research article synthesis and antimicrobial studies of...

Research ArticleSynthesis and Antimicrobial Studies of PyrimidinePyrazole Heterocycles

Rakesh Kumar1 Jyoti Arora12 Sonam Ruhil3 Neetu Phougat3

Anil K Chhillar3 and Ashok K Prasad2

1 Department of Chemistry Bio-organic Laboratory Kirori Mal College University of Delhi Delhi 110 007 India2Department of Chemistry Bio-organic Laboratory University of Delhi Delhi 110 007 India3 Centre for Biotechnology Maharshi Dayanand University Rohtak 124 001 India

Correspondence should be addressed to Rakesh Kumar rakeshkpemailcom

Received 30 April 2014 Revised 19 July 2014 Accepted 29 July 2014 Published 25 August 2014

Academic Editor Adriana I Segall

Copyright copy 2014 Rakesh Kumar et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Prompted from the diversity of the wider use and being an integral part of genetic material an effort was made to synthesizepyrimidine pyrazole derivatives of pharmaceutical interest by oxidative cyclization of chalcones with satisfactory yield andpurity A novel series of 13-dimethyl-6-hydroxy-24-dioxo-5-(11015840-phenyl-31015840-aryl-1H-pyrazol-51015840-yl)-1234-tetrahydropyrimidines(5andashd) and 13-diaryl-6-hydroxy-4-oxo-2-thioxo-5-(11015840-phenyl-31015840-aryl-1H-pyrazol-51015840-yl)-1234-tetrahydropyrimidines (5endashl) hasbeen synthesizedThe structures of these compounds were established on the basis of FT-IR 1HNMR 13CNMR andmass spectralanalysis All the synthesized compounds were screened for their antimicrobial activity against bacteria and fungi Among all thecompounds 5g was found to be the most active as its MIC was 3125 120583gmL against S aureus and B cereus The compounds 5h 5cand 5e also possess antibacterial activity with MIC values as 6250 12500 and 50000120583gmL respectively The compounds 5c and5j were found to have antifungal activity against Aspergillus spp As antifungal drugs lag behind the antibacterial drugs thereforewe tried in vitro combination of these two compounds with standard antifungal drugs (polyene and azole) against Aspergillus sppThe combination of ketoconazole with 5c and 5j showed synergy at 1 8 (625 5000120583gmL) and 1 4 (25 100 120583gmL) against Afumigatus (ITCC 4517) and A fumigatus (VPCI 19096) respectively

1 Introduction

Nitrogen heterocycles are of special interest as they constitutean important class of natural and nonnatural products manyof which exhibit useful biological activities Pyrimidinebeing an integral part of DNA and RNA imparts diversepharmacological properties such as bactericide fungicidevermicide insecticide and anticancer and antiviral agents[1] Certain pyrimidine derivatives are also known to displayantimalarial antifilarial and antileishmanial activities [2]

The pyrazole derivatives are well known to have antimi-crobial [3] antifungal [4] antitubercular [5] anticancer[6] analgesic [7] anti-inflammatory [8] antipyretic [9]anticonvulsant [10] antidepressant [11] muscle relaxing [12]antiulcer [13] antiarrhythmic [14] and antidiabetic [15]activities With growing application of their synthesis andbioactivity chemists and biologists in recent years have

directed considerable attention to the study of pyrazolederivatives In view of the above mentioned importance ofpyrimidines and pyrazoles we tried to accommodate thesemoieties in a single molecular framework to synthesize thelinked heterocycles for enhancing biological activity

2 Results and Discussion

21 Chemistry (E)-1-(1101584031015840-Dimethyl-61015840-hydroxy-2101584041015840-dioxo-11015840210158403101584041015840-tetrahydropyrimidin-51015840-yl)-3-aryl-prop-2-ene-1-ones (4andashd) and (E)-1-(1101584031015840-diaryl-61015840-hydroxy-41015840-oxo-21015840-thiooxo-11015840210158403101584041015840-tetrahydropyrimidin-51015840-yl)-3-aryl-prop-2-ene-1-ones (4endashl) were synthesized by the Claisen conden-sation of 5-acetyl barbituricthiobarbituric acid (2andashc) witharomatic aldehydes 3andashd in methanol in the presence ofNaOH as a base at 60∘C [16] Further cyclocondensation ofpropenones 4andashl with phenylhydrazine in acidic condition

Hindawi Publishing CorporationAdvances in ChemistryVolume 2014 Article ID 329681 12 pageshttpdxdoiorg1011552014329681

2 Advances in Chemistry

in dioxane as solvent yielded 13-dimethyl-6-hydroxy-24-dioxo-5-(11015840-phenyl-31015840-aryl-1H-pyrazol-51015840-yl)-1234-tetra-hydropyrimidines (5andashd) and 13-diaryl-6-hydroxy-4-oxo-2-thioxo-5-(11015840-phenyl-31015840-aryl-1H-pyrazol-51015840-yl)-1234-tetra-hydropyrimidines (5endashl) in 46ndash81 yields [17] Structureand yield of compounds that is 4andashl and 5andashl are listed inTable 1 The 5-acetyl-13-diarylthiobarbituric acids (2b-c) inturn were synthesized by the following known method from13-diarylthiobarbituric acids (1b-c) and acetic anhydride[18 19] (Scheme 1)

All the compounds synthesized were characterized by IR1H NMR 13C NMR and mass spectroscopy Spectroscopicdata was in complete agreement with the structures assignedfor these compounds IR spectrum of cyclized derivatives ofbarbituric acid (5andashd) showed band in the region of 1700ndash1740 cmminus1 for carbonyl group (at C2) The other carbonylgroup at C4 showed band in the region of 1640ndash1699 cmminus1whereas cyclized derivatives of thiobarbituric acid (5endashl)showed band in the region of 1050ndash1100 cmminus1 which indi-cates the presence of thiocarbonyl group (at C2) and othercarbonyl groups at C4 showed band in the region of 1625ndash1680 cmminus1 Frequency band of OH group appears at 3200ndash3450 cmminus1 in the compounds 5andashl In 1H NMR spectrachemical shift values of all the compoundswere in accordancewith the expected values Aromatic protons of compounds4andashl resonated in the region of120575 686ndash782 Twodoublets of120572-H (attached to C2) at 120575 806 (119869 = 1611Hz) and120573-H (attachedto C3) at 841 (119869 = 1611Hz) respectively of 4f demonstratethe formation of 120572 120573-unsaturated carbonyl moiety and 119869 =1611Hz indicates that the ethylenemoiety in the enone link-age is in trans confirmation in the chalcone Disappearance ofthese doublets in 5f indicates the absence of chalconemoietyAll other phenyl protons in the compounds 5andashl appearedin the aromatic region at 120575 682ndash758 In 13C NMR of 4fall the characteristic peaks were in good agreement withthe proposed structure Carbonyl carbon at C-1 and C-41015840appeared at 120575 1846 and 1682 respectively The characteristicpeak of C=S appeared at 120575 1789 The C-2 and C-3 carbonsappeared at 120575 1145 and 1397 respectively The OCH

3carbon

appeared at 120575 554 The aromatic carbons attached to OCH3

(ie C-410158401015840) appeared at 120575 1629 The other aromatic carbonsof 4f resonated in the region of 120575 1273ndash1317 and the aromaticcarbon attached to nitrogen appeared at 1486 In 13CNMRof5f disappearance of peak at 120575 1846 indicates the cyclizationof chalcone Carbonyl carbon at C-4 appeared at 120575 1640 Thecharacteristic peak of C=S appeared at 120575 1800 C-6 carbonappeared at 120575 1608The pyrazole carbon at C-41015840 appeared at 120575883 [20]The OCH

3carbon appeared at 120575 553The aromatic

carbon attached to OCH3 that is C-410158401015840 appeared at 120575 1614

Theother aromatic carbons resonated in the region of 120575 1274ndash1295 and the aromatic carbon attached to nitrogen appearedat 120575 14713 Details of 1H NMR and 13C NMR spectra of 5andashlare given in experimental section

22 Biology

221 Antifungal Activity The antifungal activity againstAspergillus spp was evaluated by different methods [21ndash23]

that is disc diffusion assay (DDA) microbroth dilution assay(MDA) and percent spore germination inhibition (PSGI)The Minimum Inhibitory Concentration (MIC) values ofAmphotericin B (Amp B) and Nystatin (NYS) against allthe three Aspergillus species were found to be 075 120583gdiscand 100 120583gdisc respectively by DDA and 195 120583gmL and390 120583gmL respectively by MDA and PSGI The MIC of 5ccompound was 4675 120583gdisc against all the tested isolatesof Aspergillus spp by DDA whereas 5j compound possessesa slight higher MIC against A flavus and A niger that is1875 120583gdisc but against A fumigatus it possesses the sameMIC that is 4675120583gdisc The MIC of 5c by MDA andPSGI was found to be 2500 120583gmL against A fumigatus and5000 120583gmL againstA flavus andA nigerTheMIC of 5jwasfound to be 5000 120583gmL against A fumigatus and A flavusand 1000 120583gmL against A niger respectively by MDA andPSGI (Table 2)

Results revealed that the synthesized compounds 5c and5j exhibited mild antifungal activity which is lower thanthe standard drugs Some other substituted pyrimidines andpyrazoles have earlier been reported as potent antifungalagents against a number of pathogenic fungi alone and incombination [24 25]

As these compounds showed promising activity so wefurther tried these compounds in combination with standardantifungal drugs to evaluate their synergistic behaviour ifanyTherefore the compounds 5c and 5jwere tried for in vitrocombination with polyenes and azoles

(1) In Vitro Combination Study of Pyrimidine Pyrazole Ana-logues (5c and 5j) with Antifungal Drugs Among the humanpathogenic species of Aspergillus A fumigatus is the primarycausative agent of human infection followed by A flavusand A niger [23] Therefore A fumigatus [ITCC 4517 (IARIIndian Agricultural Research Institute Delhi) ITCC 1634clinical isolate VPCI 19096 (VPCI Vallabhbhai Patel ChestInstitute Delhi)] was selected for in vitro combination studyof pyrimidine pyrazole analogues with antifungal drugsThe data of in vitro combination was analysed by FractionInhibitory Concentration Index (FICI) model [24] and sum-marized in Tables 3ndash6

(11) In Vitro FIC Index of 5c with Polyene (Amp B NYS) andAzole (KTZ FLZ) In combination of Amp B and NYS with5c the FICI values were found to be in the range of 08 to 103indifference (IND) was declared against A fumigatus strains(Table 3)TheMIC end point value of 5c reduced from 31498to 7871250 120583gmL But the MIC of Amp B and NYS almostremains the same that is 196 120583gmL and 312 120583gmL

The combination of 5c with KTZ and FLZ reducedthe MIC end point value of KTZ and FLZ from 3937 to787120583gmL and from 31498 to 6290120583gmL respectivelyagainst A fumigatus strains The MIC of 5c reduced from31498 to 6290120583gmL in combination with KTZ and withFLZ it gets reduced to 25198 Depending upon FICI modelindifference (IND) and synergy (SYN) was observed Thecombination of KTZ with 5c showed SYN against onlyone strain of A fumigatus that is ITCC 4517 at 1 8(625 5000 120583gmL FICI = 040) (Table 4) The FICI (GM)

Advances in Chemistry 3

Table1Structureform

ulaandyield

sofcom

poun

ds5andashl

Entry

RX

Ar

Chalcone

(4andashl)

Cyclisedprod

uct(5andashl)

Yield(

)

2a3a4a5a

ndashCH

3O

p-CH

3

N

NO

OO

OH

CH3

H3C

CH3

N

NO

OO

HNN

CH3

H3C

CH3

66

2a3b4b

5b

ndashCH

3O

p-OCH

3

N

NO

OO

OH

OCH

3CH

3

H3C

N

NO

OO

HNN

OCH

3

CH3

H3C

66

2a3c4c5c

ndashCH

3O

p-Br

N

NO

OO

OH

BrCH

3

H3C

N

NO

OO

H

NN

Br

CH3

H3C

80

2a3d

4d5d

ndashCH

3O

p-Cl

N

NO

OO

OH

ClCH

3

H3C

N

NO

OO

H

NN

Cl

CH3

H3C

66


Table1Con

tinued

Entry

RX

Ar

Chalcone

(4andashl)

Cyclisedprod

uct(5andashl)

Yield(

)

2b3a4e5e

C 6H

6S

p-CH

3

N

NS

OO

OH

CH3

N

NO

SO

HNN

CH3

64

2b3b4f5f

C 6H

6S

p-OCH

3

N

NS

OO

OH

OCH

3N

NO

SO

HNN

OCH

380

2b3c4g

5g

C 6H

6S

p-Br

N

NO

SO

HNN

BrN

NO

SO

HNN

Br46

2b3d

4h5h

C 6H

6S

p-Cl

N

NS

OO

OH

ClN

NO

SO

HNN

Cl78


Table1Con

tinued

Entry

RX

Ar

Chalcone

(4andashl)

Cyclisedprod

uct(5andashl)

Yield(

)

2c3a4i5i

o-OCH

3C6H

5S

p-CH

3

N

NS

OO

OH

CH3

OCH

3

OCH

3

N

NO

SO

H

NN

OCH

3

OCH

3

CH3

68

2c3b4j5j

o-OCH

3C6H

5S

p-OCH

3

N

NS

OO

OH

OCH

3

OCH

3

OCH

3

N

NO

SO

HNN

OCH

3

OCH

3

OCH

368

2c3c4k

5k

o-OCH

3C6H

5S

p-Br

N

NO

SO

HNN

Br

OCH

3

OCH

3

N

NO

SO

HNN

Br

OCH

3

OCH

3

80

2c3d

4l5l

o-OCH

3C6H

5S

p-Cl

N

NS

OO

OH

Cl

OCH

3

OCH

3

N

NO

SO

HNN

Cl

OCH

3

OCH

3

81


Table 2 Antifungal activity of pyrimidine pyrazole analogues

CompoundMIC

DDA (120583gdisc) MDA (120583gmL) PSGI (120583gmL)A flavus A niger A fumigatus A flavus A niger A fumigatus A flavus A niger A fumigatus

