13.18 (13.26)

GK7-11 -3-OCH3 C32H24FN5O3 57 221 70.45 (70.34)

4.43 (4.35)

12.84 (12.94)

GK7-12 -4-OCH3 C32H24FN5O3 58 247 70.45 (70.33)

4.43 (4.50)

12.84 (12.92)

GK7-13 -4-Br C31H21BrFN5O2 67 174 62.94 (62.82)

3.56 (3.47)

11.78 (11.89)




N'-((3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)isonicotino-hydrazide (IV)

Compound 3-(4-fluorophenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde IIb (0.01




75%; m.p.: 153 ºC; Anal. calcd. for C22H16FN5O: C-68.56, H-4.18, N-18.17;

Found: C-68.68, H-4.09, N-18.24%.

1-(2-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-(pyridin-4-yl)-1,3,4-oxa-

diazol-3(2H)-yl)ethanone (V)

Acetic anhydride (0.03 mol) was added to compound N'-((3-(4-fluorophenyl)-1-




recrystallized from ethanol (95%) to give compound V. Yield: 71%; m.p.: 189 ºC;

Anal. calcd. for C24H18FN5O2: C-67.44, H-4.24, N-16.38; Found: C-67.33, H-4.16,

N-16.44%.

1-(2-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)-3-phenylprop-2-en-1-one (VI) (GK7-1)

A mixture of intermediate compound 1-(2-(3-(4-fluorophenyl)-1-phenyl-1H-





ºC; Anal. calcd. for C31H22FN5O2: C-72.22, H-4.30, N-13.58; Found: C-72.31, H-

4.37, N-13.65%.







SECTION 8

PREPARATION OF 1-(2-(3-(4-METHOXYPHENYL)-1-PHENYL-1H-PYRAZOL-4-YL)-5-(PYRIDIN-4-YL)-1,3,4-OXADIAZOL-3(2H)-YL)-3-(ARYL)PROP-2-EN-1-

ONES

SYNTHETIC SCHEME 8



PHYSICAL CONSTANTS OF 1-(2-(3-(4-METHOXYPHENYL)-1-PHENYL-1H-PYRAZOL-4-YL)-5-(PYRIDIN-4-YL)-1,3,4-OXADIAZOL-3(2H)-YL)-3-

(ARYL)PROP-2-EN-1-ONES

TABLE 8


% Yield

M.P. °C


Calcd (Found)

Calcd (Found)

Calcd (Found)

GK8-1 -H C32H25N5O3 61 221 72.85 (72.73)

4.78 (4.86)

13.27 (13.36)

GK8-2 -2-Cl C32H24ClN5O3 65 213 68.39 (68.28)

4.30 (4.38)

12.46 (12.54)

GK8-3 -3-Cl C32H24ClN5O3 63 227 68.39 (68.48)

4.30 (4.23)

12.46 (12.53)

GK8-4 -4-Cl C32H24ClN5O3 64 237 68.39 (68.49)

4.30 (4.37)

12.46 (12.37)

GK8-5 -4-F C32H24FN5O3 59 198 70.45 (70.34)

4.43 (4.50)

12.84 (12.92)

GK8-6 -2-CH3 C33H27N5O3 64 231 73.18 (73.28)

5.02 (5.10)

12.93 (12.85)

GK8-7 -4-CH3 C33H27N5O3 61 247 73.18 (73.29)

5.02 (5.09)

12.93 (12.84)

GK8-8 -3-NO2 C32H24N6O5 66 207 67.13 (67.04)

4.22 (4.30)

14.68 (14.76)

GK8-9 -4-NO2 C32H24N6O5 64 234 67.13 (67.05)

4.22 (4.29)

14.68 (14.77)

GK8-10 -4-OH C32H25N5O4 66 249 70.71 (70.82)

4.64 (4.71)

12.88 (12.79)

GK8-11 -3-OCH3 C33H27N5O4 61 224 71.08 (71.19)

4.88 (4.95)

12.56 (12.48)

GK8-12 -4-OCH3 C33H27N5O4 63 251 71.08 (71.00)

4.88 (4.95)

12.56 (12.47)

GK8-13 -4-Br C32H24BrN5O3 67 203 63.37 (63.26)

3.99 (3.92)

11.55 (11.64)




N'-((3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)isonicotino-hydrazide (IV)

Compound 3-(4-methoxyphenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde IIc (0.01




79%; m.p.: 173 ºC; Anal. calcd. for C23H19N5O2: C-69.51, H-4.82, N-17.62; Found:

C-69.40, H-4.89, N-17.70%.

