research article new conjugates of quinoxaline as potent...

Research ArticleNew Conjugates of Quinoxaline as Potent Antitubercular andAntibacterial Agents

Ramalingam Peraman1 Rajendran Kuppusamy2

Sunil Kumar Killi3 and Y Padmanabha Reddy1

1Raghavendra Institute of Pharmaceutical Education and Research (RIPER) Andhra Pradesh 5215002 India2College of Pharmacy Gulf Medical University Ajman UAE3Medicinal Chemistry Division National Institute of Pharmaceutical Education and Research (NIPER) Kolkata 700032 India

Correspondence should be addressed to Ramalingam Peraman drramalingampgmailcom

Received 28 October 2015 Revised 10 February 2016 Accepted 14 February 2016

Academic Editor Maria Cristina Breschi

Copyright copy 2016 Ramalingam Peraman et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Considering quinoxaline as a privileged structure for the design of potent intercalating agents some new sugar conjugates ofquinoxaline were synthesized and characterized by IR 1HNMR 13CNMR andmass spectral data In vitro testing for antitubercularand antimicrobial activities was performed against Mycobacterium tuberculosis H37Rv and some pathogenic bacteria Resultsrevealed that conjugate containing ribose moiety demonstrated the most promising activity against Mycobacteria and bacteriawith minimum inhibitory concentrations (MIC) of 065 and 207120583M respectively Other conjugates from xylose glucose andmannose were moderately active whilst disaccharides conjugates were found to be less active In silico docking analysis of prototypecompound revealed that ATP site of DNA gyrase B subunit could be a possible site for inhibitory action of these synthesizedcompounds

1 Introduction

The World Health Organization (WHO) tuberculosis report2015 stated that an annual total of new tuberculosis (TB)cases which had been about 57 million until 2013 rose tomore than 6 million in 2014 (an increase of 6) Unfor-tunately extensively drug-resistant TB (XDR-TB) cases hadbeen reported by 105 countries in the year 2015 and amongthem 97 of patients with multidrug resistant-TB (MDR-TB) have recorded positive for XDR-TB [1] These reportsindicated that the prevalence of the disease is the worstand is due to the emergence of multidrug resistant strainsof Mycobacterium tuberculosis H37Rv [2 3] Thus theseresistant states of tuberculosis (MDR-TB and XDR-TB) haveincreased the concern about tuberculosis as an incurabledisease and as a threat to public health [4 5] Recently WorldHealthOrganization (WHO) has advised against the strategictherapy by adding a new drug into a failing antituberculardrug regimen that increases the drug resistant behavior ofthe strain It indicated that the present treatment is extremely

complicated and needs new drug with novel mechanismexclusively to fight againstmultidrug resistant strains To addthe immune compromised patients with the longer durationsof therapy also emphasize the need for new antitubercularmolecule with novel mode of action [6ndash8]

In search of heterocyclic moiety for the design of newantitubercular agent quinoxaline is well known as privilegedstructure (PS) for easy construction of chemical scaffold [910] Quinoxaline class of drugs (triostin A echinomycin) arewell documented for their biological accessibility and theywere used as DNA intercalating agents [11] In the light ofliterature several reports on biologically active quinoxalinederivatives such as tricyclic quinoxaline pyridinylquinox-alines and pyridinylpyridopyrazines (as potent inhibitorsof protein kinase) [12] olaquindox quindoxin and carba-dox (as potent antibacterial agents) [13] and quinoxaline-2-carboxylate 14-dioxide (as potent antitubercular agents)[14] have been reported Outstandingly few derivatives suchas 14-dioxides sulphonamide spiro schiff bases mannich

Hindawi Publishing CorporationInternational Journal of Medicinal ChemistryVolume 2016 Article ID 6471352 8 pageshttpdxdoiorg10115520166471352

2 International Journal of Medicinal Chemistry

NH

HN O

ONH

HN O

N NH

HN O

NN

CH

R

R-CHOaldoses

Acetic acidethanol

(2)(1)