5c 4675 4675 4675 500 500 250 500 500 2505e mdash mdash mdash mdash mdash mdash mdash mdash mdash5f mdash mdash mdash mdash mdash mdash mdash mdash mdash5g mdash mdash mdash mdash mdash mdash mdash mdash mdash5h mdash mdash mdash mdash mdash mdash mdash mdash mdash5i mdash mdash mdash mdash mdash mdash mdash mdash mdash5j 1875 1875 4675 500 1000 500 500 1000 5005k mdash mdash mdash mdash mdash mdash mdash mdash mdash5l mdash mdash mdash mdash mdash mdash mdash mdash mdashmdash no significant inhibition

Table 3 In vitro combination of compound 5c with polyene (AmpB NYS) against A fumigatus

Strain MIC (120583gmL) FIC index Interpretation5c AmpB NYS AmpB + 5c NYS + 5c AmpB + 5c NYS + 5c AmpB + 5c NYS + 5c

ITCC 4517 250 195 39 156625 3121250 083 (08 + 003) 085 (08 + 005) IND INDITCC 1634 500 195 39 3121250 3121250 162 (16 + 002) 083 (08 + 003) IND INDVPCI 19096 250 195 39 156625 3121250 083 (08 + 003) 085 (08 + 005) IND INDGeometric mean 31498 195 39 196787 3121250 103 (100 + 03) 083 (08 + 003) IND INDIND indifference

N

NX

OO

OHR

R

N

N

O

X

R

ROH

NN

N

N

R

R

X

O

OH

N

NR

R

X

O

OH

O

Acetic anhydride

12

34 5

612

3

Compounds CompoundsR Y

3a 4a 4e4i 5a 5e 5i3b 4b 4f4j 5b 5f 5j

X

O

S

S

3c 4c 4g4k 5c 5g 5k3d 4d 4h4l 5d 5h 5l

YY

Br

Cl

ArndashCHO (3andashd)

DMAP 3h 80∘C NaOH MeOHreflux 48h

110∘C 14-Dioxane

1andashc 2andashc

5andashl4andashl

1ndash5 3ndash5

1a 2a 4andashd5andashd

ndashCH3

PhNHNH2

ndashC6H51b 2b 4endashh5endashh1c 2c 4indashl5indashl

CH3

OCH3

CH3

ondashOCH3C6H4

1998400 2

998400

3998400

4998400

5998400

1998400998400

2998400998400

3998400998400

4998400998400

5998400998400

6998400998400

19984002

998400

3998400

4998400

5998400

6998400

1998400998400 2

998400998400

3998400998400

4998400998400

5998400998400

6998400998400

Scheme 1 Synthesis of pyrimidine pyrazole derivatives


Table 4 In vitro combination of compound 5c with azole (KTZ FLZ) against A fumigatus

Strain MIC (120583gmL) FIC index Interpretation5c KTZ FLZ KTZ + 5c FLZ + 5c KTZ + 5c FLZ + 5c KTZ + 5c FLZ + 5c

ITCC 4517 250 3125 500 625500 5002000 040 (02 + 02) 09 (01 + 08) SYN INDITCC 1634 500 6250 250 2501000 10004000 060 (04 + 02) 12 (04 + 08) IND INDVPCI 19096 250 3125 250 1250500 5002000 060 (04 + 02) 10 (02 + 08) IND INDGeometric mean 31498 3937 31498 787629 62925198 052 (032 + 020) 10 (02 + 08) IND INDIND indifference SYN synergy

Table 5 In vitro combination of compound 5j with polyene (AmpB NYS) against A fumigatus

Strain MIC (120583gmL) FIC index Interpretation5j AmpB NYS AmpB + 5j NYS + 5j AmpB + 5j NYS + 5j AmpB + 5j NYS + 5j


values for the rest of combination were 052 and 102 INDoccurred

Since the MIC value of KTZ is significantly reduced incombination with 5c this compound may be a potentialcandidate for further research and may be developed as apotential candidate to be used in combination therapy againstfungal infections

(12) In Vitro FIC Index of 5j with Polyene (Amp B NYS) andAzole (KTZ FLZ) The MIC (GM) end point value of AmpB and NYS in combination with 5j remains almost the samethat is 196 and 393 120583gmL respectively But the MIC (GM)end point value of 5j in combination with Amp B and NYSreduced from 39684 to 624 and 1570 120583gmL respectivelyThe FICI (GM) values were found to be 103 and 105 withAmp B and NYS combination with 5j showed IND againstthe tested strain (Table 5)

The combination of azole (KTZ and FLZ) with 5j reducedthe MIC (GM) end point value of KTZ from 3933 to 2500and from 31498 to 6299120583gmL of FLZ The MIC (GM) endpoint value of 5j reduced from 39685 to 100 120583gmLwith KTZand 25198 120583gmLwith FLZ But this reduction is not asmuchsignificant as the combination of KTZ with 5j which showedsynergy against only one A fumigatus VPCI 19096 that is1 4 (25 100 120583gmL) The FICI (GM) values for the othercombinations were 070 and 083 indifference was declared(Table 6)

222 Antibacterial Activity Among all the analogues themost active compound was 5g whose MIC was 3125 120583gmLagainst S aureus and B cereus and the second and third mostactive compounds were 5h and 5c which showed MIC at6250120583gmL against B cereus and S aureus and 125 120583gmLagainst S aureus respectively The other two compounds 5eand 5j showed activity at 500120583gmL against S aureus and Ecoli respectively Erythromycin was used as a standard drug(Table 7)

It has already been reported that the pyrimidine pyrazoleanalogues have strong antibacterial activity against a numberof pathogenic bacteria [26] Therefore we have tried toevaluate their in vitro antibacterial potential against grampositive as well as gram negative bacteria

The compound 5g showed potent antibacterial activityagainst gram positive bacteria S aureus and B cereus Theseresults suggest that theremay be a useful practical applicationfrom the chemistry of pyrimidine pyrazole analogues

3 Experimental

31 General All reagents were of commercial grade and wereused as received Solvents were dried and purified usingstandard techniques 1H-NMR (400MHz) and 13C-NMR(1005MHz) were recorded on JNM ECX-400P (Jeol USA)spectrometer using TMS as an internal standard Chemicalshifts are reported in parts per million (ppm) Mass spectrawere recorded on API-2000 mass spectrometer IR absorp-tion spectra were recorded in the 400ndash4000 cmminus1 range ona Perkin-Elmer FT-IR spectrometer model 2000 using KBrpallets Melting points were determined using Buchi M-560and are uncorrectedThese reactions were monitored by thinlayer chromatography (TLC) on aluminium plates coatedwith silica gel 60 F

254(Merck) UV radiation and iodine were

used as the visualizing agents Column chromatography wasperformed on silica gel (100ndash200 mesh)

32 General Procedure for the Synthesis of Chalcone Analogues(4andashl) A solution of 2andashc (1mmol) and corresponding arylaldehydes 3andashd (1mmol) in 20mL of methanol was treatedwith sodium hydroxide as base at 60∘CThe reaction mixturewas refluxed for 50 h After completion of reaction it wasconcentrated and extracted with chloroform (3 times 20mL)Thecombined organic extract was dried over anhydrous sodiumsulphate and concentrated under reduced pressureThe crudeproduct was purified by column chromatography


Table 6 In vitro combination of compound 5j with azole (KTZ and FLZ) against A fumigatus

Strain MIC (120583gmL) FIC index Interpretation5j KTZ FLZ KTZ + 5j FLZ + 5j KTZ + 5j FLZ + 5j KTZ + 5j FLZ + 5j

ITCC 4517 25000 3125 50000 250010000 500020000 120 (08 + 04) 090 (01 + 08) IND INDITCC 1634 50000 6250 25000 250010000 1000040000 060 (04 + 02) 120 (04 + 08) IND INDVPCI 19096 50000 3125 25000 25010000 500020000 050 (04 + 01) 060 (02 + 04) SYN INDGeometric mean 39685 3937 31490 250010000 629925198 07 (05 + 02) 083 (02 + 063) IND INDIND indifference

Table 7 Antibacterial activity of pyrimidine pyrazole analogues

Compound Bacterial pathogens (MIC 120583gmL)S aureus B cereus E coli S typhi M luteus B pumilus B subtilis

5c 125 mdash mdash mdash mdash mdash mdash5e 500 mdash mdash mdash mdash mdash mdash5f mdash mdash mdash mdash mdash mdash mdash5g 3125 3125 mdash mdash mdash mdash mdash5h 6250 6250 mdash mdash mdash mdash mdash5i mdash mdash mdash mdash mdash mdash mdash5j mdash mdash mdash mdash mdash mdash mdash5k mdash mdash mdash mdash mdash mdash mdash5l mdash mdash mdash mdash mdash mdash mdashERY 1562 1562 781 3125 1562 1562 1562ERY erythromycin (standard drug)mdash no significant inhibition

321 (E)-1-(1101584031015840-Dimethyl-61015840-hydroxy-2101584041015840-dioxo-11015840210158403101584041015840-tetrahydropyrimidin-51015840-yl)-3-(p-tolyl)-prop-2-ene-1-one (4a)Theproduct was obtained as mentioned in general procedurefrom 2a and 3a as yellow solid in 72 yield Mp 1870∘C IR]max (cm

minus1) = 1662 1718 (C=O) 2925 (CndashH) 3432 (OH) 1HNMR (400MHz CDCl

3) 120575 (ppm) 234 (3H s ndashCH

3) 320

(6H s NndashCH3) 729 (2H d 119869 = 732Hz ArH) 762 (2H

d 119869 = 804Hz ArH) 795 (1H d 119869 = 1611Hz 120572ndashH) 845(1H d 119869 = 1611Hz 120573ndashH) 1694 (1H s ndashOH) 13C NMR(100MHz CDCl

3) 120575 (ppm) 2105 2767 2784 11910 12637

12843 12900 12998 13185 13938 14181 14565 1498415469 16322 16583 18202

322 (E)-1-(1101584031015840-Diphenyl-61015840-hydroxy-41015840-oxo-21015840-thiooxo-11015840210158403101584041015840-tetrahydropyrimidin-51015840-yl)-3-(p-tolyl)-prop-2-ene-1-one(4e) The product was obtained as mentioned in generalprocedure from 2b and 3a as yellow solid in 67 yieldMp 2846∘C IR ]max (cmminus1) = 1039 (C=S) 1690 (C=O)2924 (CndashH) 3433 (OH) 1H NMR (400MHz CDCl

3) 120575

(ppm) 238 (3H s ndashCH3) 718 (2H d 119869 = 805Hz ArH)

728ndash731 (2H m ArH) 745ndash758 (10H m ArH) 809 (1Hd 119869 = 1538Hz 120572-H) 851 (1H d 119869 = 1684Hz 120573-H) 1679(1H s ndashOH) 13C NMR (100MHz CDCl

3) 120575 (ppm) 2168

(ndashCH3) 11915 12855 12863 12877 12911 12955 12961

12967 12981 13182 13972 14296 14862 15994 1686317874 (C=S) 18518

323 (E)-1-(1101584031015840-Bis(210158401015840-methoxyphenyl)-61015840-hydroxy-41015840-oxo-21015840-thiooxo-11015840210158403101584041015840-tetrahydro pyrimidin-51015840-yl)-3-(p-tolyl)-prop-2-ene-1-one (4i) The product was obtained asmentioned in general procedure from 2c and 3a as yellowsolid in 68 yield Mp 2205∘C IR ]max (cmminus1) = 1025(C=S) 1663 (C=O) 2926 (CndashH) 3434 (OH) 1H NMR(400MHz CDCl

3) 120575 (ppm) 235 (3H s ndashCH

3) 384 (6H

s ndashOCH3) 703ndash710 (4H m ArH) 716 (2H d 119869 = 732Hz

ArH) 721ndash726 (2H m ArH) 744 (2H d 119869 = 805Hz ArH)755 (2H d 119869 = 805Hz ArH) 803 (1H d 119869 = 1611Hz120572ndashH) 851 (1H d 119869 = 1611Hz 120573-H) 1684 (1H s ndashOH)13C NMR (100MHz CDCl

3) 120575 (ppm) 2163 (ndashCH

3) 5614

(ndashOCH3) 11957 12106 12119 12857 12953 12972 12982

13022 13059 13196 14246 14783 15953 16840 17854(C=S) 18494

33 General Procedure for the Synthesis of Pyrimidine PyrazoleHeterocycles (5andashl) To the mixture of corresponding chal-cone4andashl (1mmol) and phenylhydrazine (15mmol) in 20mLof 14-dioxane 2 drops of acetic acid were addedThe reactionmixture was refluxed at 110∘C overnight After completionof reaction as monitored by TLC reaction mixture wasconcentrated and extracted with chloroform (3times 20mL)Thecombined organic extract was dried over anhydrous sodiumsulphate and concentrated under reduced pressureThe crudeproduct was purified by column chromatography (40 Ethylacetate pet ether)


331 13-Dimethyl-6-hydroxy-24-dioxo-5-(11015840-phenyl-31015840-(p-tol-yl)-1H-pyrazol-51015840 -yl)-1234 tetrahydropyrimidine (5a) Theproduct was obtained as mentioned in general procedurefrom 4a as white solid Mp 150ndash152∘C IR ]max (cmminus1)1646 1702 (2 times C=O) 2924 (CndashH) 3210 (ndashOH) 1H NMR(400MHz CDCl

