12 chapter 4 Synthesis and biological activities of...

Chapter:-4 Synthesis and biological activities of Isoxazole &Pyrazole

40 Synthesis, Characterization and Biological Evaluation of some Chalcones and their

Derivatives

CHAPTER-4 Synthesis and biological activities of Isoxazoles and

Pyrazoles



Derivatives

3.1 Introduction

Aryl ketones and aromatic aldehydes were condensed in presence of base resulted

Chalcones.

Isoxazole is an azole with an oxygen atom next to nitrogen. Isoxazole rings are found in

natural products like ibotonic acid .Isoxazoles are the basic for a number of drugs like cox-2

inhibitor, nitric oxide donor–furaxan etc. A highly appreciable number of five membered

heterocycles containing nitrogen atom and oxygen atoms obtained by laboratory synthesis.

Which are having potential therapeutic and pharmaco therapeutic activities. Some of useful

synthetic analogues with improved therapeutic activity can be obtained from single lead

compound by structural modifications. A lot of modifications have been done during the last few

years on Isoxazole nucleous.

Chalcone derivatives have different activities1-9. Therefore new compounds are

synthesized.

Synthesis of heterocyclic molecules inventive advance methods are available, this subject

is ever innovative area for the world of chemistry. Pyrazoles and isoxazoles nucleus blocks have

used widely for pharma world. Their derivatives are brilliantly used with high pharmacology

properties. Like Hypoglycemic, Analgesic, Antiinflammatory, Anti-bacterial, Anti-HIV and

Anti-cancer activity10, with other hand use in schizophrenia, Hypertension and alzheimer

disease11. They are also used in Insecticides12 and Pesticides. Pyrazoles are used in recently Anti-

parasites activity13 and kinase inhibitor.

Pyrazoles and isoxazoles are well known five member heterocyclic compounds and

several procedures for its synthesis have been extensively studied.

NH

N

O

N

1,3-oxazole 1H-imidazole

Fig-3.1



Derivatives

Henry Feuer and Sheldon Markofsky14,15 using the Michael-type addition between

sodium 1-alkane nitronates and a-nitro olefins, which were generated insitu from 2-nitroalkyl

acetates leads largely to the formation of 3,5-dialkyI isoxazoles. The latter also are obtained by

the demethylolation of 2-alkyl-2,4-dinitro 1-alkanols and by the rearrangement of secondary 8-

dinitroalkanes in weakly basic media. The Michael-type addition between 2-alkane nitronates

and α-nitro olefins can really proceeds in reasonably good yields16-20. In contrast, 1-alkane

nitronates give the desired Michael adducts, secondary α-dinitro alkanes, only in poor yields, No

explanations have been given to account for the poor yields in this reaction. however, reports in

the literature in which attempts to prepare phenyl-substituted α -dinitro alkenes gave rise largely

to isoxazoles and isoxaoline N-oxides21-23 For example, Heim obtained in the mbase-catalyzed

reaction between phenyl nitro methane and benzaldehyde, in addition to 1,2,3-triphenyl- l,3-

dinitropropane and nitrostilbene, 3,4,5- triphenylisoxazole. Heim and other workers22,24-26 were

able to show that phenyl-substituted α-dinitro compounds were unstable in the presence of base

and eliminated nitrous acid to form isoxazoline N-oxides and isoxazoles

R

H

NO2-

R1

H

NO2-

H+

RH

NO2-

H

O2-N

R1

N OR

R1

+HNO2

+

Fig-3.2

Tweedie S. R. et al.27 have synthesized hetraryl amines couples with aryl halides

catalysed by palladium & base.

N

O

NH2

+

Br

CN

N

O

NH

Br

pd2(dba)3 ligand

micro wave 2 hrs

Fig-3.3



Derivatives

Yavari I. et al28 were synthesized isoxazole derivatives in the presence of

triphenylphosphine by the reaction of acetylenes and alkyl 2-nitroethanoates.

PPh3 +COOMe

COOMe

+ EtONO2

Oreflux

N O

COOMe

MeOOC COOEt

Fig-3.4

3.2 Biological activity:-

Oxazolidine-2-one, benzo[d]isoxazole are made in Cushman M. et al.29.

O

O

OCH3MeOOC

N

O

OCH3

Fig-3.5

New isoxazole and pyrazole series found by D. Thomas 30. Some compounds are having

effective properties which is made from glutarate.

N X

OR

R1 COOH

R=pyridine derivatives

R1=aryl & heteroaryl derivatives

Fig-3.6

Liljefors T. et al.31 have synthesized a series of Aryl piperidyl isoxazololes and evaluated

for GABAA antagonists. 2 & 4-substituted compounds having good activities.



Derivatives

O N

NHOH

Ph

O N

NHOH

OPh

O N

S

NH

OH

Ph

Fig-3.7

The strength of binding on receptors of indazole derivatives and isoxazole derivatives

have described by Barceló32.

Amgad G. Habeeb et al.33 also reported a isoxazolines belonging various

substitutes at 3rd position of the aromatic ring, which made for analysis as analgesic inhibitory,

anti-inflammatory agents.