NH2NH2

NH2

(3andashf)R =

Aldohexoses a = glucose b = mannose c = maltose d = lactose

Aldopentoses e = ribose f = xylose

Figure 1 Schematic route for synthesis of sugar conjugates of quinoxaline

bases keto and amido are reported to possess potent antimi-crobial property Among them spiro [15] 14-dioxide [16]and schiff base [17] of quinoxaline are proven to be the mostsuitable antibacterial and antitubercular leads Nonethelessthe reliability of above agents for new drug design is notoptimistic because of their structural toxicity contributed byhigh lipophilicity and resistance to metabolism

With reference to the biological safety profile of sugarconjugates derived fromnatural and synthetic agents [18ndash20]and in continuation with our earlier studies on quinoxaline[21ndash25] herein we report some saccharide (sugar) linkedquinoxaline In this work the hydrazino intermediate waspreferred to achieve sugar conjugates in order to mimicthe structural resemblance to nucleosides and other activehydrazide drugs In synthetic part quinoxaline 23 (1H4H)-diones (1) was used to prepare hydrazino quinoxa-line as an intermediate (2) then the intermediate (2) wassubsequently condensed with different sugars (aldohexosesaldopentoses and disaccharides) to afforded sugar conjugatesof quinoxaline (3andashf) Compounds were purified by columnchromatography and the purity was confirmed using TLCand HPLC technique The structure establishment was doneby IR 1HNMR and 13C NMR and mass spectral data Allsynthons including starting compounds were screened fortheir antitubercular (Mycobacterium tuberculosis H37Rv) andantibacterial (Staphylococcus aureus Escherichia coli Proteusvulgaris Pseudomonas aeroginosa and Salmonella typhi)activities Results were obtained as minimum inhibitoryconcentration (MIC) in micro molar units (120583M) As anattempt to predict the mode of action of these compoundsa prototype compound was evaluated on DNA gyrase by insilico docking analysis

2 Results and Discussion

21 Chemistry The synthetic route for sugar conjugateswas designed in two step reactions (Figure 1) The start-ing material quinoxaline 23(1H 4H)-dione 1 was obtainedas yellowish crystals from an acid catalyzed condensationreaction between ortho phenylenediamine and oxalic acidChemical reactions of synthetic scheme were performedbased on conventional heating method Reaction progresswas monitored on silica gel coated TLC plate The temper-ature of the reaction for converting compound 2 to 3andashf wascontrolled because of thermolabile nature of sugars that arevulnerable for charring at higher temperature Compounds

were found to be stable crystals except compound 2 The yield was more than 60 except for disaccharide derivatives(3c and 3d) All monosaccharide derivatives were yellowishcrystals whilst disaccharides derivatives appeared as creamywhite In TLC the retardation factors (119877

119891value) for sugar

conjugates (3andashf) were lower than compounds 1 and 2 thusindicating the more polar nature of sugar conjugates Thecalculated log119875 and C log119875 values of sugar conjugates arein good agreement with our prediction that they are morehydrophilic than parent compound (1) The melting pointof the synthesized compounds was more than 200∘C thiscould be due to the high degree of hydrogen bonding offeredby ndashOH residues of sugar moiety The physical data of thesynthesized compounds are shown in Table 1 Structure of thesynthesized compounds was established by UV IR 1HNMR13CNMR and mass spectral data Assignment of proton andcarbon to the structure was performed based on the reportby Bailey and Butterfield [26]The bathochromic shift of 120582maxfor compound 3andashf indicated the formation conjugated C=Nbond The conversion of quinoxaline-23(1H 4H)-diones 1to intermediate 2 was established by spectral characteristicssuch as (a) disappearance of coupled vibration of C=O (b)appearance of coupled band for NH

2 (c) the appearance

of 13C NMR signal for C=N and (d) 1H NMR for ndashNH2

The conjugate formation with sugar was established by (a)1H NMR signal at 423 and 497 ppm for anomeric CHndash ofsugar (b) 13C NMR signals within 100ndash60 ppm for sugarstructure residue and (c) the presence of broad absorptionband for ndashOH group in IR spectrum (3400ndash3600 cmminus1)The detailed spectral characteristics of the compounds areshown in Table 2 A prototype 1H NMR spectrum of glucoseconjugate is shown in Figure 2