3) 120575 (ppm) 234 (3H s ndashCH

3) 328 (3H

s NndashCH3) 336 (3H s NndashCH

3) 693 (2H d 119869 = 808Hz

ArH) 706 (1H t ArH) 718 (2H d 119869 = 808Hz ArH)725ndash730 (4H m Pyrazole H ArH) 1285 (1H s ndashOH)13C NMR (100MHz CDCl

3) 120575 (ppm) 2104 (ndashCH

3) 2751

(NndashCH3) 10742 11589 12600 12946 12957 12979 13919

14781 15350 15921 16528 ESI-MS119898119911 [M +H]+ = 3881

33213-Dimethyl-6-hydroxy-24-dioxo-5-(11015840-phenyl-31015840-(p-me-thoxyphenyl)-1H-pyrazol-51015840-yl)-1234-tetrahydropyrimidine(5b) The product was obtained as mentioned in generalprocedure from 4b aslight brown solid Mp 170-171∘C IR]max (cm

minus1) 1647 1716 (2 times C=O) 2924 (CndashH) 3245 (ndashOH)1H NMR (400MHz CDCl

3) 120575 (ppm) 335 (3H s NndashCH

3)

339 (3H s NndashCH3) 380 (3H s ndashOCH

3) 689ndash694 (4H m

ArH) 707 (1H t ArH) 725ndash733 (5H m pyrazole H ArH)1283 (1H s ndashOH) 13C NMR (100MHz CDCl

3) 120575 (ppm)

2765 (NndashCH3) 2967 (NndashCH

3) 5533 (ndashOCH

3) 8608

11445 11627 12413 12747 12954 13239 14808 1518815961 16154 16208 16549 ESI-MS119898119911 [M +H]+ = 4041

33313-Dimethyl-6-hydroxy-24-dioxo-5-(11015840-phenyl-31015840-(p-bro-mo)-1H-pyrazol-51015840-yl)-24-dioxo-1234-tetrahydropyrimidine(5c) The product was obtained as mentioned in generalprocedure from 4c as white solid Mp 197-198∘C IR ]max(cmminus1) 1699 1734 (2 times C=O) 2925 (CndashH) 3417 (ndashOH) 1HNMR (400MHz CDCl

3) 120575 (ppm) 328 (3H s NndashCH

3)

335 (3H s NndashCH3) 692 (2H d 119869 = 805Hz ArH) 709

(1H t ArH) 727ndash731 (5H m Pyrazole H ArH) 752 (2H d119869 = 805Hz ArH) 1282 (1H s ndashOH) 13C NMR (100MHzCDCl

3) 120575 (ppm) 2784 (NndashCH

3) 8614 11618 12226 12436

12787 12966 13229 13977 14776 15145 16145 1619516499 ESI-MS119898119911 [M +H]+ = 4533

334 13-Dimethyl-6-hydroxy-24-dioxo-5-(11015840 -phenyl-31015840 -(p-chloro)-1H-pyrazol-51015840-yl)-1234-tetrahydropyrimidine (5d)Theproduct was obtained as mentioned in general procedurefrom 4d as light brown solid Mp 121ndash123∘C IR ]max (cm

minus1)1642 1702 (2 times C=O) 2923 (CndashH) 3319 (ndashOH) 1H NMR(400MHz CDCl

3) 120575 (ppm) 328 (3H s NndashCH

3) 336 (3H

s NndashCH3) 692 (2H d 119869 = 805Hz ArH) 707ndash711 (2H

m ArH) 724ndash748 (6H m ArH pyrazole H) 1283 (1Hs ndashOH) 13C NMR (100MHz CDCl

3) 120575 (ppm) 2771 (Nndash

CH3) 8769 11627 11988 12109 12436 12504 12756 12900

12933 12949 13004 13416 13909 14762 15171 16140 ESI-MS119898119911 [M +H]+ = 4081

335 1 3-Diphenyl-6-hydroxy-4-oxo-2-thiooxo-5-(11015840 -phenyl-31015840-(p-tolyl)-1H-pyrazol-51015840-yl)-1234-tetrahydropyrimidine (5e)Theproduct was obtained as mentioned in general procedurefrom 4e as light brown solid Mp 131ndash133∘C IR ]max (cm

minus1)1071 (C=S) 1676 (C=O) 2924 (CndashH) 3245 (ndashOH) 1H NMR

(400MHz CDCl3) 120575 (ppm) 235 (3H s ndashCH

3) 690 (2H d

119869 = 808Hz ArH) 706 (1H t ArH) 717ndash730 (9H m ArH)732ndash738 (3H m ArH) 740ndash753 (5H m Pyrazole H ArH)1282 (1H s ndashOH) 13C NMR (100MHz CDCl

3) 120575 (ppm)

2124 (NndashCH3) 8832 12427 12555 12832 12870 12886

12938 12955 12982 13748 13825 13953 14035 1469316075 16133 16397 18024 (C=S) ESI-MS119898119911 [M +H]+ =5281

336 1 3-Diphenyl-6-hydroxy-4-oxo-2-thiooxo-5-(11015840 -phenyl-31015840-(p-methoxyphenyl)-1H-pyrazol-51015840-yl)-1234-tetrahydropy-rimidine (5f) The product was obtained as mentioned ingeneral procedure from 4f as green solid Mp 120-121∘CIR ]max (cmminus1) 1030 (C=S) 1676 (C=O) 2924 (CndashH) 3214(ndashOH) 1H NMR (400MHz CDCl

3) 120575 (ppm) 382 (3H s

ndashOCH3) 690ndash693 (4H m ArH) 708 (1H t ArH) 721ndash740

(10H m ArH) 743ndash758 (5H m Pyrazole H ArH) 1283(1H s ndashOH) 13C NMR (100MHz CDCl

3) 120575 (ppm) 5532

(ndashOCH3) 8835 11449 11641 12745 12868 12937 12944

12947 12953 1312 13976 14032 14713 15980 1608616149 16409 18003 (C=S) ESI-MS119898119911 [M +H]+ = 5454

337 1 3-Diphenyl-6-hydroxy-4-oxo-2-thiooxo-5-(11015840 -phenyl-31015840-(p-bromo)-1H-pyrazol-51015840-yl)-1234-tetrahydropyrimidine(5g) The product was obtained as mentioned in generalprocedure from 4g as light green solid Mp 209-210∘CIR ]max (cmminus1) 1071 (C=S) 1675 (C=O) 2925 (CndashH) 3182(ndashOH) 1H NMR (400MHz CDCl

3) 120575 (ppm) 689 (2H d

119869 = 805Hz ArH) 708 (1H t ArH) 726ndash728 (4H m ArH)733 (2H d 119869 = 732Hz ArH) 740 (2H d 119869 = 805HzArH) 744ndash757 (9H m Pyrazole H ArH) 1280 (1H sndashOH) 13C NMR (100MHz CDCl

3) 120575 (ppm) 8836 10631

11631 12211 12493 12537 12783 12865 12939 1294612966 13233 13611 13909 13989 14674 16055 1613516418 17992 (C=S) ESI-MS119898119911 [M +H]+ = 5920

338 1 3-Diphenyl-6-hydroxy-4-oxo-2-thiooxo-5-(11015840 -phenyl-31015840-(p-chloro)-1H-pyrazol-51015840-yl)-1234-tetrahydropyrimidine(5h) The product was obtained as mentioned in generalprocedure from 4h as dark green solid Mp 207-208∘CIR ]max (cmminus1) 1089 (C=S) 1675 (C=O) 2924 (CndashH) 3198(ndashOH) 1H NMR (400MHz CDCl

3) 120575 (ppm) 689 (2H d


3) 120575 (ppm)

8850 10595 11630 12751 12864 12939 12947 1296513423 13866 13948 13989 14659 16096 16135 1642117994 (C=S) ESI-MS119898119911 [M +H]+ = 5481

339 1 3-Bis(210158401015840 -methoxyphenyl)-6-hydroxy4-oxo-2-thioxo-5-(11015840-phenyl-31015840-(p-tolyl)-1H-pyrazol-51015840-yl)-1234-tetrahydro-pyrimidine (5i) The product was obtained as mentioned ingeneral procedure from 4i as light brown solid Mp 107ndash109∘C IR ]max (cm

minus1) 1075 (C=S) 1677 (C=O) 2925 (CndashH)3302 (ndashOH) 1H NMR (400MHz CDCl

3) 120575 (ppm) 236

(3H s ndashCH3) 385 (6H sndashOCH

3) 691 (2H d 119869 = 732Hz

ArH) 700ndash712 (6H m ArH) 718ndash730 (5H m ArH)


730ndash743 (5H m Pyrazole H ArH) 1289 (1H s ndashOH)13C NMR (100MHz CDCl

3) 120575 (ppm) 2961 (ndashCH

3) 5601

(ndashOCH3) 8553 10537 11220 11272 11594 12102 12557

12851 12956 12967 12979 12999 14016 14836 1546617837 (C=S) ESI-MS119898119911 [M +H]+ = 5881

3310 1 3-Bis(210158401015840 -methoxyphenyl)-6-hydroxy-4-oxo-2-thio-oxo-5-(11015840-phenyl-31015840-(p-methoxyphenyl)-1H-pyrazol-51015840-yl)-1234-tetrahydropyrimidine (5j) The product was obtained asmentioned in general procedure from 4j as light green solidMp 127ndash129∘C IR ]max (cmminus1) 1074 (C=S) 1627 (C=O)2926 (CndashH) 3422 (ndashOH) 1H NMR (400MHz CDCl

3)

120575 (ppm) 383 (9H s ndashOCH3) 683ndash692 (7H m ArH)

701ndash711 (7H m ArH) 720ndash732 (4H m pyrazole H ArH)1280 (1H s ndashOH) 13C NMR (100MHz CDCl

3) 120575 (ppm)

5532 (ndashOCH3) 8815 11278 11353 11445 11633 12101

12153 12181 12432 12753 12916 12946 12984 1301814675 15493 15955 16776 18532 (C=S) ESI-MS 119898119911[M +H]+ = 6041

3311 1 3-Bis(210158401015840 -methoxyphenyl)-6-hydroxy-4-oxo-2-thio-oxo-5-(11015840-phenyl-31015840-(p-bromo)-1H-pyrazol-51015840-yl)-1234-tet-rahydropyrimidine (5k) The product was obtained asmentioned in general procedure from 4k as light yellowsolid Mp 112-113∘C IR ]max (cmminus1) 1044 (C=S) 1674(C=O) 2925 (CndashH) 3287 (ndashOH) 1H NMR (400MHzCDCl

3) 120575 (ppm) 378 (6H s ndashOCH

3) 682ndash684 (2H m

ArH) 693ndash704 (5H m ArH) 712ndash725 (6H m ArH)732ndash739 (3H m ArH) 745ndash747 (2H m pyrazole H ArH)1277 (1H s ndashOH) 13C NMR (100MHz CDCl

3) 120575 (ppm)

5636 (ndashOCH3) 8836 11626 12103 12113 12790 12800

12960 12970 12989 13025 13230 13930 13936 1467715451 15970 16094 16393 17953 (C=S) ESI-MS 119898119911[M +H]+ = 6520

3312 1 3-Bis(210158401015840 -methoxyphenyl)-4-oxo-2-thiooxo-6-hy-droxy-5-(11015840-phenyl-31015840-(p-chloro)-1H-pyrazol-51015840-yl)-1234-tet-rahydropyrimidine (5l) The product was obtained asmentioned in general procedure from 4l as light yellow solidMp 232-233∘C IR ]max (cmminus1) 1043 (C=S) 1654 (C=O)2927 (CndashH) 3437 (ndashOH) 1H NMR (400MHz CDCl

3)


698ndash709 (5H m ArH) 723ndash728 (5H m ArH) 733ndash745(6H m pyrazole H ArH) 1283 (1H s ndashOH) 13C NMR(100MHz CDCl

3) 120575 (ppm) 5619 (ndashOCH

3) 8818 11223

11606 12091 12452 12760 12934 12959 12988 1342613888 15489 16060 16397 18519 (C=S) ESI-MS 119898119911[M +H]+ = 6093

34 Antifungal Susceptibility Test The pathogenic isolates ofAspergillus fumigatus (ITCC 4517 (IARI Indian AgriculturalResearch Institute Delhi) ITCC 1634 (IARI Delhi) clini-cal isolate 19096 (VPCI Vallabhbhai Patel Chest InstituteDelhi)) Aspergillus flavus (clinical isolate 22396 (VPCIDelhi)) and Aspergillus niger (clinical isolate 5696 (VPCIDelhi)) were employed in the current studyThese pathogenicspecies of Aspergillus namely A fumigatus A flavus and

A niger were cultured in laboratory on Sabouraud dextrose(SD) agar plates The plates were inoculated with stockcultures ofA fumigatusA flavus andA niger and incubatedin a BOD incubator at 37∘C The spores were harvested from96 h cultures and suspended homogeneously in phosphatebuffer saline (PBS) The spores in the suspension werecounted and their number was adjusted to 108 sporesmLbefore performing the experiments The antifungal activityof compounds was analysed by MDA DDA and PSGI Eachassay was repeated at least three times on different days AmpBwas used as a standard drug in antifungal susceptibility test

341 Disc Diffusion Assay (DDA) The disc diffusion assaywas performed in radiation sterilized petri plates (100 cmdiameter Tarsons) The SD agar plates were prepared andplated with a standardized suspension of 1 times 108 sporemLof Aspergillus spp Then plates were allowed to dry anddiscs (50mm in diameter) ofWhatman filter paper number1 were placed on the surface of the agar The differentconcentrations of compounds in the range of 750ndash10046120583gwere impregnated on the discs An additional disc for solvent(DMSO) was also placed on agar plate The plates wereincubated at 37∘C and examined at 24 h 48 h for zone ofinhibition if any around the discs The concentration whichdeveloped the zone of inhibition of at least 60mm diameterwas taken as end point (Minimum Inhibitory ConcentrationMIC)