When isoxazolines have not Carbon-3 Me substituent, shown potency analgesic and AI

activities.

N

O

R2

R3

R1

Me

R1= H, Me

R2,R

3= H, F,SMe,SO2Me

Fig-3.8

Chih Y. Ho et al.34 have repoted a series of pyrazol-phenylamines dervatives have

developed to keep potency against the angiogenesis task, the receptor tyrosine enzyme obtained

moving factor and to develop the broad tumor cell antiproliferative activity of these derivatives.

These work finds in (JNJ-10198409).

Giovannoni M. P. et al.35 have synthesized a number of arylpiperazinyl

alkylpyridazinones and checked for painkiller activity. They were observed that they checked

compounds at the appropriate dose, shown high pain remover activity, in specific compounds,



Derivatives

substitute molecules leading in which was able to reduce huge abdominal methods by more than

half in test. In the investigation of the compound’s action it seen analgesic effect.

NH

N

NH

F

H3CO

H3CO

N

N O

NHO

(H2C)3

N

N

Cl

Fig-3.9

Christian Peifer et al.36 have reported the discovery of isoxazoleas a potent biphasic

inhibitors. In the designed of isoxazoles, some molecules have 76 enzymes and tested of their

cellular effects shown 18 (CKP138) to be a high dual inhibitors of CK1δ and p38α. And In 2006,

Johnson & Johnson Pharmaceutical Research & Development37, has been reported the synthesis

of a series of Amino dihydrobenzopyrano isoxazole derivatives using substituted

salicylaldehydes and ethyl 4-bromocrotonate. Among the synthesized isoxazoles, few have

proven that most potency blockers with potent serotonin (5-HT) reuptake inhibiting activity.

Serotonin is one of the important monoamine for human body and the deficit of 5-HT mainly

lead to the depression.

O N

N

F

N

N

O N

O

R2

R1

R1,R

2 = H,Me.NHAr

Fig-3.10



Derivatives

Carr J. B. et. al.38 have been synthesized a series of highly substituted isoxazoles and

screened for helminthic activity checked by dose range of 17 to 499 mg/kg to the mouse

roundworm, Nlppostrongjlus Erazikensis. They were found that the newly synthesized isoxazole

derivatives have potent anthelmintic activity.

O N

R1

R2

R2=H,Br,Cl

R1=Cl,Br,OH,CH3SO3,CH3CONH2

Fig-3.11

Biological evaluate of potency HAD-C3 and HAD-C8 isoxazoles and pyrazoles based di

azide suitable for bind profile by photo labeling experiment in cell is shown. In isoxazoles and

pyrazoles based compounds showed less nanomolar activity against HAD-C3 and HAD-C8. The

pyrazoles base the active HAD-C8 inhibitor reports in the literatures with IC-50 of 18 nm.

In studies suggestions the unlike the isoxazoles base ligand the pyrazole base ligand

having flexible to the another binding site as HAD-C8. Some molecules shown the different

activities at minimum concentration, indicates they are cells holey and the azides or diazides

group doesn’t obstruct with the neuro-protection property, cellular cyto-toxicity, or influence cell

permeability39.

Anti oxidant antimicrobial activities of P.Manoj kumar et.al.40-43 synthesized some new

series of 1-isonicotinyl 3,5 dimethyl-4-arylazo isoxazoles which shows Antioxidant Antibacterial

and Antimicrobial activities against staphy lococcus aurous and antibacterial against albican. The

antioxidant activity is compared with standard drug ascorbic acid.

Y X

ZN N

O

NHCOCH3

O

X=C/O Y=N/O Z=C/N

Fig-3.12



Derivatives

Immunological activities of Stanislaw ryng and Michael zimeki synthesized some new

derivatives of isoxazoles including isoxazole triazoline derivatives which shown immune

modulator activity. The compounds were tested for their ability to affect the proliferative

response of moule sphlenocytes to conconavalin (A) and secondary humoral immune response of

sphlenocytes to sheep red blood cells measured as the number of antibody forming cells and

Cyclosporine A served as a reference compound.

NHO

N

S

N

NH

R

R= aromatic &aliphatic

NN

NO

COOEt

COOEt

nociceptive activity

Fig-3.13

K.Karthikeyan, T.veenuseelan et.al.44-46 was developed a systematic procedure for the

synthesis of pyrazolyl isoxazole and they performed the activity of anti nociceptive action by

using various animal tissues. The lead molecule was synthesized by using 1, 3 dipolar cyclo

addition of pyrazole derived nitric oxide with various dipolarophiles suchmas N-substituted

maleimide, diethyl acetylene dicarboxylate and phenyl acetylene. The given structure of

synthesized pyrazolyl isoxazoles shows maximum anti nociceptive activity.

Five member N2 contained heterocyclic compound possess wide spectrum of activity47.