22 Antibacterial and Antitubercular Activities Compounds(1 to 3andashf) were screened for their in vitro antibacterial andantitubercular activities using microdilution assay methodand microplate alamar blue assay (MABA) method respec-tively The obtained results were presented in Table 3 Theconcentration range used for screening was from 004 to96 120583gmL and then the obtained MIC (in 120583gmL) was con-verted to micromolar (120583M) concentration Result revealedthat compound 3e (ribose conjugate) exhibited promisingantibacterial and antitubercular activities with respectiveMIC of 207 and 065 120583M Compound 3f (xylose conjugate)was also equally effective against S aureus and E coli but notagainst other pathogens of this study Antibacterial activity

International Journal of Medicinal Chemistry 3

Table 1 Physical data of the synthesized compounds

Comp code yield Melting point 119877119891valuea 120582max in nm (ethanol) log119875b Clog119875b

1 64 212ndash13∘C 0715 247 minus006 minus02922 62 gt300∘C 0825 272 minus003 minus09423a (glucose) 65 290ndash92∘C 0438 298 minus189 minus11923b (mannose) 66 269ndash71∘C 0456 297 minus189 minus11923c (maltose) 47 gt300∘C 0628 286 minus363 minus29353d (lactose) 44 gt300∘C 0602 286 minus363 minus29353e (ribose) 64 286ndash88∘C 0502 292 minus136 minus08113f (xylose) 63 224ndash15∘C 0545 293 minus136 minus0811aTLC using silica gel GF254 and a mixture of chloroform and methanol (80 20 vv) bValues were calculated

39 8 7 6 5 4 2 11011(ppm)

095

024

033

039

070

200

200

111

062

050

263

212

120

221

041

Figure 2 H1- NMR spectrum of 3-(2-120573D-glucopyranosylidenehydrazinyl)quinoxalin-2(1H)-one (3a)

of compound 3a (glucose conjugate) was quite considerable(MIC 142 120583M) but it was equipotent to compound2 Amongaldohexoses compound 3a (glucose) was moderately activeagainst M tuberculosis (MIC 71120583M) than compounds 1and 2 It was noted that there was no true compound thatwas active against Salmonella typhi except compound 3e(MIC 78 120583M) It was evident that conjugates of pentoses(compounds 3e and 3f) showed promising antibacterialactivity against Staphylococcus aureus and Proteus vulgarisand are quite comparable to ciprofloxacin The intermediate(compound 2) showed MIC of 36 120583M against E coli assimilar to conjugates of pentoses (3e and 3f) thus the potencyof compound 2 is in good agreement with our earlier studies

The screening for antitubercular activity revealed thatall sugar conjugates exhibited better activity as comparedto parent compound 1 and intermediate compounds 2thus clubbing of sugar to quinoxaline could be a benefi-cial approach in design of antitubercular agents Amongthem conjugates monosaccharide showed better activity ascompared to the hydrazine derivative 2 and disaccharides(3c and 3d) The most promising antibacterial activity wasshown by ribose conjugate 3e (MIC 065 120583M) followedby xylose 3f glucose 3a and mannose 3b conjugates withrespective MIC values of 39 71 and 71 120583M Overall itwas noticed that disaccharides linkage has low value indesign of antibacterial and antitubercular leads as comparedto monosaccharides Among monosaccharides aldopentose

derivatives are more potent as compared to aldohexoses Thestructures of active compounds are shown in Figure 3 Theeffect of stereoisomerism of sugar in this study was quitesignificant and this can be supported by the comparisonbetween ribose derivative (3e) and xylose derivative (3f) Itwas noted that ribose derivative is 7 times more potent thanxylose derivative However both compounds 3a and 3b areequipotent in antitubercular activity but differ in antibacterialactivity