342 Percent Spore Germination Inhibition Assay (PSGI)Different concentrations of the test compounds in 900120583Lof culture medium were prepared in 96-well flat-bottomedmicroculture plates (Tarson) by double dilution methodEach well was then inoculated with 100 120583L of spore sus-pension (100 plusmn 5 spores) The plates were incubated at37∘C for 16 h and then examined for spore germinationunder inverted microscope (Nikon diphot) The numberof germinated and nongerminated spores was counted Thelowest concentration of the compound which resulted ingt90 inhibition of germination of spores in the wells wasconsidered as MIC

90

343 Microbroth Dilution Assay (MDA) The test was per-formed in 96-well culture plates (Tarson) Various con-centrations of compounds in the range of 1250ndash43 120583gmLwere prepared in 900120583L of culture medium by doubledilutionmethod Eachwell was inoculatedwith 10120583L of sporesuspension (1times 108 sporemL) and incubated for 48 h at 37∘CAfter 48 h the plateswere assessed visuallyTheoptically clearwell was taken as end point MIC

35 Antifungal Drugs and Pyrimidine Pyrazole AnaloguesCheckerboard Testing In vitro combination of pyrimidinepyrazole analogues was studied with antifungal drug AmpB(Himedia) and NYS (Himedia) The starting range of finalconcentration was taken as approximate one fold higherthan individual MIC to compute all in vitro interac-tions (Antagonistic Synergy SYN and Indifference IND)The final concentrations of antifungal agents which ranged


from 3125 to 002120583gmL forAmpB 625 to 009 forNYS and400 to 3125 120583gmL for 5c 5j were taken Aliquots of 45 120583L ofeach drug at a concentration four times the targeted final weredispensed in the wells in order to obtain a two-dimensionalcheckerboard (8times 8 combination) [27] Each well then wasinoculated with 10120583L of spore suspension (1 times 108 sporemL)The plates were incubated at 37∘C for 48 h The plates werethen assessed visually The optically clear well was taken asend point MIC

36 Drug Interaction Modelling The drug interaction wasdetermined by the most popular FICI model The FICIrepresents the sum of the FICs (Fraction Inhibitory Concen-tration) of each drug tested The FIC of a drug was definedas MIC of a drug in combination divided by MIC of thesame drug alone (MIC of drug in combinationMIC of drugalone) FICI = 1 (revealed indifference) FICI le 05 (revealedsynergy) and FICI gt 4 (revealed antagonism) [28]

37 Antibacterial Susceptibility Test The antibacterial activityof compoundwas analysed bymicrobroth dilution Resazurinbased assay [29] Each assay was repeated at least three timeson different daysThe different pathogenic species of bacteriaStaphylococcus aureus (MTCC number 3160) Bacillus cereus(MTCC number 10085) Escherichia coli (MTCC number433) Salmonella typhi (MTCC number 733) Micrococcusluteus (MTCC number 8132) Bacillus pumilis (MTCC num-ber 2299) and Bacillus subtilis (MTCC number 8142) werecultured in Luria broth Using aseptic techniques a singlecolony was transferred into a 100mL Luria broth and placedin incubator at 35∘C After 12ndash18 h of incubation the culturewas centrifuged at 4000 rpm for 5 minutes The supernatantwas discarded and pellet was resuspended in 20mL PBSand centrifuged again at 4000 rpm for 5min This step wasrepeated until the supernatant was clear The pellet was thensuspended in 20mL PBS The optical density of the bacteriawas recorded at 500 nm and serial dilutions were carried outwith appropriate aseptic techniques until the optical densitywas in the range of 05ndash10 representing 5 times 106 CFUmL

371 Resazurin Based Microtitre Dilution Assay Resazurinbased MDA was performed in 96-well plates under asepticconditionsThe concentrations of compounds in the range of2000ndash78120583gmL were prepared in 100120583L of culture mediumby serial dilution method 10 120583L of Resazurin indicator solu-tion (5X) was added in each well Finally 10 120583L of bacterialsuspension was added (5 times 106 CFUmL) to each well toachieve a concentration of 5 times 105 CFUmL Each plate hada set of controls a column with erythromycin as positivecontrol The plates were prepared in triplicate and incubatedat 37∘C for 24 hThe colour change was then assessed visuallyThe lowest concentration at which colour change occurredwas taken as the MIC value

4 Conclusion

In search of novel antimicrobial molecules we came acrossthat pyrimidine pyrazole heterocycles can be of interest as5g showed significant antibacterial activity The compounds5e and 5h also showed moderate antibacterial activity 5jshowed moderate antifungal activity Out of all heterocycles5c possesses both antifungal and antibacterial activity Ourstudies showed that these novel heterocycles can supplementthe existing antifungal therapy Monotherapy can be replacedby combination therapy Therefore 5c 5g and 5j might beof great interest for the development of novel antimicrobialmolecule

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors would like to thank Council of Scientificand Industrial Research (CSIR) New Delhi and DefenceResearch and Development Organisation (DRDO) for thefinancial support

References

[1] A L Stuart N K Ayisi G Tourigny and V S Gupta ldquoAntiviralactivity antimetabolic activity and cytotoxicity of 31015840-substituteddeoxypyrimidine nucleosidesrdquo Journal of Pharmaceutical Sci-ences vol 74 no 3 pp 246ndash249 1985

[2] A Agarwal N Goyal P M S Chauhan and S GuptaldquoDihydropyrido[23-d]pyrimidines as a new class of antileish-manial agentsrdquo Bioorganic and Medicinal Chemistry vol 13 no24 pp 6678ndash6684 2005

[3] R E Mitchell D R Greenwood and V Sarojini ldquoAn antibac-terial pyrazole derivative from Burkholderia glumae a bacterialpathogen of ricerdquo Phytochemistry vol 69 no 15 pp 2704ndash27072008

[4] R Basawaraj B Yadav and S S Sangapure ldquoSynthesis ofsome 1H-pyrazolines bearing benzofuran as biologically activeagentsrdquo Indian Journal of Heterocyclic Chemistry vol 11 no 1pp 31ndash34 2001

[5] K T Ashish and M Anil ldquoSynthesis and antifungal activityof 4-substituted-37-dimethylpyrazolo [34-e] [124] triazinerdquoIndian Journal of Chemistry B vol 45 p 489 2006

[6] B P Chetan and V V Mulwar ldquoSynthesis and evaluationof certain pyrazolines and related compounds for their antitubercular anti bacterial and anti fungal activitiesrdquo IndianJournal of Chemistry B vol 44 article 232 2000

[7] K S Nimavat and K H Popat ldquoSynthesis anticancer anti-tubercular and antimicrobial activities of 1-substituted 3-aryl-5-(3rsquo-bromophenyl) pyrazolinerdquo Indian Journal of HeterocyclicChemistry vol 16 p 333 2007

[8] R H Udupi A R Bhat and K Krishna ldquoSynthesis and investi-gation of some new pyrazoline derivatives for their antimicro-bial anti inflammatory and analgesic activitiesrdquo Indian Journalof Heterocyclic Chemistry vol 8 p 143 1998


[9] F R Souza V T Souza V Ratzlaff et al ldquoHypothermicand antipyretic effects of 3-methyl- and 3-phenyl-5-hydroxy-5-trichloromethyl-45-dihydro-1H-pyrazole-1-carboxyamides inmicerdquoEuropean Journal of Pharmacology vol 451 no 2 pp 141ndash147 2002

[10] K Ashok Archana and S Sharma ldquoSynthesis of potentialquinazolinyl pyrazolines as anticonvulsant agentsrdquo Indian Jour-nal of Heterocyclic Chemistry vol 9 p 197 2001

[11] M Abdel-Aziz G E A Abuo-Rahma and A A HassanldquoSynthesis of novel pyrazole derivatives and evaluation of theirantidepressant and anticonvulsant activitiesrdquo European Journalof Medicinal Chemistry vol 44 no 9 pp 3480ndash3487 2009

[12] L A Elvin E C John C G Leon J L John and H EReiff ldquoSynthesis and muscle relaxant property of 3-amino-4-aryl pyrazolesrdquo Journal of Medicinal Chemistry vol 7 no 3 pp259ndash268 1964

[13] G Doria C Passarotti R Sala et al ldquoSynthesis and antiulceractivity of (E)-5-[2-(3-pyridyl) ethenyl ]-1 H7 H-pyrazolo [15-a] pyrimidine-7-onesrdquo Farmaco vol 41 p 417 1986

[14] W H Robert ldquoThe antiarrhythmic and antiinflammatoryactivity of a series of tricyclic pyrazolesrdquo Journal of HeterocyclicChemistry vol 13 no 3 pp 545ndash553 2009

[15] R Soliman H Mokhtar and H F Mohamed ldquoSynthesis andantidiabetic activity of some sulfonylurea derivatives of 35-disubstituted pyrazolesrdquo Journal of Pharmaceutical Sciences vol72 no 9 pp 999ndash1004 1983

[16] R Kumar J Arora A K Prasad N Islam and A K VermaldquoSynthesis and antimicrobial activity of pyrimidine chalconesrdquoMedicinal Chemistry Research vol 22 no 11 pp 5624ndash56312013

[17] A Solankee S Lad S Solankee and G Patel ldquoChalconespyrazolines and aminopyrimidines as antibacterial agentsrdquoIndian Journal of Chemistry B vol 48 article 1442 2009

[18] B S Jursic and D M Neumann ldquoPreparation of 5-formyl-and 5-acetylbarbituric acids including the corresponding Schiffbases and phenylhydrazonesrdquo Tetrahedron Letters vol 42 no48 pp 8435ndash8439 2001

[19] F S Crossley E Miller W H Hartung and M L MooreldquoThiobarbiturates III Some N-substituted derivativesrdquo Journalof Organic Chemistry vol 5 no 3 pp 238ndash243 1940

[20] P Cabildo R M Claramunt and J Elguero ldquo 13C NMRchemical shifts of N-unsubstituted and N-methyl-pyrazolederivativesrdquoOrganicMagnetic Resonance vol 22 no 9 pp 603ndash607 1984

[21] V Yadav J Gupta R Mandhan et al ldquoInvestigations on anti-Aspergillus properties of bacterial productsrdquo Letters in AppliedMicrobiology vol 41 no 4 pp 309ndash314 2005

[22] S Ruhil M Balhara S Dhankhar M Kumar V Kumarand A K Chhillar ldquoAdvancement in infection control ofopportunistic pathogen (Aspergillus spp) adjunctive agentsrdquoCurrent Pharmaceutical Biotechnology vol 14 no 2 pp 226ndash232 2013

[23] T R T Dagenais and N P Keller ldquoPathogenesis of Aspergillusfumigatus in invasive aspergillosisrdquo Clinical MicrobiologyReviews vol 22 no 3 pp 447ndash465 2009

[24] J Smith and D Andes ldquoTherapeutic drug monitoring ofantifungals pharmacokinetic and pharmacodynamic consider-ationsrdquoTherapeutic Drug Monitoring vol 30 no 2 pp 167ndash1722008

[25] S Bondock W Khalifa and A A Fadda ldquoSynthesis andantimicrobial activity of some new 4-hetarylpyrazole and

furo[23-c]pyrazole derivativesrdquo European Journal of MedicinalChemistry vol 46 no 6 pp 2555ndash2561 2011

[26] K S Jain T S Chitre P B Miniyar et al ldquoBiological andmedicinal significance of pyrimidinesrdquo Current Science vol 90no 6 pp 793ndash803 2006

[27] E M OrsquoShaughnessy J Meletiadis T Stergiopoulou J PDemchok and T J Walsh ldquoAntifungal interactions withinthe triple combination of amphotericin B caspofungin andvoriconazole against Aspergillus speciesrdquo Journal of Antimicro-bial Chemotherapy vol 58 no 6 pp 1168ndash1176 2006

[28] S Ruhil M Balhara S Dhankhar V Kumar and A K ChhillarldquoInvasive aspergillosis adjunctive combination therapyrdquo Mini-Reviews in Medicinal Chemistry vol 12 no 12 pp 1261ndash12722012

[29] S Dhankhar M Kumar S Ruhil M Balhara and A KChhillar ldquoAnalysis toward innovative herbal antibacterial ampantifungal drugsrdquo Recent Patents on Anti-Infective Drug Discov-ery vol 7 no 3 pp 242ndash248 2012

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy


Carbohydrate Chemistry

International Journal of


Journal of

Chemistry


Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


in dioxane as solvent yielded 13-dimethyl-6-hydroxy-24-dioxo-5-(11015840-phenyl-31015840-aryl-1H-pyrazol-51015840-yl)-1234-tetra-hydropyrimidines (5andashd) and 13-diaryl-6-hydroxy-4-oxo-2-thioxo-5-(11015840-phenyl-31015840-aryl-1H-pyrazol-51015840-yl)-1234-tetra-hydropyrimidines (5endashl) in 46ndash81 yields [17] Structureand yield of compounds that is 4andashl and 5andashl are listed inTable 1 The 5-acetyl-13-diarylthiobarbituric acids (2b-c) inturn were synthesized by the following known method from13-diarylthiobarbituric acids (1b-c) and acetic anhydride[18 19] (Scheme 1)