Isoxazole48-50 and Pyrazole51-52 have proven record of biological activities, which contains two

nitrogen atoms. In view of the pharmacological profiles of these two chemical moieties as

described above, we considered it interesting to synthesized two chemically different but

pharmacologically compatible molecules with the aim of obtaining some novel heterocyclic

systems with potentially improved biological properties. In the present investigation a new series

of novel 3-[bis-3,5(methyltrifluoro)phenyl]-5-phenylisoxazole / 3-[bis-



Derivatives

3,5(methyltrifluoro)phenyl]-5-(4-chlorophenyl)-1H-pyrazole [TV-116 TO 145] were synthesize

and evaluate for vitro microbial activity.

3.3 Current work

With the biodynamic activities of chalcones and as a fine synthon for different

fluorinated compounds, the awareness has been paying attention on the creation of new

chalcones. With a observation to obtained compounds having good biological activity, two new

synthesized 3-[bis-3,5(methyltrifluoro)phenyl]-5-phenylisoxazole and 3-[bis-

3,5(methyltrifluoro)phenyl]-5-(4-chlorophenyl)-1H-pyrazole by the Cyclization of different (E)-

1-[bis-3,5(methyltrifluoro)phenyl]-3-phenylprop-2-en-1-one by hydroxyl amine/sodium acetate

and hydrazine hydride.

We have synthesised two new series of 3-[bis-3,5(methyltrifluoro)phenyl]-5-

phenylisoxazole and 3-[bis-3,5(methyltrifluoro)phenyl]-5-(4-chlorophenyl)-1H-pyrazole (TV -

116 to 145) The structures of all the synthesized compounds were elucidated by FT-IR, mass

spectra, 1H NMR and elemental analyses. The newly synthesized compounds were subjected to

antimicrobial activity



Derivatives

Series:- 2 Isoxazole

3.4 Reaction Scheme

Methanol

O

RCF3

CF3

R= TV 116 to 130

CF3

CF3

N O

R

NH2OH.HCl/CH3COONa

Fig-3.14

Table 3.1 Physical Data Table of Series-2

Code R1 M.F. M.W.

M.P.

ºC

Yield

%

Rf1 Rf2

TV-116 4-Cl C17H8ClF6NO 391 165 76 0.40 0.69

TV-117 4-F C17H8F7NO 375 145 71 0.48 0.60

TV-118 4-Br C17H8BrF6NO 436 164 80 0.45 0.68

TV-119 4-CH3 C18H11F6NO 371 154 77 0.50 0.65

TV-120 4-OCH3 C18H11F6NO2 387 157 58 0.49 0.69

TV-121 3-Cl C17H8ClF6NO 491 157 60 0.59 0.61

TV-122 4-F C17H8F7NO 374 159 76 0.40 0.68

TV-123 3-Br C17H8BrF6NO 436 167 73 0.48 0.62

TV-124 3-OCH3 C18H11F6NO2 387 171 81 0.45 0.68

TV-125 3,4-DiOCH3 C19H13F6NO3 417 167 70 0.50 0.69

TV-126 2-Cl C17H7Cl2F6NO 391 168 57 0.49 0.60

TV-127 2-F C17H8ClF6NO 375 149 63 0.45 0.68

TV-128 2-Br C17H8F7NO 436 159 62 0.43 0.65

TV-129 2-OCH3 C18H11F6NO2 387 182 61 0.47 0.76

TV-130 H C17H9F6NO 344 169 72 0.49 0.68



Derivatives

Table-3.1

TLC Solvent system Rf1: Hexane: Ethyl acetate – 7:3;

Rf2: Chloroform: Methanol - 9:1.

3.5 Plausible Reaction Mechanism

HR1

OF3C

F3C

OHNH2

R1

F3C

F3C

O

O :NH2

R1

F3C

F3C

O

O :NH2

H

F3C

F3CN O

OH H

R1

F3C

F3CN O

H

R1H

-H2O

F3C

F3CN O

R1

F3C

F3CN O

R1

Fig-3.15



Derivatives

3.6 Experimental

3.6.1 Materials and Methods

Open capillary tubes are used for melting points. TLC has been checked for formation of

compounds regularly and spots were seen by iodine. FT-IR-8400 instrument is using for IR

spectra. Shimadzu GC-MS-QP-2010 model used for Mass spectra. Brucker Ac 400 MHz

spectrometer was used for 1H NMR.

3.6.2 General procedure for the synthesis of 3-[bis-3,5(methyltrifluoro)phenyl]-5-(4-

substitutedphenyl)isoxazole (TV- 116 to 130)

A mixture of (E)-1-[bis-3,5(methyltrifluoro)phenyl]-3-(4-substitutedphenyl)propenone (0.021

Mole), hydroxylamine hydrochloride (0.021 Mole) and Sodium acetate in ethyl alcohol (25 ML)

was refluxed for 6.5 hrs. The solvent was distilled out under vacuum and added into chilled

water. The solid was filtered, washed and crystallized. TLC was used for completion of the

reaction.