In view to antibacterial screening results Salmonellaspecies was resistant to all compounds except compounds3e and 3f which indicated the importance of aldopentosein design of antibacterial leads against Salmonella speciesAntitubercular activity of all conjugates (log119875 gt minus1) is betterthan compounds 1 and 2 (log119875 lt 1) which indicated theimportance of log119875 parameter in defining the activity Theantitubercular activity of disaccharide conjugates 3c and 3d(maltose and lactose conjugates) is relatively very low (15times less than ribose) and the possible reason could bethat they are high molecular weight compounds with morehydrophilic (log119875more thanminus30) natureThus disaccharidelinked conjugates are likely to exhibit less permeability to cellwall thereby it leads to inadequate cellular concentrationAldopentose accounts for their better penetration into the cellwall ofMycobacterium species conjugates (3e and 3f) becauseof their low molecular weight and optimal hydrophilicity(log119875 gt minus1 and lt minus2) In addition stereoisomer effect alsoplays important role in their relative potency

23 In Silico Docking Analysis TheDNAgyrase is an enzymeresponsible for the topological state of DNA and playingimportant role in transcription process It is the target for fewantibiotics such as many antibiotics including nalidixic acidnovobiocin and ciprofloxacin Particularly fluoroquinolonesact as an antibacterial through DNA cleavage by inhibitingATPase activity of DNA gyrase As Adenosine itself containsa nucleotide and a sugarmoiety we predicted that the synthe-sized molecules (3andashf) may inhibit the ATPase binding siteof DNA gyrase Further to elucidate the probable mechanismof action of our designed compounds we have initially donethe molecular docking studies of our designed molecule (3a)with DNA gyrase B subunit using PDB ID 4HYP Resultsshown that the structure of compound 3a tightly bounds tothe ATP binding site (Figure 4) and showed binding energy


Table2Spectralcharacteris

ticso

fthe

synthesiz

edcompo

unds

Snu

mber

Com

pcode

Molecular

form

ula

Molecular

weight

IR(cmminus1)

1HNMR(120575

ppm)

(DMSO

-d6CDCl3)

13CN

MR(120575

ppm)

(DMSO

-d6CDCl3)

ESIM

S

11

C 8H6N2O2

16214

3158

(NH)1685

(C=O

)16121500(C

=Cstr

etching)764

(ArC

-Hout

ofplane)

1190(sN

H)696ndash710

711ndash714

(m

quinox)

1556(C

=O)125312321154(A

rC)

162

(M+)

22

C 8H8N4O

17617

3150

(NHweak)1681(C=

O)15601500

(C=C

)759(A

rC-H

)97

0(sN

H)78

9ndash78

176

4ndash75

7(m

qu

inox)74

1(sNH)68(sN

H2)

1556(C

=O)1483(C

=N)1421

1421

13641316

1309

1288128112301224

(quino

x)

176

(M+)

33a

C 15H18N4O6

33832

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

995(sN

H)826

(sN

H)78

1ndash682

(m

Ar-H)598

(sN

H)491421(s

anom

ericCH

)392ndash295(cpxglucosyl)

1602(C

=O)1487(C

=N)

142ndash122(quino

x)982(C1CH

ndashNH)735724702692

(C2ndashC5)631(ndashCH2OH)

339

(M+1)

43b

C 15H18N4O6

33832

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

995(sN

H)826

(sN

H)78

1ndash682

(m

Ar-H)598

(sN

H)421

(sano

meric

CH)392ndash295(cpxglucosyl)

1602(C

=O)1487(C

=N)

142ndash122(quino

x)982(C1CH

ndashNH)735724702692


339

(M+1)

53c

C 20H28N4O11

50045

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

1022(sN

H)833

(sN

H)79

6ndash690

(m

Ar-H)611(sN

H)522

(sano

meric

CH)423ndash319

(cpxm

altosyl)

1611

(C=O

)1489(C

=N)

1431ndash1215

(quino

x)1002(C1CH

ndashNH)72ndash70(m

altosyl)

608(ndashCH2OH)

501

(M+1)

63d

C 20H28N4O11

50045

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

104(sN

H)833

(sN

H)804ndash6

82(m

Ar-H)673

(sN

H)558

(sano

meric

CH)418ndash302(cpxlactosyl)

1613

(C=O

)1487(C

=N)

1436ndash

1213

(quino

x)1033

(C1CH

ndashNH)71ndash76(la

ctosyl)612

(ndashCH2OH)