All the compounds synthesized were characterized by IR1H NMR 13C NMR and mass spectroscopy Spectroscopicdata was in complete agreement with the structures assignedfor these compounds IR spectrum of cyclized derivatives ofbarbituric acid (5andashd) showed band in the region of 1700ndash1740 cmminus1 for carbonyl group (at C2) The other carbonylgroup at C4 showed band in the region of 1640ndash1699 cmminus1whereas cyclized derivatives of thiobarbituric acid (5endashl)showed band in the region of 1050ndash1100 cmminus1 which indi-cates the presence of thiocarbonyl group (at C2) and othercarbonyl groups at C4 showed band in the region of 1625ndash1680 cmminus1 Frequency band of OH group appears at 3200ndash3450 cmminus1 in the compounds 5andashl In 1H NMR spectrachemical shift values of all the compoundswere in accordancewith the expected values Aromatic protons of compounds4andashl resonated in the region of120575 686ndash782 Twodoublets of120572-H (attached to C2) at 120575 806 (119869 = 1611Hz) and120573-H (attachedto C3) at 841 (119869 = 1611Hz) respectively of 4f demonstratethe formation of 120572 120573-unsaturated carbonyl moiety and 119869 =1611Hz indicates that the ethylenemoiety in the enone link-age is in trans confirmation in the chalcone Disappearance ofthese doublets in 5f indicates the absence of chalconemoietyAll other phenyl protons in the compounds 5andashl appearedin the aromatic region at 120575 682ndash758 In 13C NMR of 4fall the characteristic peaks were in good agreement withthe proposed structure Carbonyl carbon at C-1 and C-41015840appeared at 120575 1846 and 1682 respectively The characteristicpeak of C=S appeared at 120575 1789 The C-2 and C-3 carbonsappeared at 120575 1145 and 1397 respectively The OCH

3carbon

appeared at 120575 554 The aromatic carbons attached to OCH3

(ie C-410158401015840) appeared at 120575 1629 The other aromatic carbonsof 4f resonated in the region of 120575 1273ndash1317 and the aromaticcarbon attached to nitrogen appeared at 1486 In 13CNMRof5f disappearance of peak at 120575 1846 indicates the cyclizationof chalcone Carbonyl carbon at C-4 appeared at 120575 1640 Thecharacteristic peak of C=S appeared at 120575 1800 C-6 carbonappeared at 120575 1608The pyrazole carbon at C-41015840 appeared at 120575883 [20]The OCH

3carbon appeared at 120575 553The aromatic

carbon attached to OCH3 that is C-410158401015840 appeared at 120575 1614

Theother aromatic carbons resonated in the region of 120575 1274ndash1295 and the aromatic carbon attached to nitrogen appearedat 120575 14713 Details of 1H NMR and 13C NMR spectra of 5andashlare given in experimental section

22 Biology

221 Antifungal Activity The antifungal activity againstAspergillus spp was evaluated by different methods [21ndash23]

that is disc diffusion assay (DDA) microbroth dilution assay(MDA) and percent spore germination inhibition (PSGI)The Minimum Inhibitory Concentration (MIC) values ofAmphotericin B (Amp B) and Nystatin (NYS) against allthe three Aspergillus species were found to be 075 120583gdiscand 100 120583gdisc respectively by DDA and 195 120583gmL and390 120583gmL respectively by MDA and PSGI The MIC of 5ccompound was 4675 120583gdisc against all the tested isolatesof Aspergillus spp by DDA whereas 5j compound possessesa slight higher MIC against A flavus and A niger that is1875 120583gdisc but against A fumigatus it possesses the sameMIC that is 4675120583gdisc The MIC of 5c by MDA andPSGI was found to be 2500 120583gmL against A fumigatus and5000 120583gmL againstA flavus andA nigerTheMIC of 5jwasfound to be 5000 120583gmL against A fumigatus and A flavusand 1000 120583gmL against A niger respectively by MDA andPSGI (Table 2)

Results revealed that the synthesized compounds 5c and5j exhibited mild antifungal activity which is lower thanthe standard drugs Some other substituted pyrimidines andpyrazoles have earlier been reported as potent antifungalagents against a number of pathogenic fungi alone and incombination [24 25]

As these compounds showed promising activity so wefurther tried these compounds in combination with standardantifungal drugs to evaluate their synergistic behaviour ifanyTherefore the compounds 5c and 5jwere tried for in vitrocombination with polyenes and azoles

(1) In Vitro Combination Study of Pyrimidine Pyrazole Ana-logues (5c and 5j) with Antifungal Drugs Among the humanpathogenic species of Aspergillus A fumigatus is the primarycausative agent of human infection followed by A flavusand A niger [23] Therefore A fumigatus [ITCC 4517 (IARIIndian Agricultural Research Institute Delhi) ITCC 1634clinical isolate VPCI 19096 (VPCI Vallabhbhai Patel ChestInstitute Delhi)] was selected for in vitro combination studyof pyrimidine pyrazole analogues with antifungal drugsThe data of in vitro combination was analysed by FractionInhibitory Concentration Index (FICI) model [24] and sum-marized in Tables 3ndash6

(11) In Vitro FIC Index of 5c with Polyene (Amp B NYS) andAzole (KTZ FLZ) In combination of Amp B and NYS with5c the FICI values were found to be in the range of 08 to 103indifference (IND) was declared against A fumigatus strains(Table 3)TheMIC end point value of 5c reduced from 31498to 7871250 120583gmL But the MIC of Amp B and NYS almostremains the same that is 196 120583gmL and 312 120583gmL

The combination of 5c with KTZ and FLZ reducedthe MIC end point value of KTZ and FLZ from 3937 to787120583gmL and from 31498 to 6290120583gmL respectivelyagainst A fumigatus strains The MIC of 5c reduced from31498 to 6290120583gmL in combination with KTZ and withFLZ it gets reduced to 25198 Depending upon FICI modelindifference (IND) and synergy (SYN) was observed Thecombination of KTZ with 5c showed SYN against onlyone strain of A fumigatus that is ITCC 4517 at 1 8(625 5000 120583gmL FICI = 040) (Table 4) The FICI (GM)


Table1Structureform

ulaandyield

sofcom

poun

ds5andashl

Entry

RX

Ar

Chalcone

(4andashl)

Cyclisedprod

uct(5andashl)

Yield(

)

2a3a4a5a

ndashCH

3O

p-CH

3

N

NO

OO

OH

CH3

H3C

CH3

N

NO

OO

HNN

CH3

H3C

CH3

66

2a3b4b

5b

ndashCH

3O

p-OCH

3

N

NO

OO

OH

OCH

3CH

3

H3C

N

NO

OO

HNN

OCH

3

CH3

H3C

66

2a3c4c5c

ndashCH

3O

p-Br

N

NO

OO

OH

BrCH

3

H3C

N

NO

OO

H

NN

Br

CH3

H3C

80

2a3d

4d5d

ndashCH

3O

p-Cl

N

NO

OO

OH

ClCH

3

H3C

N

NO

OO

H

NN

Cl

CH3

H3C

66


Table1Con

tinued

Entry

RX

Ar

Chalcone

(4andashl)

Cyclisedprod

uct(5andashl)

Yield(

)

2b3a4e5e

C 6H

6S

p-CH

3

N

NS

OO

OH

CH3

N

NO

SO

HNN

CH3

64

2b3b4f5f

C 6H

6S

p-OCH

3

N

NS

OO

OH

OCH

3N

NO

SO

HNN

OCH

380

2b3c4g

5g

C 6H

6S

p-Br

N

NO

SO

HNN

BrN

NO

SO

HNN

Br46

2b3d

4h5h

C 6H

6S

p-Cl

N

NS

OO

OH

ClN

NO

SO

HNN

Cl78


Table1Con

tinued

Entry

RX

Ar

Chalcone

(4andashl)

Cyclisedprod

uct(5andashl)

Yield(

)

2c3a4i5i

o-OCH

3C6H

5S

p-CH

3

N

NS

OO

OH

CH3

OCH

3

OCH

3

N

NO

SO

H

NN

OCH

3

OCH

3

CH3

68

2c3b4j5j

o-OCH

3C6H

5S

p-OCH

3

N

NS

OO

OH

OCH

3

OCH

3

OCH

3

N

NO

SO

HNN

OCH

3

OCH

3

OCH

368

2c3c4k

5k

o-OCH

3C6H

5S

p-Br

N

NO

SO

HNN

Br

OCH

3

OCH

3

N

NO

SO

HNN

Br

OCH

3

OCH

3

80

2c3d

4l5l

o-OCH

3C6H

5S

p-Cl

N

NS

OO

OH

Cl

OCH

3

OCH

3

N

NO

SO

HNN

Cl

OCH

3

OCH

3

81



CompoundMIC






N

NX

OO

OHR

R

N

N

O

X

R

ROH

NN

N

N

R

R

X

O

OH

N

NR

R

X

O

OH

O

Acetic anhydride

12

34 5

612

3


3a 4a 4e4i 5a 5e 5i3b 4b 4f4j 5b 5f 5j

X

O

S

S

3c 4c 4g4k 5c 5g 5k3d 4d 4h4l 5d 5h 5l

YY

Br

Cl



110∘C 14-Dioxane

1andashc 2andashc

5andashl4andashl

1ndash5 3ndash5


ndashCH3

PhNHNH2


CH3

OCH3

CH3

ondashOCH3C6H4

1998400 2

998400

3998400

4998400

5998400

1998400998400

2998400998400

3998400998400

4998400998400

5998400998400

6998400998400

19984002

998400

3998400

4998400

5998400

6998400

1998400998400 2

998400998400

3998400998400

4998400998400

5998400998400

6998400998400
















3 Experimental














3) 120575 (ppm) 234 (3H s ndashCH

3) 320



3) 120575 (ppm) 2105 2767 2784 11910 12637

12843 12900 12998 13185 13938 14181 14565 1498415469 16322 16583 18202


3) 120575



3) 120575 (ppm) 2168

(ndashCH3) 11915 12855 12863 12877 12911 12955 12961

12967 12981 13182 13972 14296 14862 15994 1686317874 (C=S) 18518


3) 120575 (ppm) 235 (3H s ndashCH

3) 384 (6H



3) 120575 (ppm) 2163 (ndashCH

3) 5614

(ndashOCH3) 11957 12106 12119 12857 12953 12972 12982

13022 13059 13196 14246 14783 15953 16840 17854(C=S) 18494




3) 120575 (ppm) 234 (3H s ndashCH

3) 328 (3H


3) 693 (2H d 119869 = 808Hz


3) 120575 (ppm) 2104 (ndashCH

3) 2751

(NndashCH3) 10742 11589 12600 12946 12957 12979 13919

14781 15350 15921 16528 ESI-MS119898119911 [M +H]+ = 3881



3) 120575 (ppm) 335 (3H s NndashCH

3)


3) 689ndash694 (4H m


3) 120575 (ppm)


3) 5533 (ndashOCH

3) 8608

11445 11627 12413 12747 12954 13239 14808 1518815961 16154 16208 16549 ESI-MS119898119911 [M +H]+ = 4041


3) 120575 (ppm) 328 (3H s NndashCH

3)



3) 120575 (ppm) 2784 (NndashCH

3) 8614 11618 12226 12436

12787 12966 13229 13977 14776 15145 16145 1619516499 ESI-MS119898119911 [M +H]+ = 4533



3) 120575 (ppm) 328 (3H s NndashCH

3) 336 (3H



3) 120575 (ppm) 2771 (Nndash

CH3) 8769 11627 11988 12109 12436 12504 12756 12900

12933 12949 13004 13416 13909 14762 15171 16140 ESI-MS119898119911 [M +H]+ = 4081




3) 690 (2H d


3) 120575 (ppm)

2124 (NndashCH3) 8832 12427 12555 12832 12870 12886

12938 12955 12982 13748 13825 13953 14035 1469316075 16133 16397 18024 (C=S) ESI-MS119898119911 [M +H]+ =5281


3) 120575 (ppm) 382 (3H s



3) 120575 (ppm) 5532

(ndashOCH3) 8835 11449 11641 12745 12868 12937 12944

12947 12953 1312 13976 14032 14713 15980 1608616149 16409 18003 (C=S) ESI-MS119898119911 [M +H]+ = 5454


3) 120575 (ppm) 689 (2H d


3) 120575 (ppm) 8836 10631

11631 12211 12493 12537 12783 12865 12939 1294612966 13233 13611 13909 13989 14674 16055 1613516418 17992 (C=S) ESI-MS119898119911 [M +H]+ = 5920


3) 120575 (ppm) 689 (2H d


3) 120575 (ppm)

8850 10595 11630 12751 12864 12939 12947 1296513423 13866 13948 13989 14659 16096 16135 1642117994 (C=S) ESI-MS119898119911 [M +H]+ = 5481



3) 120575 (ppm) 236


3) 691 (2H d 119869 = 732Hz




3) 120575 (ppm) 2961 (ndashCH

3) 5601

(ndashOCH3) 8553 10537 11220 11272 11594 12102 12557

12851 12956 12967 12979 12999 14016 14836 1546617837 (C=S) ESI-MS119898119911 [M +H]+ = 5881


3)



3) 120575 (ppm)

5532 (ndashOCH3) 8815 11278 11353 11445 11633 12101

12153 12181 12432 12753 12916 12946 12984 1301814675 15493 15955 16776 18532 (C=S) ESI-MS 119898119911[M +H]+ = 6041


3) 120575 (ppm) 378 (6H s ndashOCH

3) 682ndash684 (2H m


3) 120575 (ppm)

5636 (ndashOCH3) 8836 11626 12103 12113 12790 12800

12960 12970 12989 13025 13230 13930 13936 1467715451 15970 16094 16393 17953 (C=S) ESI-MS 119898119911[M +H]+ = 6520


3)