3.6.2.1 3-[bis-3,5(methyltrifluoro)phenyl]-5-(4-chlorophenyl)isoxazole (TV-116)

CF3

F3C Cl

N O

Yield: 77%; mp 203ºC; Analytical Calculation for C17H8ClF6NO : Carbon, 51.13; Hydrogen,

2.06; Chlorine, 9.05; Fluorine, 29.10; Nitrogen, 3.58; Oxygen, 4.08; Found: Carbon, 52.02;

Hydrogen, 2.02; Chlorine, 9.01; Fluorine, 29.04; Nitrogen, 3.49; Oxygen, 4.01; IR (cm-1): 3049

(C-H stretching of aromatic ring), 1703 (C=O stretching ), 1681, 1585 and 1531 (C=C stretching

of aromatic ring), 1240 (N-O stretching ), 1084 (C-H in plane deformation of aromatic ring),

1012 (C-F stretching), 829 (C-H out of plane bending of 1,4-disubutituion); MS: m/z 391; 1H

NMR (DMSO-d6) δ ppm: 5.27-5.28 (s, 1H ,Ha), 7.06-7.08 (d, 1H, Hb), 7.10-7.14 (m, 1H, Hc),

7.27-7.29 (d, 2H, Hdd’,), 7.46-7.48 (m, 2H, Hee’,), 7.82-7.83 (m, 1H, Hf).



Derivatives

3.6.2.2 3-[bis-3,5(methyltrifluoro)phenyl]-5-(4-fluorophenyl)isoxazole (TV-117).

Yield: 58%; mp 201ºC; Analytical Calculation for C17H8F7NO: Carbon, 54.41; Hydrogen, 2.15;

Fluorine, 35.44; Nitrogen, 3.73; Oxygen, 4.26; Found: Carbon, 54.31; Hydrogen, 2.06; Fluorine,

30.37; Nitrogen, 3.63; Oxygen, 4.15%; MS: m/z 375.

3.6.2.3 3-[bis-3,5(methyltrifluoro)phenyl]-5-(4-bromophenyl)isoxazole (TV-118).

Yield: 67%; mp 189ºC; Analytical Calculation for C17H8BrF6NO: Carbon, 46.82; Hydrogen,

1.85; Bromine, 18.32; Fluorine, 26.14; Nitrogen, 3.21; Oxygen, 3.67; Found: Carbon, 46.71;

Hydrogen, 1.67; Bromine, 18.21; Fluorine, 26.05; Nitrogen, 3.11; Oxygen, 3.54%; MS: m/z 436.

3.6.2.4 3-[bis-3,5(methyltrifluoro)phenyl]-5-(4-methylphenyl)isoxazole (TV-119).

CF3

F3C F

N O

CF3

F3C Br

N O



Derivatives

Yield: 68%; mp 186ºC; Analytical Calculation for C17H9F7O: Carbon, 58.23; Hydrogen, 2.99;



3.6.2.5 3-[bis-3,5(methyltrifluoro)phenyl]-5-(4-methoxyphenyl)isoxazole (TV-120)

Yield: 74%; mp 221ºC; Analytical Calculation for C17H9BrF6O: Carbon, 55.82; Hydrogen, 2.86;



3.6.2.6 3-[bis-3,5(methyltrifluoro)phenyl]-5-(3-chlorophenyl)isoxazole (TV-121).

CF3

F3C CH3

N O

CF3

F3C OCH3

N O

CF3

F3C

N O

Cl



Derivatives

Yield: 56%; mp 204ºC; Analytical Calculation for C19H14F6O3: Carbon, 52.13; Hydrogen, 2.06;

Chlorine, 9.05; Fluorine, 29.10; Nitrogen, 3.58; Oxygen, 4.08; Found: Carbon, 52.02; Hydrogen,

2.02; Chlorine, 9.01; Fluorine, 29.04; Nitrogen, 3.49; Oxygen, 4.01%; MS: m/z 391.

3.6.2.7 3-[bis-3,5(methyltrifluoro)phenyl]-5-(3-fluorophenyl)isoxazole (TV-122).

Yield: 76%; mp 224ºC; Analytical Calculation for C17H8Cl2F6O: Carbon, 54.41; Hydrogen, 2.15;



3.6.2.8 3-[bis-3,5(methyltrifluoro)phenyl]-5-(3-bromophenyl)isoxazole (TV-123).


Bromine, 18.32; Fluorine, 26.14; Nitrogen, 3.21; Oxygen, 3.67; Found: Carbon, 46.62;


3.6.2.9 3-[bis-3,5(methyltrifluoro)phenyl]-5-(3- methoxyphenyl)isoxazole (TV-124)

CF3

F3C

N O

F

CF3

F3C

N O

Br



Derivatives

Yield: 80%; mp 195ºC; Analytical Calculation for C17H9ClF6O: Carbon, 55.82; Hydrogen, 2.86;


29.32; Nitrogen, 3.54; Oxygen, 8.12% MS: m/z 387.

3.6.2.10 3-[bis-3,5(methyltrifluoro)phenyl]-5-(3,4-dimethoxyphenyl)isoxazole (TV-125)

Yield: 77%; mp 182ºC; Analytical Calculation for C17H9BrF6O: Carbon, 54.69; Hydrogen, 3.14;

Fluorine, 27.32; Nitrogen, 3.36; Oxygen, 11.50; Found: Carbon, 54.52; Hydrogen, 3.07;

Fluorine, 27.23; Nitrogen, 3.24; Oxygen, 11.43%; MS: m/z 417.