501

(M+1)

73e

C 13H16N4O5

30829

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

1013

(sN

H)847

(sN

H)79

2ndash685

(m

Ar-H)624

(sN

H)421

(sano

meric

CH)223ndash4

37(cpxribosyl)

1618

(C=O

)1505(C

=N)

144ndash

123(quino

x)965(C1CH

ndashNH)735718

694

(C2ndashC4)64

2(ndashCH2OH)

309

(M+1)

83f

C 13H16N4O5

30829

3450ndash3250(O

Hstr

etch

broad)1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

1034(sN

H)865

(sN

H)802ndash6

71(m

Ar-H)632

(sN

H)478

(sano

meric

CH)223ndash4

37(cpxX

ylosyl)

1621(C=

O)1500(C

=N)

143ndash121(qu

inox)

975(C1CH

ndashNH)774751709


309

(M+1)


Table 3 Antibacterial and antitubercular activity of compounds synthesized (in 120583M)

Compcode

Antibacterial activity (MIC in 120583M) MIC againstMycobacterium tuberculosis H37Rv (in 120583M)

SA EC PV PA ST1 296 148 296 296 gt592 gt5922 136 36 136 136 gt545 2723a 142 71 142 142 gt284 713b gt284 gt284 gt284 gt284 gt284 713c gt192 gt192 gt192 gt192 gt192 963d gt192 gt192 gt192 gt192 gt192 963e 207 207 207 207 78 0653f 207 207 39 39 155 39AMX 044 087 175 328 175 mdashCIP 193 096 362 193 724 mdashINH mdash mdash mdash mdash mdash 0145Blank mdash mdash mdash mdash mdash mdash

NH

HN O

N

HN O

OH

HHO H

HHO

H

H

OH NH

HN O

N

HN

O

OH

OH

H

H

H

H

HOD-Glucose conjugate (3a) D-Ribose conjugate (3e)

Figure 3 Structures of most active compounds 3-(2-120573D-glucopyranosylidene hydrazinyl)quinoxalin-2(1H)-one (3a) and 3-(2- 120572D ribofur-anosylidene hydrazinyl)quinoxalin-2(1H)-one (3e)

Figure 4 Key molecular interactions (hydrogen bonds (green)electrostatic interactions (orange)) of compound 3a with the keyamino acids present in ATP binding pocket of DNA gyrase enzyme(PDB ID 4HYP)

of minus70 The hydroxyl groups (ndashOH) of sugar moiety showedhydrogen bonds with SER 116 GLY 118 Asp 45 ASN46 ASP49 and VAL 122 whilst the quinoxaline moiety accountedfor pi-pi- stacking interaction with ASP 49 and Asp 45The linker imine group is well recognized for nonclassicalhydrogen bonding interaction with the HIS120 PHE 104

Recent reports say that the hydrogen bonding interactionsASN46 ASN45 and GLY118 are crucial for the activityThusthe molecular docking results suggested that the synthesizedcompounds may inhibit the ATPase activity of DNA gyraseby firmly binding into the ATP binding pocket The dockedmolecule with DNA gyrase is shown in Figure 4

3 Experimental

31 Materials Purity of compounds was confirmed usingTLC (aluminum 60F

254) and HPLC (Agilent LC 1200 C

18

(250mm times 46mm 5 micron) Column) techniques Themelting point was determined by open capillary tubemethodand is uncorrected The UV spectrum was obtained usinga UV-Visible spectrum (Shimadzu UV-Visible Double beamSpectrometer) Functional groups were established by IRspectra using a Fourier transform-infrared spectrophotome-ter (Alpha E Bruker ATR technique) at resolution of 4 cmminus1The carbon and proton of the structure components wereassigned using proton nuclear magnetic resonance spectrum(1HNMR 400MHz) using a Varian VXR Unity (California)using TMS as internal standard and DMSO-d

6CDCl

3as

solvent and carbon nuclear magnetic resonance spectrum(13C NMR 300MHz) using Brukers UXNMR (Germany)


using DMSO-d6CDCl

3as solvent The mass spectrum from

Shimadzu LCMS -2010A (Japan) was used to confirmmolec-ular weight All reagents used were of analytical or syntheticgrade