3) 120575 (ppm) 5619 (ndashOCH

3) 8818 11223

11606 12091 12452 12760 12934 12959 12988 1342613888 15489 16060 16397 18519 (C=S) ESI-MS 119898119911[M +H]+ = 6093





90








4 Conclusion




Acknowledgments


References









































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Table1Structureform

ulaandyield

sofcom

poun

ds5andashl

Entry

RX

Ar

Chalcone

(4andashl)

Cyclisedprod

uct(5andashl)

Yield(

)

2a3a4a5a

ndashCH

3O

p-CH

3

N

NO

OO

OH

CH3

H3C

CH3

N

NO

OO

HNN

CH3

H3C

CH3

66

2a3b4b

5b

ndashCH

3O

p-OCH

3

N

NO

OO

OH

OCH

3CH

3

H3C

N

NO

OO

HNN

OCH

3

CH3

H3C

66

2a3c4c5c

ndashCH

3O

p-Br

N

NO

OO

OH

BrCH

3

H3C

N

NO

OO

H

NN

Br

CH3

H3C

80

2a3d

4d5d

ndashCH

3O

p-Cl

N

NO

OO

OH

ClCH

3

H3C

N

NO

OO

H

NN

Cl

CH3

H3C

66


Table1Con

tinued

Entry

RX

Ar

Chalcone

(4andashl)

Cyclisedprod

uct(5andashl)

Yield(

)

2b3a4e5e

C 6H

6S

p-CH

3

N

NS

OO

OH

CH3

N

NO

SO

HNN

CH3

64

2b3b4f5f

C 6H

6S

p-OCH

3

N

NS

OO

OH

OCH

3N

NO

SO

HNN

OCH

380

2b3c4g

5g

C 6H

6S

p-Br

N

NO

SO

HNN

BrN

NO

SO

HNN

Br46

2b3d

4h5h

C 6H

6S

p-Cl

N

NS

OO

OH

ClN

NO

SO

HNN

Cl78


Table1Con

tinued

Entry

RX

Ar

Chalcone

(4andashl)

Cyclisedprod

uct(5andashl)

Yield(

)

2c3a4i5i

o-OCH

3C6H

5S

p-CH

3

N

NS

OO

OH

CH3

OCH

3

OCH

3

N

NO

SO

H

NN

OCH

3

OCH

3

CH3

68

2c3b4j5j

o-OCH

3C6H

5S

p-OCH

3

N

NS

OO

OH

OCH

3

OCH

3

OCH

3

N

NO

SO

HNN

OCH

3

OCH

3

OCH

368

2c3c4k

5k

o-OCH

3C6H

5S

p-Br

N

NO

SO

HNN

Br

OCH

3

OCH

3

N

NO

SO

HNN

Br

OCH

3

OCH

3

80

2c3d

4l5l

o-OCH

3C6H

5S

p-Cl

N

NS

OO

OH

Cl

OCH

3

OCH

3

N

NO

SO

HNN

Cl

OCH

3

OCH

3

81



CompoundMIC






N

NX

OO

OHR

R

N

N

O

X

R

ROH

NN

N

N

R

R

X

O

OH

N

NR

R

X

O

OH

O

Acetic anhydride

12

34 5

612

3


3a 4a 4e4i 5a 5e 5i3b 4b 4f4j 5b 5f 5j

X

O

S

S

3c 4c 4g4k 5c 5g 5k3d 4d 4h4l 5d 5h 5l

YY

Br

Cl



110∘C 14-Dioxane

1andashc 2andashc

5andashl4andashl

1ndash5 3ndash5


ndashCH3

PhNHNH2


CH3

OCH3

CH3

ondashOCH3C6H4

1998400 2

998400

3998400

4998400

5998400

1998400998400

2998400998400

3998400998400

4998400998400

5998400998400

6998400998400

19984002

998400

3998400

4998400

5998400

6998400

1998400998400 2

998400998400

3998400998400

4998400998400

5998400998400

6998400998400
















3 Experimental














3) 120575 (ppm) 234 (3H s ndashCH

3) 320



3) 120575 (ppm) 2105 2767 2784 11910 12637

12843 12900 12998 13185 13938 14181 14565 1498415469 16322 16583 18202


3) 120575



3) 120575 (ppm) 2168

(ndashCH3) 11915 12855 12863 12877 12911 12955 12961

12967 12981 13182 13972 14296 14862 15994 1686317874 (C=S) 18518


3) 120575 (ppm) 235 (3H s ndashCH

3) 384 (6H



3) 120575 (ppm) 2163 (ndashCH

3) 5614

(ndashOCH3) 11957 12106 12119 12857 12953 12972 12982

13022 13059 13196 14246 14783 15953 16840 17854(C=S) 18494




3) 120575 (ppm) 234 (3H s ndashCH

3) 328 (3H


3) 693 (2H d 119869 = 808Hz


3) 120575 (ppm) 2104 (ndashCH

3) 2751

(NndashCH3) 10742 11589 12600 12946 12957 12979 13919

14781 15350 15921 16528 ESI-MS119898119911 [M +H]+ = 3881



3) 120575 (ppm) 335 (3H s NndashCH

3)


3) 689ndash694 (4H m


3) 120575 (ppm)


3) 5533 (ndashOCH

3) 8608

11445 11627 12413 12747 12954 13239 14808 1518815961 16154 16208 16549 ESI-MS119898119911 [M +H]+ = 4041


3) 120575 (ppm) 328 (3H s NndashCH

3)



3) 120575 (ppm) 2784 (NndashCH

3) 8614 11618 12226 12436

12787 12966 13229 13977 14776 15145 16145 1619516499 ESI-MS119898119911 [M +H]+ = 4533



3) 120575 (ppm) 328 (3H s NndashCH

3) 336 (3H



3) 120575 (ppm) 2771 (Nndash

CH3) 8769 11627 11988 12109 12436 12504 12756 12900

12933 12949 13004 13416 13909 14762 15171 16140 ESI-MS119898119911 [M +H]+ = 4081




3) 690 (2H d


3) 120575 (ppm)

2124 (NndashCH3) 8832 12427 12555 12832 12870 12886

12938 12955 12982 13748 13825 13953 14035 1469316075 16133 16397 18024 (C=S) ESI-MS119898119911 [M +H]+ =5281


3) 120575 (ppm) 382 (3H s



3) 120575 (ppm) 5532

(ndashOCH3) 8835 11449 11641 12745 12868 12937 12944

12947 12953 1312 13976 14032 14713 15980 1608616149 16409 18003 (C=S) ESI-MS119898119911 [M +H]+ = 5454


3) 120575 (ppm) 689 (2H d


3) 120575 (ppm) 8836 10631

11631 12211 12493 12537 12783 12865 12939 1294612966 13233 13611 13909 13989 14674 16055 1613516418 17992 (C=S) ESI-MS119898119911 [M +H]+ = 5920


3) 120575 (ppm) 689 (2H d


3) 120575 (ppm)

8850 10595 11630 12751 12864 12939 12947 1296513423 13866 13948 13989 14659 16096 16135 1642117994 (C=S) ESI-MS119898119911 [M +H]+ = 5481



3) 120575 (ppm) 236


3) 691 (2H d 119869 = 732Hz




3) 120575 (ppm) 2961 (ndashCH

3) 5601

(ndashOCH3) 8553 10537 11220 11272 11594 12102 12557

12851 12956 12967 12979 12999 14016 14836 1546617837 (C=S) ESI-MS119898119911 [M +H]+ = 5881


3)



3) 120575 (ppm)

5532 (ndashOCH3) 8815 11278 11353 11445 11633 12101

12153 12181 12432 12753 12916 12946 12984 1301814675 15493 15955 16776 18532 (C=S) ESI-MS 119898119911[M +H]+ = 6041


3) 120575 (ppm) 378 (6H s ndashOCH

3) 682ndash684 (2H m


3) 120575 (ppm)

5636 (ndashOCH3) 8836 11626 12103 12113 12790 12800

12960 12970 12989 13025 13230 13930 13936 1467715451 15970 16094 16393 17953 (C=S) ESI-MS 119898119911[M +H]+ = 6520


3)



3) 120575 (ppm) 5619 (ndashOCH

3) 8818 11223

11606 12091 12452 12760 12934 12959 12988 1342613888 15489 16060 16397 18519 (C=S) ESI-MS 119898119911[M +H]+ = 6093





90








4 Conclusion




Acknowledgments


References









































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Table1Con

tinued

Entry

RX

Ar

Chalcone

(4andashl)

Cyclisedprod

uct(5andashl)

Yield(

)

2b3a4e5e

C 6H

6S

p-CH

3

N

NS

OO

OH

CH3

N

NO

SO

HNN

CH3

64

2b3b4f5f

C 6H

6S

p-OCH

3

N

NS

OO

OH

OCH

3N

NO

SO

HNN

OCH

380

2b3c4g

5g

C 6H

6S

p-Br

N

NO

SO

HNN

BrN

NO

SO

HNN

Br46

2b3d

4h5h

C 6H

6S

p-Cl

N

NS

OO

OH

ClN

NO

SO

HNN

Cl78


Table1Con

tinued

Entry

RX

Ar

Chalcone

(4andashl)

Cyclisedprod

uct(5andashl)

Yield(

)

2c3a4i5i

o-OCH

3C6H

5S

p-CH

3

N

NS

OO

OH

CH3

OCH

3

OCH

3

N

NO

SO

H

NN

OCH

3

OCH

3

CH3

68

2c3b4j5j

o-OCH

3C6H

5S

p-OCH

3

N

NS

OO

OH

OCH

3

OCH

3

OCH

3

N

NO

SO

HNN

OCH

3

OCH

3

OCH

368

2c3c4k

5k

o-OCH

3C6H

5S

p-Br

N

NO

SO

HNN

Br

OCH

3

OCH

3

N

NO

SO

HNN

Br

OCH

3

OCH

3

80

2c3d

4l5l

o-OCH

3C6H

5S

p-Cl

N

NS

OO

OH

Cl

OCH

3

OCH

3

N

NO

SO

HNN

Cl

OCH

3

OCH

3

81



CompoundMIC






N

NX

OO

OHR

R

N

N

O

X

R

ROH

NN

N

N

R

R

X

O

OH

N

NR

R

X

O

OH

O

Acetic anhydride

12

34 5

612

3


3a 4a 4e4i 5a 5e 5i3b 4b 4f4j 5b 5f 5j

X

O

S

S

3c 4c 4g4k 5c 5g 5k3d 4d 4h4l 5d 5h 5l

YY

Br

Cl



110∘C 14-Dioxane

1andashc 2andashc

5andashl4andashl

1ndash5 3ndash5


ndashCH3

PhNHNH2


CH3

OCH3

CH3

ondashOCH3C6H4

1998400 2

998400

3998400

4998400

5998400

1998400998400

2998400998400

3998400998400

4998400998400

5998400998400

6998400998400

19984002

998400

3998400

4998400

5998400

6998400

1998400998400 2

998400998400

3998400998400

4998400998400

5998400998400

6998400998400
















3 Experimental














3) 120575 (ppm) 234 (3H s ndashCH

3) 320



3) 120575 (ppm) 2105 2767 2784 11910 12637

12843 12900 12998 13185 13938 14181 14565 1498415469 16322 16583 18202


3) 120575



3) 120575 (ppm) 2168

(ndashCH3) 11915 12855 12863 12877 12911 12955 12961

12967 12981 13182 13972 14296 14862 15994 1686317874 (C=S) 18518


3) 120575 (ppm) 235 (3H s ndashCH

3) 384 (6H



3) 120575 (ppm) 2163 (ndashCH

3) 5614

(ndashOCH3) 11957 12106 12119 12857 12953 12972 12982

13022 13059 13196 14246 14783 15953 16840 17854(C=S) 18494




3) 120575 (ppm) 234 (3H s ndashCH

3) 328 (3H


3) 693 (2H d 119869 = 808Hz


3) 120575 (ppm) 2104 (ndashCH

3) 2751

(NndashCH3) 10742 11589 12600 12946 12957 12979 13919

14781 15350 15921 16528 ESI-MS119898119911 [M +H]+ = 3881



3) 120575 (ppm) 335 (3H s NndashCH

3)


3) 689ndash694 (4H m


3) 120575 (ppm)


3) 5533 (ndashOCH

3) 8608

11445 11627 12413 12747 12954 13239 14808 1518815961 16154 16208 16549 ESI-MS119898119911 [M +H]+ = 4041


3) 120575 (ppm) 328 (3H s NndashCH

3)



3) 120575 (ppm) 2784 (NndashCH

3) 8614 11618 12226 12436

12787 12966 13229 13977 14776 15145 16145 1619516499 ESI-MS119898119911 [M +H]+ = 4533



3) 120575 (ppm) 328 (3H s NndashCH

3) 336 (3H



3) 120575 (ppm) 2771 (Nndash

CH3) 8769 11627 11988 12109 12436 12504 12756 12900

12933 12949 13004 13416 13909 14762 15171 16140 ESI-MS119898119911 [M +H]+ = 4081




3) 690 (2H d


3) 120575 (ppm)

2124 (NndashCH3) 8832 12427 12555 12832 12870 12886

12938 12955 12982 13748 13825 13953 14035 1469316075 16133 16397 18024 (C=S) ESI-MS119898119911 [M +H]+ =5281


3) 120575 (ppm) 382 (3H s



3) 120575 (ppm) 5532

(ndashOCH3) 8835 11449 11641 12745 12868 12937 12944

12947 12953 1312 13976 14032 14713 15980 1608616149 16409 18003 (C=S) ESI-MS119898119911 [M +H]+ = 5454


3) 120575 (ppm) 689 (2H d


3) 120575 (ppm) 8836 10631

11631 12211 12493 12537 12783 12865 12939 1294612966 13233 13611 13909 13989 14674 16055 1613516418 17992 (C=S) ESI-MS119898119911 [M +H]+ = 5920