3.6.2.11 3-[bis-3,5(methyltrifluoro)phenyl]-5-(2-chlorophenyl)isoxazole (TV-126)

CF3

F3C

N O

OCH3

CF3

F3C

N O

OCH3

OCH3

CF3

F3C

N O

Cl



Derivatives

Yield: 58%; mp 242ºC; Analytical Calculation for C17H9ClF6O: Carbon, 52.13; Hydrogen, 2.06;

Chlorine, 9.05; Fluorine, 29.10; Nitrogen, 3.58; Oxygen, 4.08; Found: Carbon, 52.08; Hydrogen,

2.04; Chlorine, 9.01; Fluorine, 29.01; Nitrogen, 3.43; Oxygen, 4.01% MS: m/z 391.

3.6.2.12 3-[bis-3,5(methyltrifluoro)phenyl]-5-(2-fluorophenyl)isoxazole (TV-127)



35.37; Nitrogen, 3.63; Oxygen, 4.15% MS: m/z 375.

3.6.2.13 3-[bis-3,5(methyltrifluoro)phenyl]-5-(2-bromophenyl)isoxazole (TV-128)


Bromine, 18.32; Fluorine, 26.14; Nitrogen, 3.21; Oxygen, 3.67; Found: Carbon, 46.71;


3.6.2.14 3-[bis-3,5(methyltrifluoro)phenyl]-5-(2-methoxyphenyl)isoxazole (TV-129).

CF3

F3C

N O

F

CF3

F3C

N O

Br



Derivatives




3.6.2.15 3-[bis-3,5(methyltrifluoro)phenyl]-5-phenylisoxazole (TV-130)


Fluorine, 33.11; Oxygen, 4.65; Found: Carbon, 59.31; Hydrogen, 2.93; Fluorine, 33.11; Oxygen,

4.65%; MS: m/z 344.

CF3

F3C

N O

H3CO

CF3

F3C

N O



Derivatives

Series:- 3 Pyrazole

3.7 Reaction Scheme

O

CF3

CF3

R

CF3

CF3

N NH

R

Methanol

R = TV 130 to 145

NH2NH2.H20

sodium acetate

Fig-3.16

Table 3.2 Physical Data Table of Series-3

Code R1 M.F. MW MP

Yield % R f1 Rf2

TV-131 4-Cl C17H9ClF6N2 390 165 76 0.40 0.69

TV-132 4-F C17H9F7N2 374 145 71 0.48 0.60

TV-133 4-Br C17H9BrF6N2 435 164 80 0.45 0.68

TV-134 4-CH3 C18H12F6N2 370 154 77 0.50 0.65

TV-135 4-OCH3 C18H12F6N2 386 157 58 0.49 0.69

TV-136 3-Cl C17H9ClF6N2 490 157 60 0.59 0.61

TV-137 4-F C17H9F7N2 374 159 76 0.40 0.68

TV-138 3-Br C17H9BrF6N2 435 167 73 0.48 0.62

TV-139 3-OCH3 C18H12F6N2 386 171 81 0.45 0.68

TV-140 3,4-DiOCH3

C19H14F6N2 416 167 70 0.50 0.69

TV-141 2-Cl C17H8ClF6N2 390 168 57 0.49 0.60

TV-142 2-F C17H9ClF6N2 374 149 63 0.45 0.68

TV-143 2-Br C17H9F7N2 435 159 62 0.43 0.65

TV-144 2-OCH3 C18H12F6N2 386 182 61 0.47 0.76

TV-145 H C17H10F6N2 343 169 72 0.49 0.68



Derivatives

Table-3.2

TLC Solvent system Rf1: Hexane: Ethyl acetate – 8:2;

Rf2: Chloroform: Methanol - 7:3.

3.8 Plausible Reaction Mechanism

Fig-3.17

NH2NH2

R1

F3C

F3C

O

HN :NH2

R1

F3C

F3C

O

HN :NH2HR1

OF3C

F3C

H

H

F3C

F3CN NH

H

R1F3C

F3CN NH

OH H

R1F3C

F3CN NH

R1

-H2O

F3C

F3CN O

R1



Derivatives

3.9 Experimental

3.9.1 Materials and Methods

Melting points were determined in open capillary tubes and are uncorrected. Formation

of the compounds was routinely checked by TLC on silica gel-G plates of 0.5 mm thickness and

spots were located by iodine. IR spectra were recorded Shimadzu FT-IR-8400 instrument using

potassium bromide pellet method. Mass spectra were recorded on Shimadzu GC-MS-QP-2010

model using direct injection probe technique. 1H NMR was determined in DMSO-d6 solution on

a bruker Ac 400 MHz spectrometer. Elemental analysis of the all the synthesized compounds

was carried out on elemental vario EL III carlo erba 1108 model and the results are in

agreements with the structures assigned.