32 Synthesis and Characterization The starting materialquinoxalin-23-dione 1 was synthesized as stated in literature[27] The product was obtained as yellowish silky needlecrystals The conversion of compound 1 to compound 2 wascarried out as per our earlier report [28]

321 Synthesis of 3-(2-Hexopyranosylidene hydrazinyl)quin-oxalin-2(1H)-one (3andashd) and 3-(2-Pentofuranosylidene hy-drazinyl)quinoxalin-2(1H)-one (3e 3f) A mixture of com-pound 2 (0015mol) and various hexoses and riboses(0015mol) in absolute alcohol containing catalytic amountof acetic acid was heated under reflux for 8 h Care wastaken to avoid charring of carbohydrates if so reactionmixture was discarded The reaction mixture was cooled andallowed overnight in refrigerator The formed product wasfiltered and washed with small quantity of purified water andrecrystallized from 95 ethanol The purity of the productwas confirmed on silica gel coated TLC plate and HPLCanalysis

All compoundswere subjected for purification by columnchromatography The obtained compounds purity was testedusing HPLC technique Thus obtained compounds werecharacterized by UV IR 1H NMR and 13C NMR and massspectral data The physical and spectral characteristics ofthe synthesized compounds are presented in Tables 1 and 2respectively

33 Antibacterial and Antitubercular Activities

331 In Vitro Antibacterial Screening by Microdilution Meth-od Compounds were tested against bacterial pathogensnamely Staphylococcus aureus ATCC 25923 Escherichia coliATCC 25922 Proteus vulgaris ATCC 29905 Pseudomonasaeroginosa ATCC 27853 and Salmonella typhi ATCC 14028 bybroth microdilution technique using 96-well plate The plateincluded positive control negative control blank and serialdilution tests and standards (in DMSO) in the concentrationrange from 004 to 96 120583gmL After the addition of 100 120583Linoculums (2 times 106 test organismsmL) to wells the plateswere incubated at 36 plusmn 1∘C After 18 hours of incubationthe final volume of each well was made up to 200120583L andthen 20120583L of 10-fold dilution of Alamar blue was addedThen plate was incubated for 30min The color intensity ofeach well was documented and the MIC was recorded Thelowest concentration used that did not result in the change ofcolour from blue to pink The results were calculated in 120583Mconcentrations and shown in Table 3

332 Antitubercular Screening by Microplate Alamar BlueAssay (MABA) Method A stock solution of the test com-pounds was prepared inDMSO at 1mgmL andwas sterilizedby passage through 045 120583 Nylon based membrane filtersControls received 50 120583L DMSO whilst isoniazid (INH) was

included as positive drug control The inoculum used was1 100 dilutions to represent 1 of the mycobacterial popula-tion (102ndash103 CFUmL)All the compoundswere screened forantitubercular activity by serial addition at a concentrationrange from 004 to 96 120583gmL At the end of 5th day ofincubation 50120583L of 1 1 dilution of Alamar blue stocksolution assay medium was transferred to all wells for a finalassay volume of 250 120583L per well yielding a final concentrationof 10 vv Alamar blue The plates were read against anexcitation wavelength of 530 nm and an emission wavelengthof 590 nm It was recorded to determine whether any ofthe test compounds fluorescence at the emission wavelengththus interferes with the assay Then plates were returned toincubator for 30min and then fluorescence was read Thepercent viability was determined as fluorescence counts inthe presence of test compound as a percentage of that in thevehicle control A compound is considered to be active onlyif it shows inhibition of 90 The results were calculated in120583M concentrations and shown in Table 3