3) 120575 (ppm) 689 (2H d


3) 120575 (ppm)

8850 10595 11630 12751 12864 12939 12947 1296513423 13866 13948 13989 14659 16096 16135 1642117994 (C=S) ESI-MS119898119911 [M +H]+ = 5481



3) 120575 (ppm) 236


3) 691 (2H d 119869 = 732Hz




3) 120575 (ppm) 2961 (ndashCH

3) 5601

(ndashOCH3) 8553 10537 11220 11272 11594 12102 12557

12851 12956 12967 12979 12999 14016 14836 1546617837 (C=S) ESI-MS119898119911 [M +H]+ = 5881


3)



3) 120575 (ppm)

5532 (ndashOCH3) 8815 11278 11353 11445 11633 12101

12153 12181 12432 12753 12916 12946 12984 1301814675 15493 15955 16776 18532 (C=S) ESI-MS 119898119911[M +H]+ = 6041


3) 120575 (ppm) 378 (6H s ndashOCH

3) 682ndash684 (2H m


3) 120575 (ppm)

5636 (ndashOCH3) 8836 11626 12103 12113 12790 12800

12960 12970 12989 13025 13230 13930 13936 1467715451 15970 16094 16393 17953 (C=S) ESI-MS 119898119911[M +H]+ = 6520


3)



3) 120575 (ppm) 5619 (ndashOCH

3) 8818 11223

11606 12091 12452 12760 12934 12959 12988 1342613888 15489 16060 16397 18519 (C=S) ESI-MS 119898119911[M +H]+ = 6093





90








4 Conclusion




Acknowledgments


References









































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Table1Con

tinued

Entry

RX

Ar

Chalcone

(4andashl)

Cyclisedprod

uct(5andashl)

Yield(

)

2c3a4i5i

o-OCH

3C6H

5S

p-CH

3

N

NS

OO

OH

CH3

OCH

3

OCH

3

N

NO

SO

H

NN

OCH

3

OCH

3

CH3

68

2c3b4j5j

o-OCH

3C6H

5S

p-OCH

3

N

NS

OO

OH

OCH

3

OCH

3

OCH

3

N

NO

SO

HNN

OCH

3

OCH

3

OCH

368

2c3c4k

5k

o-OCH

3C6H

5S

p-Br

N

NO

SO

HNN

Br

OCH

3

OCH

3

N

NO

SO

HNN

Br

OCH

3

OCH

3

80

2c3d

4l5l

o-OCH

3C6H

5S

p-Cl

N

NS

OO

OH

Cl

OCH

3

OCH

3

N

NO

SO

HNN

Cl

OCH

3

OCH

3

81



CompoundMIC






N

NX

OO

OHR

R

N

N

O

X

R

ROH

NN

N

N

R

R

X

O

OH

N

NR

R

X

O

OH

O

Acetic anhydride

12

34 5

612

3


3a 4a 4e4i 5a 5e 5i3b 4b 4f4j 5b 5f 5j

X

O

S

S

3c 4c 4g4k 5c 5g 5k3d 4d 4h4l 5d 5h 5l

YY

Br

Cl



110∘C 14-Dioxane

1andashc 2andashc

5andashl4andashl

1ndash5 3ndash5


ndashCH3

PhNHNH2


CH3

OCH3

CH3

ondashOCH3C6H4

1998400 2

998400

3998400

4998400

5998400

1998400998400

2998400998400

3998400998400

4998400998400

5998400998400

6998400998400

19984002

998400

3998400

4998400

5998400

6998400

1998400998400 2

998400998400

3998400998400

4998400998400

5998400998400

6998400998400
















3 Experimental














3) 120575 (ppm) 234 (3H s ndashCH

3) 320



3) 120575 (ppm) 2105 2767 2784 11910 12637

12843 12900 12998 13185 13938 14181 14565 1498415469 16322 16583 18202


3) 120575



3) 120575 (ppm) 2168

(ndashCH3) 11915 12855 12863 12877 12911 12955 12961

12967 12981 13182 13972 14296 14862 15994 1686317874 (C=S) 18518


3) 120575 (ppm) 235 (3H s ndashCH

3) 384 (6H



3) 120575 (ppm) 2163 (ndashCH

3) 5614

(ndashOCH3) 11957 12106 12119 12857 12953 12972 12982

13022 13059 13196 14246 14783 15953 16840 17854(C=S) 18494




3) 120575 (ppm) 234 (3H s ndashCH

3) 328 (3H


3) 693 (2H d 119869 = 808Hz


3) 120575 (ppm) 2104 (ndashCH

3) 2751

(NndashCH3) 10742 11589 12600 12946 12957 12979 13919

14781 15350 15921 16528 ESI-MS119898119911 [M +H]+ = 3881



3) 120575 (ppm) 335 (3H s NndashCH

3)


3) 689ndash694 (4H m


3) 120575 (ppm)


3) 5533 (ndashOCH

3) 8608

11445 11627 12413 12747 12954 13239 14808 1518815961 16154 16208 16549 ESI-MS119898119911 [M +H]+ = 4041


3) 120575 (ppm) 328 (3H s NndashCH

3)



3) 120575 (ppm) 2784 (NndashCH

3) 8614 11618 12226 12436

12787 12966 13229 13977 14776 15145 16145 1619516499 ESI-MS119898119911 [M +H]+ = 4533



3) 120575 (ppm) 328 (3H s NndashCH

3) 336 (3H



3) 120575 (ppm) 2771 (Nndash

CH3) 8769 11627 11988 12109 12436 12504 12756 12900

12933 12949 13004 13416 13909 14762 15171 16140 ESI-MS119898119911 [M +H]+ = 4081




3) 690 (2H d


3) 120575 (ppm)

2124 (NndashCH3) 8832 12427 12555 12832 12870 12886

12938 12955 12982 13748 13825 13953 14035 1469316075 16133 16397 18024 (C=S) ESI-MS119898119911 [M +H]+ =5281


3) 120575 (ppm) 382 (3H s



3) 120575 (ppm) 5532

(ndashOCH3) 8835 11449 11641 12745 12868 12937 12944

12947 12953 1312 13976 14032 14713 15980 1608616149 16409 18003 (C=S) ESI-MS119898119911 [M +H]+ = 5454


3) 120575 (ppm) 689 (2H d


3) 120575 (ppm) 8836 10631

11631 12211 12493 12537 12783 12865 12939 1294612966 13233 13611 13909 13989 14674 16055 1613516418 17992 (C=S) ESI-MS119898119911 [M +H]+ = 5920


3) 120575 (ppm) 689 (2H d


3) 120575 (ppm)

8850 10595 11630 12751 12864 12939 12947 1296513423 13866 13948 13989 14659 16096 16135 1642117994 (C=S) ESI-MS119898119911 [M +H]+ = 5481



3) 120575 (ppm) 236


3) 691 (2H d 119869 = 732Hz




3) 120575 (ppm) 2961 (ndashCH

3) 5601

(ndashOCH3) 8553 10537 11220 11272 11594 12102 12557

12851 12956 12967 12979 12999 14016 14836 1546617837 (C=S) ESI-MS119898119911 [M +H]+ = 5881


3)



3) 120575 (ppm)

5532 (ndashOCH3) 8815 11278 11353 11445 11633 12101

12153 12181 12432 12753 12916 12946 12984 1301814675 15493 15955 16776 18532 (C=S) ESI-MS 119898119911[M +H]+ = 6041


3) 120575 (ppm) 378 (6H s ndashOCH

3) 682ndash684 (2H m


3) 120575 (ppm)

5636 (ndashOCH3) 8836 11626 12103 12113 12790 12800

12960 12970 12989 13025 13230 13930 13936 1467715451 15970 16094 16393 17953 (C=S) ESI-MS 119898119911[M +H]+ = 6520


3)



3) 120575 (ppm) 5619 (ndashOCH

3) 8818 11223

11606 12091 12452 12760 12934 12959 12988 1342613888 15489 16060 16397 18519 (C=S) ESI-MS 119898119911[M +H]+ = 6093





90








4 Conclusion




Acknowledgments


References









































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



CompoundMIC






N

NX

OO

OHR

R

N

N

O

X

R

ROH

NN

N

N

R

R

X

O

OH

N

NR

R

X

O

OH

O

Acetic anhydride

12

34 5

612

3


3a 4a 4e4i 5a 5e 5i3b 4b 4f4j 5b 5f 5j

X

O

S

S

3c 4c 4g4k 5c 5g 5k3d 4d 4h4l 5d 5h 5l

YY

Br

Cl



110∘C 14-Dioxane

1andashc 2andashc

5andashl4andashl

1ndash5 3ndash5


ndashCH3

PhNHNH2


CH3

OCH3

CH3

ondashOCH3C6H4

1998400 2

998400

3998400

4998400

5998400

1998400998400

2998400998400

3998400998400

4998400998400

5998400998400

6998400998400

19984002

998400

3998400

4998400

5998400

6998400

1998400998400 2

998400998400

3998400998400

4998400998400

5998400998400

6998400998400
















3 Experimental














3) 120575 (ppm) 234 (3H s ndashCH

3) 320



3) 120575 (ppm) 2105 2767 2784 11910 12637

12843 12900 12998 13185 13938 14181 14565 1498415469 16322 16583 18202


3) 120575



3) 120575 (ppm) 2168

(ndashCH3) 11915 12855 12863 12877 12911 12955 12961

12967 12981 13182 13972 14296 14862 15994 1686317874 (C=S) 18518


3) 120575 (ppm) 235 (3H s ndashCH

3) 384 (6H



3) 120575 (ppm) 2163 (ndashCH

3) 5614

(ndashOCH3) 11957 12106 12119 12857 12953 12972 12982

13022 13059 13196 14246 14783 15953 16840 17854(C=S) 18494




3) 120575 (ppm) 234 (3H s ndashCH

3) 328 (3H


3) 693 (2H d 119869 = 808Hz


3) 120575 (ppm) 2104 (ndashCH

3) 2751

(NndashCH3) 10742 11589 12600 12946 12957 12979 13919

14781 15350 15921 16528 ESI-MS119898119911 [M +H]+ = 3881



3) 120575 (ppm) 335 (3H s NndashCH

3)


3) 689ndash694 (4H m


3) 120575 (ppm)


3) 5533 (ndashOCH

3) 8608

11445 11627 12413 12747 12954 13239 14808 1518815961 16154 16208 16549 ESI-MS119898119911 [M +H]+ = 4041


3) 120575 (ppm) 328 (3H s NndashCH

3)



3) 120575 (ppm) 2784 (NndashCH

3) 8614 11618 12226 12436

12787 12966 13229 13977 14776 15145 16145 1619516499 ESI-MS119898119911 [M +H]+ = 4533



3) 120575 (ppm) 328 (3H s NndashCH

3) 336 (3H



3) 120575 (ppm) 2771 (Nndash

CH3) 8769 11627 11988 12109 12436 12504 12756 12900

12933 12949 13004 13416 13909 14762 15171 16140 ESI-MS119898119911 [M +H]+ = 4081




3) 690 (2H d


3) 120575 (ppm)

2124 (NndashCH3) 8832 12427 12555 12832 12870 12886

12938 12955 12982 13748 13825 13953 14035 1469316075 16133 16397 18024 (C=S) ESI-MS119898119911 [M +H]+ =5281


3) 120575 (ppm) 382 (3H s



3) 120575 (ppm) 5532

(ndashOCH3) 8835 11449 11641 12745 12868 12937 12944

12947 12953 1312 13976 14032 14713 15980 1608616149 16409 18003 (C=S) ESI-MS119898119911 [M +H]+ = 5454


3) 120575 (ppm) 689 (2H d


3) 120575 (ppm) 8836 10631

11631 12211 12493 12537 12783 12865 12939 1294612966 13233 13611 13909 13989 14674 16055 1613516418 17992 (C=S) ESI-MS119898119911 [M +H]+ = 5920


3) 120575 (ppm) 689 (2H d


3) 120575 (ppm)

8850 10595 11630 12751 12864 12939 12947 1296513423 13866 13948 13989 14659 16096 16135 1642117994 (C=S) ESI-MS119898119911 [M +H]+ = 5481



3) 120575 (ppm) 236


3) 691 (2H d 119869 = 732Hz




3) 120575 (ppm) 2961 (ndashCH

3) 5601

(ndashOCH3) 8553 10537 11220 11272 11594 12102 12557

12851 12956 12967 12979 12999 14016 14836 1546617837 (C=S) ESI-MS119898119911 [M +H]+ = 5881


3)



3) 120575 (ppm)

5532 (ndashOCH3) 8815 11278 11353 11445 11633 12101

12153 12181 12432 12753 12916 12946 12984 1301814675 15493 15955 16776 18532 (C=S) ESI-MS 119898119911[M +H]+ = 6041


3) 120575 (ppm) 378 (6H s ndashOCH

3) 682ndash684 (2H m


3) 120575 (ppm)

5636 (ndashOCH3) 8836 11626 12103 12113 12790 12800

12960 12970 12989 13025 13230 13930 13936 1467715451 15970 16094 16393 17953 (C=S) ESI-MS 119898119911[M +H]+ = 6520


3)