3.9.2 General procedure for the synthesis of 3-[bis-3,5(methyltrifluoro)phenyl]-5-

(substitutedphenyl)-1H-pyrazole (TV- 131 to 145)

A mixture of (E)-1-[bis-3,5(methyltrifluoro)phenyl]-3-(4-substitutedphenyl)prop-2-en-1-one

(0.02 mol), hydrazine hydrate (0.02 mol) and sodium acetate in ethanol (30 ml) was refluxed for

4 hr. The mixture was concentrated by distilling out the solvent under reduced pressure and

poured into ice water. The precipitate obtained was filtered, washed and recrystallized. The

completion of the reaction was monitored by TLC.

3.9.2.1 3-[bis-3,5(methyltrifluoro)phenyl]-5-(4-chlorophenyl)-1H-pyrazole (TV-131)

CF3

F3C Cl

N NH

Yield: 77%; mp 203ºC; Analytical Calculation for C17H9ClF6N2 : Carbon, 52.26; Hydrogen,

2.32; Chlorine, 9.07; Fluorine, 29.18; Nitrogen, 7.17; Found: Carbon, 52.16; Hydrogen, 2.14;



Derivatives

Chlorine, 8.94; Fluorine, 29.02; Nitrogen, 7.01%; IR (cm-1): 3363/3271 (Carbon-H stretch of

aromatic ring), 1703 (Carbon=O stretch), 1662, 1597 and 1523 (Carbon=Carbon stretch of

aromatic ring), 1070 (C-H in plane deformation of aromatic ring), 1014 (C-F stretching), 833 (C-

H out of plane bending of 1,4-disubutituion), 1012 (C-F stretching); MS: m/z 390; 1H NMR

(DMSO-d6) δ ppm: 7.09-7.11 (s, 1H ,Ha), 7.27-7.29 (d, 2H, Hbb’), 7.44-7.46 (d, 2H, Hcc’), 7.61-

7.65 (m,1H, Hdd’,), 7.88 (s, 1H, He), 12.50 (s, 1H, Hf).

3.9.2.2 3-[bis-3,5(methyltrifluoro)phenyl]-5-(4-fluorophenyl)-1H-pyrazole (TV-132)

Yield: 58%; mp 201ºC; Analytical Calculation for C17H9F7N2: Carbon, 54.56; Hydrogen, 2.42;

Fluorine, 35.53; Nitrogen, 7.49; Found: Carbon, 54.46; Hydrogen, 2.12; Fluorine, 35.23;

Nitrogen, 7.33%; MS: m/z 374.

3.9.2.3 3-[bis-3,5(methyltrifluoro)phenyl]-5-(4-bromophenyl)-1H-pyrazole (TV-133)

Yield: 67%; mp 189ºC; Analytical Calculation for C17H9BrF6N2: Chlorine, 46.92; Hydrogen,

2.08; Bromine, 18.36; Fluorine, 26.19; Nitrogen, 6.44; Found: Carbon, 46.52; Hydrogen, 2.01;

Bromine, 18.21; Fluorine, 26.01; Nitrogen, 6.44%; MS: m/z 435.

CF3

F3C

N NH

F

CF3

F3C Br

N NH



Derivatives

3.9.2.4 3-[bis-3,5(methyltrifluoro)phenyl]-5-(4-methylphenyl)-1H-pyrazole (TV-134).



Nitrogen, 7.23 %; MS: m/z 370.

3.9.2.5 3-[bis-3,5(methyltrifluoro)phenyl]-5-(4-methoxyphenyl)-1H-pyrazole (TV-135).

Yield: 74%; mp 221ºC; Analytical Calculation for C18H13F6ON2: Carbon, 55.97; Hydrogen, 3.13;



3.9.2.6 3-[bis-3,5(methyltrifluoro)phenyl]-5-(3-chlorophenyl)-1H-pyrazole (TV-136).

CF3

F3C CH3

N NH

CF3

F3C OCH3

N NH



Derivatives

Yield: 56%; mp 204ºC; Analytical Calculation for C17H9ClF6N2: Carbon, 52.26; Hydrogen, 2.32;

Chlorine, 9.07; Fluorine, 29.18; Nitrogen, 7.17; Found: Carbon, 52.06; Hydrogen, 2.04;

Chlorine, 8.74; Fluorine, 29.12; Nitrogen, 7.10%%; MS: m/z 390.



Fluorine, 35.53; Nitrogen, 7.49; Found: Chlorine, 54.36; Hydrogen, 2.14; Fluorine, 35.13;


3.9.2.8 3-[bis-3,5(methyltrifluoro)phenyl]-5-(3-bromophenyl)-1H-pyrazole (TV-138).

CF3

F3C

N NH

Cl

CF3

F3C

N NH

F



Derivatives

Yield: 71%; mp 212ºC; Analytical Calculation for C17H9BrF6N2: Carbon, 46.92; Hydrogen, 2.08;

Bromine, 18.36; Fluorine, 26.19; Nitrogen, 6.44; Found: Carbon, 46.82; Hydrogen, 2.01;


3.9.2.9 3-[bis-3,5(methyltrifluoro)phenyl]-5-(3-methoxyphenyl)-1H-pyrazole (TV-139)




3.9.2.10 3-[bis-3,5(methyltrifluoro)phenyl]-5-(3,4 dimethoxyphenyl)-1H-pyrazole (TV-140).