1-(2-(3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-5-(pyridin-4-yl)-1,3,4-

oxadiazol-3(2H)-yl)ethanone (V)

Acetic anhydride (0.03 mol) was added to compound N'-((3-(4-methoxyphenyl)-1-




recrystallized from ethanol (95%) to give compound V. Yield: 72; m.p.: 189 ºC;

Anal. calcd. for C25H21N5O3: C-68.33, H-4.82, N-15.94; Found: C-68.45, H-4.74,

N-15.85%.

1-(2-(3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)-3-phenylprop-2-en-1-one (VI) (GK8-1)

A mixture of intermediate compound 1-(2-(3-(4-methoxyphenyl)-1-phenyl-1H-





ºC; Anal. calcd. for C32H25N5O3: C-72.85, H-4.78, N-13.27; Found: C-72.73, H-

4.86, N-13.36%.







SECTION 9

PREPARATION OF 1-(2-(3-(4-NITROPHENYL)-1-PHENYL-1H-PYRAZOL-4-YL)-5-(PYRIDIN-4-YL)-1,3,4-OXADIAZOL-3(2H)-YL)-3-(ARYL)PROP-2-EN-1-ONES

SYNTHETIC SCHEME 9



PHYSICAL CONSTANTS OF 1-(2-(3-(4-NITROPHENYL)-1-PHENYL-1H-PYRA- ZOL-4-YL)-5-(PYRIDIN-4-YL)-1,3,4-OXADIAZOL-3(2H)-YL)-3-(ARYL)PROP-2-

EN-1-ONES

TABLE 9


% Yield

M.P. °C


Calcd (Found)

Calcd (Found)

Calcd (Found)

GK9-1 -H C31H22N6O4 62 199 68.63 (68.52)

4.09 (4.02)

15.49 (15.58)

GK9-2 -2-Cl C31H21ClN6O4 63 211 64.53 (64.66)

3.67 (3.57)

14.57 (14.68)

GK9-3 -3-Cl C31H21ClN6O4 65 224 64.53 (64.65)

3.67 (3.75)

14.57 (14.66)

GK9-4 -4-Cl C31H21ClN6O4 61 241 64.53 (64.67)

3.67 (3.58)

14.57 (14.67)

GK9-5 -4-F C31H21FN6O4 60 197 66.42 (66.54)

3.78 (3.69)

14.99 (14.90)

GK9-6 -2-CH3 C32H24N6O4 59 229 69.06 (69.19)

4.35 (4.26)

15.10 (15.19)

GK9-7 -4-CH3 C32H24N6O4 64 257 69.06 (69.18)

4.35 (4.27)

15.10 (15.18)

GK9-8 -3-NO2 C31H21N7O6 67 238 63.37 (63.24)

3.60 (3.68)

16.69 (16.79)

GK9-9 -4-NO2 C31H21N7O6 68 214 63.37 (63.24)

3.60 (3.66)

16.69 (16.77)

GK9-10 -4-OH C31H22N6O5 65 261 66.66 (66.78)

3.97 (3.90)

15.05 (14.98)

GK9-11 -3-OCH3 C32H24N6O5 62 234 67.13 (67.01)

4.22 (4.30)

14.68 (14.78)

GK9-12 -4-OCH3 C32H24N6O5 63 263 67.13 (67.03)

4.22 (4.31)

14.68 (14.79)

GK9-13 -4-Br C31H21BrN6O4 69 189 59.91 (59.80)

3.41 (3.48)

13.52 (13.60)




N'-((3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)isonicotino-hydrazide (IV)

Compound 3-(4-nitrophenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde IId (0.01 mol)

and isoniazide III (0.01 mol) were dissolved in 1,4-dioxane (20 mL) and the



77%; m.p.: 178 ºC; Anal. calcd. for C22H16N6O3: C-64.07, H-3.91, N-20.38; Found:

C-64.19, H-3.84, N-20.29%.

1-(2-(3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-(pyridin-4-yl)-1,3,4-oxadi-

azol-3(2H)-yl)ethanone (V)

Acetic anhydride (0.03 mol) was added to compound N'-((3-(4-nitrophenyl)-1-




recrystallized from ethanol (95%) to give compound V. Yield: 70; m.p.: 177 ºC;

Anal. calcd. for C24H18N6O4: C-63.43, H-3.99, N-18.49; Found: C-63.31, H-4.07,

N-18.58%.

1-(2-(3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)-3-phenylprop-2-en-1-one (VI) (GK9-1)

A mixture of intermediate compound 1-(2-(3-(4-nitrophenyl)-1-phenyl-1H-





ºC; Anal. calcd. for C31H22N6O4: C-68.63, H-4.09, N-15.49; Found: C-68.52, H-

4.02, N-15.58%.







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studies on clinically important nitrogen and sulphur...

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