3) 120575 (ppm) 5619 (ndashOCH

3) 8818 11223

11606 12091 12452 12760 12934 12959 12988 1342613888 15489 16060 16397 18519 (C=S) ESI-MS 119898119911[M +H]+ = 6093





90








4 Conclusion




Acknowledgments


References









































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of















3 Experimental














3) 120575 (ppm) 234 (3H s ndashCH

3) 320



3) 120575 (ppm) 2105 2767 2784 11910 12637

12843 12900 12998 13185 13938 14181 14565 1498415469 16322 16583 18202


3) 120575



3) 120575 (ppm) 2168

(ndashCH3) 11915 12855 12863 12877 12911 12955 12961

12967 12981 13182 13972 14296 14862 15994 1686317874 (C=S) 18518


3) 120575 (ppm) 235 (3H s ndashCH

3) 384 (6H



3) 120575 (ppm) 2163 (ndashCH

3) 5614

(ndashOCH3) 11957 12106 12119 12857 12953 12972 12982

13022 13059 13196 14246 14783 15953 16840 17854(C=S) 18494




3) 120575 (ppm) 234 (3H s ndashCH

3) 328 (3H


3) 693 (2H d 119869 = 808Hz


3) 120575 (ppm) 2104 (ndashCH

3) 2751

(NndashCH3) 10742 11589 12600 12946 12957 12979 13919

14781 15350 15921 16528 ESI-MS119898119911 [M +H]+ = 3881



3) 120575 (ppm) 335 (3H s NndashCH

3)


3) 689ndash694 (4H m


3) 120575 (ppm)


3) 5533 (ndashOCH

3) 8608

11445 11627 12413 12747 12954 13239 14808 1518815961 16154 16208 16549 ESI-MS119898119911 [M +H]+ = 4041


3) 120575 (ppm) 328 (3H s NndashCH

3)



3) 120575 (ppm) 2784 (NndashCH

3) 8614 11618 12226 12436

12787 12966 13229 13977 14776 15145 16145 1619516499 ESI-MS119898119911 [M +H]+ = 4533



3) 120575 (ppm) 328 (3H s NndashCH

3) 336 (3H



3) 120575 (ppm) 2771 (Nndash

CH3) 8769 11627 11988 12109 12436 12504 12756 12900

12933 12949 13004 13416 13909 14762 15171 16140 ESI-MS119898119911 [M +H]+ = 4081




3) 690 (2H d


3) 120575 (ppm)

2124 (NndashCH3) 8832 12427 12555 12832 12870 12886

12938 12955 12982 13748 13825 13953 14035 1469316075 16133 16397 18024 (C=S) ESI-MS119898119911 [M +H]+ =5281


3) 120575 (ppm) 382 (3H s



3) 120575 (ppm) 5532

(ndashOCH3) 8835 11449 11641 12745 12868 12937 12944

12947 12953 1312 13976 14032 14713 15980 1608616149 16409 18003 (C=S) ESI-MS119898119911 [M +H]+ = 5454


3) 120575 (ppm) 689 (2H d


3) 120575 (ppm) 8836 10631

11631 12211 12493 12537 12783 12865 12939 1294612966 13233 13611 13909 13989 14674 16055 1613516418 17992 (C=S) ESI-MS119898119911 [M +H]+ = 5920


3) 120575 (ppm) 689 (2H d


3) 120575 (ppm)

8850 10595 11630 12751 12864 12939 12947 1296513423 13866 13948 13989 14659 16096 16135 1642117994 (C=S) ESI-MS119898119911 [M +H]+ = 5481



3) 120575 (ppm) 236


3) 691 (2H d 119869 = 732Hz




3) 120575 (ppm) 2961 (ndashCH

3) 5601

(ndashOCH3) 8553 10537 11220 11272 11594 12102 12557

12851 12956 12967 12979 12999 14016 14836 1546617837 (C=S) ESI-MS119898119911 [M +H]+ = 5881


3)



3) 120575 (ppm)

5532 (ndashOCH3) 8815 11278 11353 11445 11633 12101

12153 12181 12432 12753 12916 12946 12984 1301814675 15493 15955 16776 18532 (C=S) ESI-MS 119898119911[M +H]+ = 6041


3) 120575 (ppm) 378 (6H s ndashOCH

3) 682ndash684 (2H m


3) 120575 (ppm)

5636 (ndashOCH3) 8836 11626 12103 12113 12790 12800

12960 12970 12989 13025 13230 13930 13936 1467715451 15970 16094 16393 17953 (C=S) ESI-MS 119898119911[M +H]+ = 6520


3)



3) 120575 (ppm) 5619 (ndashOCH

3) 8818 11223

11606 12091 12452 12760 12934 12959 12988 1342613888 15489 16060 16397 18519 (C=S) ESI-MS 119898119911[M +H]+ = 6093





90








4 Conclusion




Acknowledgments


References









































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of










3) 120575 (ppm) 234 (3H s ndashCH

3) 320



3) 120575 (ppm) 2105 2767 2784 11910 12637

12843 12900 12998 13185 13938 14181 14565 1498415469 16322 16583 18202


3) 120575



3) 120575 (ppm) 2168

(ndashCH3) 11915 12855 12863 12877 12911 12955 12961

12967 12981 13182 13972 14296 14862 15994 1686317874 (C=S) 18518


3) 120575 (ppm) 235 (3H s ndashCH

3) 384 (6H



3) 120575 (ppm) 2163 (ndashCH

3) 5614

(ndashOCH3) 11957 12106 12119 12857 12953 12972 12982

13022 13059 13196 14246 14783 15953 16840 17854(C=S) 18494




3) 120575 (ppm) 234 (3H s ndashCH

3) 328 (3H


3) 693 (2H d 119869 = 808Hz


3) 120575 (ppm) 2104 (ndashCH

3) 2751

(NndashCH3) 10742 11589 12600 12946 12957 12979 13919

14781 15350 15921 16528 ESI-MS119898119911 [M +H]+ = 3881



3) 120575 (ppm) 335 (3H s NndashCH

3)


3) 689ndash694 (4H m


3) 120575 (ppm)


3) 5533 (ndashOCH

3) 8608

11445 11627 12413 12747 12954 13239 14808 1518815961 16154 16208 16549 ESI-MS119898119911 [M +H]+ = 4041


3) 120575 (ppm) 328 (3H s NndashCH

3)



3) 120575 (ppm) 2784 (NndashCH

3) 8614 11618 12226 12436

12787 12966 13229 13977 14776 15145 16145 1619516499 ESI-MS119898119911 [M +H]+ = 4533



3) 120575 (ppm) 328 (3H s NndashCH

3) 336 (3H



3) 120575 (ppm) 2771 (Nndash

CH3) 8769 11627 11988 12109 12436 12504 12756 12900

12933 12949 13004 13416 13909 14762 15171 16140 ESI-MS119898119911 [M +H]+ = 4081




3) 690 (2H d


3) 120575 (ppm)

2124 (NndashCH3) 8832 12427 12555 12832 12870 12886

12938 12955 12982 13748 13825 13953 14035 1469316075 16133 16397 18024 (C=S) ESI-MS119898119911 [M +H]+ =5281


3) 120575 (ppm) 382 (3H s



3) 120575 (ppm) 5532

(ndashOCH3) 8835 11449 11641 12745 12868 12937 12944

12947 12953 1312 13976 14032 14713 15980 1608616149 16409 18003 (C=S) ESI-MS119898119911 [M +H]+ = 5454


3) 120575 (ppm) 689 (2H d


3) 120575 (ppm) 8836 10631

11631 12211 12493 12537 12783 12865 12939 1294612966 13233 13611 13909 13989 14674 16055 1613516418 17992 (C=S) ESI-MS119898119911 [M +H]+ = 5920


3) 120575 (ppm) 689 (2H d


3) 120575 (ppm)

8850 10595 11630 12751 12864 12939 12947 1296513423 13866 13948 13989 14659 16096 16135 1642117994 (C=S) ESI-MS119898119911 [M +H]+ = 5481



3) 120575 (ppm) 236


3) 691 (2H d 119869 = 732Hz




3) 120575 (ppm) 2961 (ndashCH

3) 5601

(ndashOCH3) 8553 10537 11220 11272 11594 12102 12557

12851 12956 12967 12979 12999 14016 14836 1546617837 (C=S) ESI-MS119898119911 [M +H]+ = 5881


3)



3) 120575 (ppm)

5532 (ndashOCH3) 8815 11278 11353 11445 11633 12101

12153 12181 12432 12753 12916 12946 12984 1301814675 15493 15955 16776 18532 (C=S) ESI-MS 119898119911[M +H]+ = 6041


3) 120575 (ppm) 378 (6H s ndashOCH

3) 682ndash684 (2H m


3) 120575 (ppm)

5636 (ndashOCH3) 8836 11626 12103 12113 12790 12800

12960 12970 12989 13025 13230 13930 13936 1467715451 15970 16094 16393 17953 (C=S) ESI-MS 119898119911[M +H]+ = 6520


3)



3) 120575 (ppm) 5619 (ndashOCH

3) 8818 11223

11606 12091 12452 12760 12934 12959 12988 1342613888 15489 16060 16397 18519 (C=S) ESI-MS 119898119911[M +H]+ = 6093





90








4 Conclusion




Acknowledgments


References









































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



3) 120575 (ppm) 234 (3H s ndashCH

3) 328 (3H


3) 693 (2H d 119869 = 808Hz


3) 120575 (ppm) 2104 (ndashCH

3) 2751

(NndashCH3) 10742 11589 12600 12946 12957 12979 13919

14781 15350 15921 16528 ESI-MS119898119911 [M +H]+ = 3881



3) 120575 (ppm) 335 (3H s NndashCH

3)


3) 689ndash694 (4H m


3) 120575 (ppm)


3) 5533 (ndashOCH

3) 8608

11445 11627 12413 12747 12954 13239 14808 1518815961 16154 16208 16549 ESI-MS119898119911 [M +H]+ = 4041


3) 120575 (ppm) 328 (3H s NndashCH

3)



3) 120575 (ppm) 2784 (NndashCH

3) 8614 11618 12226 12436

12787 12966 13229 13977 14776 15145 16145 1619516499 ESI-MS119898119911 [M +H]+ = 4533



3) 120575 (ppm) 328 (3H s NndashCH

3) 336 (3H



3) 120575 (ppm) 2771 (Nndash

CH3) 8769 11627 11988 12109 12436 12504 12756 12900

12933 12949 13004 13416 13909 14762 15171 16140 ESI-MS119898119911 [M +H]+ = 4081




3) 690 (2H d


3) 120575 (ppm)

2124 (NndashCH3) 8832 12427 12555 12832 12870 12886

12938 12955 12982 13748 13825 13953 14035 1469316075 16133 16397 18024 (C=S) ESI-MS119898119911 [M +H]+ =5281


3) 120575 (ppm) 382 (3H s



3) 120575 (ppm) 5532

(ndashOCH3) 8835 11449 11641 12745 12868 12937 12944

12947 12953 1312 13976 14032 14713 15980 1608616149 16409 18003 (C=S) ESI-MS119898119911 [M +H]+ = 5454


3) 120575 (ppm) 689 (2H d


3) 120575 (ppm) 8836 10631

11631 12211 12493 12537 12783 12865 12939 1294612966 13233 13611 13909 13989 14674 16055 1613516418 17992 (C=S) ESI-MS119898119911 [M +H]+ = 5920


3) 120575 (ppm) 689 (2H d


3) 120575 (ppm)

8850 10595 11630 12751 12864 12939 12947 1296513423 13866 13948 13989 14659 16096 16135 1642117994 (C=S) ESI-MS119898119911 [M +H]+ = 5481



3) 120575 (ppm) 236


3) 691 (2H d 119869 = 732Hz




3) 120575 (ppm) 2961 (ndashCH

3) 5601

(ndashOCH3) 8553 10537 11220 11272 11594 12102 12557

12851 12956 12967 12979 12999 14016 14836 1546617837 (C=S) ESI-MS119898119911 [M +H]+ = 5881


3)



3) 120575 (ppm)

5532 (ndashOCH3) 8815 11278 11353 11445 11633 12101

12153 12181 12432 12753 12916 12946 12984 1301814675 15493 15955 16776 18532 (C=S) ESI-MS 119898119911[M +H]+ = 6041


3) 120575 (ppm) 378 (6H s ndashOCH

3) 682ndash684 (2H m


3) 120575 (ppm)

5636 (ndashOCH3) 8836 11626 12103 12113 12790 12800

12960 12970 12989 13025 13230 13930 13936 1467715451 15970 16094 16393 17953 (C=S) ESI-MS 119898119911[M +H]+ = 6520


3)



3) 120575 (ppm) 5619 (ndashOCH

3) 8818 11223

11606 12091 12452 12760 12934 12959 12988 1342613888 15489 16060 16397 18519 (C=S) ESI-MS 119898119911[M +H]+ = 6093





90








4 Conclusion




Acknowledgments


References









































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



3) 120575 (ppm) 2961 (ndashCH

3) 5601

(ndashOCH3) 8553 10537 11220 11272 11594 12102 12557

12851 12956 12967 12979 12999 14016 14836 1546617837 (C=S) ESI-MS119898119911 [M +H]+ = 5881


3)



3) 120575 (ppm)

5532 (ndashOCH3) 8815 11278 11353 11445 11633 12101

12153 12181 12432 12753 12916 12946 12984 1301814675 15493 15955 16776 18532 (C=S) ESI-MS 119898119911[M +H]+ = 6041


3) 120575 (ppm) 378 (6H s ndashOCH

3) 682ndash684 (2H m


3) 120575 (ppm)

5636 (ndashOCH3) 8836 11626 12103 12113 12790 12800

12960 12970 12989 13025 13230 13930 13936 1467715451 15970 16094 16393 17953 (C=S) ESI-MS 119898119911[M +H]+ = 6520


3)



3) 120575 (ppm) 5619 (ndashOCH

3) 8818 11223

11606 12091 12452 12760 12934 12959 12988 1342613888 15489 16060 16397 18519 (C=S) ESI-MS 119898119911[M +H]+ = 6093





90








4 Conclusion




Acknowledgments


References









































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of






4 Conclusion




Acknowledgments


References









































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

research article synthesis and antimicrobial studies of...

Documents