CF3

F3C

N NH

Br

CF3

F3C

N NH

OCH3

CF3

F3C

N NH

OCH3

OCH3



Derivatives

Yield: 77%; mp 182ºC; Analytical Calculation for C19H14F6N2O2: Carbon, 54.81; Hydrogen,

3.39; Fluorine, 27.38; Nitrogen, 6.73; Oxygen, 7.69; Found: Carbon, 54.51; Hydrogen, 3.29;

Fluorine, 27.18; Nitrogen, 6.43; Oxygen, 7.49%; MS: m/z 416.

3.9.2.11 3-[bis-3,5(methyltrifluoro)phenyl]-5-(2-chlorophenyl)-1H-pyrazole (TV-141).

Yield: 58%; mp 242ºC; Analytical Calculation for C17H9ClF6N2 : Carbon, 52.26; Hydrogen,

2.32; Chlorine, 9.07; Fluorine, 29.18; Nitrogen, 7.17; Found: Carbon, 52.06; Hydrogen, 2.02;

Chlorine, 8.82; Fluorine, 28.85; Nitrogen, 6.95%, MS: m/z 379.





3.9.2.13 3-[bis-3,5(methyltrifluoro)phenyl]-5-(2-bromophenyl)-1H-pyrazole (TV-143)

CF3

F3C

N NH

Cl

CF3

F3C

N NH

F



Derivatives

Yield: 62%; mp 224ºC; Analytical Calculation for C17H9BrF6N2: Carbon, 46.92; Hydrogen, 2.08;

Bromine, 18.36; Fluorine, 26.19; Nitrogen, 6.44; Found: Carbon, 46.72; Hydrogen, 1.95;


3.9.2.14 3-[bis-3,5(methyltrifluoro)phenyl]-5-(2-methoxyphenyl)-1H-pyrazole (TV-144).




CF3

F3C

N NH

Br

CF3

F3C

N NH

H3CO



Derivatives

3.9.2.15 3-[bis-3,5(methyltrifluoro)phenyl]-5-(phenyl)-1H-pyrazole (TV-145).




3.10 Spectral discussion

3.10.1 Mass spectral study

Shimadzu GC-MS-QP-2010 model was using for mass spectra. Proper fragmentation

came in spectral studies. Molecular weight peaks came of respective compounds. It has given

below.

CF3

F3C

N NH



Derivatives

Mass fragmentation pattern for TV-116

CF3

F3C Cl

N O

m/z=392

CF3

F3C

N O

F3C Cl

N OF3C

N O

Cl

N O

CF3

F3C

N O

CF3

N O

Cl

N O

N O

m/z=357m/z=324

m/z=289

m/z=256

m/z=281m/z=213

m/z=69

m/z=180

Fig-3.18



Derivatives

Mass fragmentation pattern for TV-131

CF3

F3C Cl

N NH

m/z=391

CF3

F3C

N NH

F3C Cl

N NHF3C

N NH

Cl

N NH

CF3

F3C

N NH

CF3

N NH

Cl

N NH

N NH

m/z=356m/z=323

m/z=288

m/z=255

m/z=280m/z=212

m/z=68

m/z=179

Fig-3.19



Derivatives

3.10.2 IR spectral study

Shimadzu FT-IR-8400 model records IR spectra using KBr pellet method. Various

functional groups here in molecule were identified by characteristic frequency obtained for them.

For Chalcones TV-116 to 145, assenting bands for secondary amine were observed at 3450-3200

cm-1 correspondingly. -N-H stretching bands at 3250-3390 cm-1 observed. Aromatic ring

skeleton (C=C starching) groups were observed at1600-1400 cm-1. C-N stretching aromatic of

isoxazole ring were observed at 1180-1200 cm-1 and 1300-1360 cm-1. C-Cl stretching were

observed at 700-850 cm-1. Another characteristic C-F (stretching vibration) was observed at

1000-1100 cm-1, which suggested formation of desired products TV - 116 to 145.

3.10.3 1H NMR spectral study

In 1H NMR DMSO-d6 used as a solvent with Brucker 400 MHz spectrometer & TMS

used as a standard. Synthesis compounds structures were proven by all protons and their

chemical shifts.

1H NMR spectra confirmed the structures of Chalcones TV - 116 to 145 on the basis of

following signals: Aromatic fluoro-ring protons observed at 7.4-7.8 δ ppm and aromatic other

ring protons observed around 7.0-7.2 δ ppm. A singlet for the (C-H) proton of five member ring

at 5.0-6.0 δ ppm, and singlets for N-H of pyrazole at 8.80-12.60 δ ppm and correspondingly.



Derivatives

Mass spectrum of TV – 116

Fig-3.20

IR spectrum of TV – 116

Fig-3.21

CF3

F3C Cl

N O

CF3

F3C Cl

N O

M.W.- 391

Chapter:-4

Synthesis, Characterization and Biological Evaluation of some Chalcones and their

1H NMR spectrum of TV – 116

Expanded 1NMR spectrum of TV

Synthesis and biological activities of Isoxazole &Pyrazole

Characterization and Biological Evaluation of some Chalcones and their Derivatives

Fig-3.22

NMR spectrum of TV – 116

Fig-3.23


72 Characterization and Biological Evaluation of some Chalcones and their



Derivatives

Mass spectrum of TV – 131

Fig-3.24

IR spectrum of TV – 131

Fig-3.25

CF3

F3C Cl

N NH

CF3

F3C Cl

N NH

M.W.- 391

Chapter:-4

Synthesis, Characterization and Biological Evaluation of some Chalcones and their

1H NMR spectrum of TV – 131

Expanded 1NMR spectrum of TV


Characterization and Biological Evaluation of some Chalcones and their Derivatives

Fig-3.26

1NMR spectrum of TV – 131

Fig-3.27


74 Characterization and Biological Evaluation of some Chalcones and their



Derivatives

3.11 Biological evaluation

3.11.1 Antimicrobial evaluation

Antibacterial and antifungal activity was tested for all compounds. Staphyl-ococcus

(Aureus) Mtcc-96, Strept-ococcus (Pyogenes) Mtcc-443 as gram positive, e-coli mtcc (442),

pseudomonas (aeruginosa) mtcc (441) as gram negative, candida (albicans) mtcc (227),

aspergillus (niger) mtcc (282), aspergillus (clavatus) mtcc (1323) was taken with different drugs.

microbial type culture collection (mtcc) strains was used. Compounds growth at lowest

concentration was prevented. For MIC broth dilution method is more appropriate.

1. For both primary and secondary screening serial dilutions were prepared.

2. In absence of antibiotic in control tube is subculture immediately.

3. Drug concentration is check by control of MIC.

4. MIC records the lowest concentration growth of organism.

5. Amount of growth is tested.

Used methods for 1st and 2nd screening: -

In stock solution synthesis drugs concentration was 2000 (µg mL-1)

First screening: - In 1st screening (250 µg mL-1), (500 µg mL-1), (1000 µg mL-1) concentration

was taken of all compounds. Only Active drug will go in 2nd screening.

Second screening: - In second screening concentration of all drugs were taken even less then

first screening.

Reading Result: -As MIC 99.2% inhibited zone was taken showing highest dilution.

Results are given below.



Derivatives

3.12 Table-1:- Screening Result of antimicrobial activity for TV-116 to 130.

Code Concentration of minimum inhibition µg mL-1

Gram Positive Gram Negative Fungal species

S.a. S. p. E.c. P.a. C. a. A. n. A.c. TV-116 15 15 84 16 14 19 18 TV-117 16 16 21 17 19 18 13 TV -118 17 18 18 15 15 15 14 TV -119 15 19 19 18 17 17 19 TV -120 18 18 18 17 13 21 15 TV -121 13 17 15 14 14 18 17 TV -122 16 16 17 21 16 15 16 TV -123 21 16 16 16 19 16 20 TV -124 18 20 18 14 21 20 15 TV -125 16 18 20 19 16 15 18 TV -126 14 20 19 16 20 16 17 TV -127 17 14 14 15 13 20 21 TV -128 15 17 16 18 16 14 17 TV -129 16 21 15 17 15 14 16 TV -130 21 15 16 21 18 15 15 Gentamycin 21 18 13 19 - - - Ampicillin 20 15 14 16 - - - Chloramphenicol 19 17 20 12 - - - Iprofloxacin 21 20 18 15 - - - Norfloxacin 10 12 10 10 - - - Nystatin - - - - 13 18 16 Gresiofulvin - - - - 22 17 19

Table-3.3



Derivatives

Antimicrobial Screening Results for TV-131 to145

Code

Concentration of minimum inhibition µg mL -1

Gram Positive Gram Negative Fungal species

S.a. S. p. E.c. P.a. C. a. A. n. A.c.

TV -131 19 14 16 19 84 18 19

TV -132 16 13 18 16 21 15 18

TV -133 15 21 15 15 18 17 15

TV -134 15 19 22 15 19 16 17

TV -135 18 18 18 18 18 17 21

TV -136 16 14 16 16 15 16 18

TV -137 21 21 15 21 17 19 15

TV -138 15 16 20 15 16 17 16

TV -139 18 18 16 18 18 15 20

TV -140 17 19 18 17 20 20 15

TV -141 14 19 16 14 19 17 16

TV -142 14 14 17 14 14 13 20

TV -143 21 16 15 21 16 14 14

TV -144 16 22 14 16 15 19 14

TV -145 18 16 17 18 16 15 15

Gentamycin 21 18 13 19 - - -

Ampicillin 20 15 14 16 - - -

Chloramphenicol 19 17 20 12 - - -

Iprofloxacin 21 20 18 15 - - -

Norfloxacin 10 12 10 10 - - -

Nystatin - - - - 13 18 16

Gresiofulvin - - - - 22 17 19

Table-3.4



Derivatives

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Derivatives

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