34 In Silico Docking Studies A crystallographic DNA gyrasewith gap (PDB ID 4HYP resolution 26 A) was taken Thiscrystal structure was a tetramer with four endogenous bind-ing sites for pyrrolopyrimidine molecules at ATP bindingpockets DNAgyrase B subunit was refined from the tetramerand water molecules were removed from all the structuresby using Chimera (1102) The energy minimizing processfor molecule 3a was done using online server PRODRGMolecular docking of compound 3a was performed withthe DNA gyrase subunit B with crystallographic complexes4HYP using Autodock 4234The rigid docking protocol wasused and the best binding mode of interaction was taken forMD simulation Polar and aromatic hydrogens were addedand Gasteiger charges were computed by Autodock tool oneach atom of the ligand The AutoTors utility was used todefine torsional degrees of freedom for the ligand The gridbox was centered in the macromolecule and the dimensionof the grid was 80 times 72 times 80 A with the spacing betweenthe grid points at 0514 A in order to include the entire pro-tein Grid potential maps were calculated using the moduleAutoGrid 40 The Lamarckian genetic algorithm was usedto perform docking simulation with an initial population of150 randomly placed individuals with a maximum numberof 250000 energy evaluations 150000 generations mutationrate of 002 a crossover rate of 08 and an elitism value of1 which were used Then 100 docking runs were performedPseudo-Solis and Wets algorithm was used for local searchmethod Finally the resulting docked conformations wereclustered together on the basis of root-mean-square deviation(RMSD) tolerance of 20 A and represented bymost favorablefree energy of bindingThe resulting output files were viewedusing discovery studio

4 Conclusion

Design of quinoxaline containing sugar conjugates has beenproven to be a beneficial attempt in search of new leadmolecule to inhibit the growth ofMycobacterium tuberculosis


H37Rv and bacteria pathogens It could serve as lead discoverystrategy for further development due to their potential novelmechanism that binds to DNA gyrase As continuationof this study further using various monosaccharides withappropriate biosteric replacement strategy will certainly yielda lead molecule for MDR-TB and XDR-TB

Conflict of Interests

The authors confirmed that this paper has no conflict ofinterests

Acknowledgment

The authors are thankful to Indian Institute of ChemicalTechnology (IICT) Hyderabad India for providing spectralsupport

References

[1] World Health Organization Global Tuberculosis Report WHOGeneva Switzerland 20th edition 2015

[2] A Zumla P Nahid and S T Cole ldquoAdvances in the devel-opment of new tuberculosis drugs and treatment regimensrdquoNature Reviews Drug Discovery vol 12 no 5 pp 388ndash404 2013

[3] R C Goldman K V Plumley and B E Laughon ldquoTheevolution of extensively drug resistant tuberculosis (XDR-TB) history status and issues for global controlrdquo InfectiousDisordersmdashDrug Targets vol 7 no 2 pp 73ndash91 2007

[4] S R Benatar ldquoExtensively drug resistant tuberculosismdashproblem will get worse in South Africa unless poverty isalleviatedrdquo British Medical Journal vol 333 article 705 2006

[5] S D Lawn and R Wilkinson ldquoExtensively drug resistanttuberculosismdasha serious wake-up call for global healthrdquo BritishMedical Journal vol 333 no 7568 pp 559ndash560 2006

[6] U R Dahle ldquoExtensively drug resistant tuberculosismdashBewarepatients lost to follow-uprdquo British Medical Journal vol 333article 705 2006

[7] N R Gandhi A Moll A W Sturm et al ldquoExtensively drug-resistant tuberculosis as a cause of death in patients co-infectedwith tuberculosis and HIV in a rural area of South AfricardquoTheLancet vol 368 no 9547 pp 1575ndash1580 2006

[8] D Manissero and K Fernandez de la Hoz ldquoExtensive drug-resistant TB a threat for Europerdquo EuropeanSurveillance vol 11Article ID E060928 2006

[9] G Ughetto A H J Wang G J Quigley G A van der MarelJ H van Boom and A Rich ldquoA comparison of the structureof echinomycin and triostin a complexed to a DNA fragmentrdquoNucleic Acids Research vol 13 no 7 pp 2305ndash2323 1985

[10] J Polanski A Kurczyk A Bak and R Musiol ldquoPrivi-leged structuresmdashdream or reality preferential organization ofazanaphthalene scaffoldrdquo Current Medicinal Chemistry vol 19no 13 pp 1921ndash1945 2012

[11] J Jampilek ldquoRecent advances in design of potential quinoxalineanti-infectivesrdquoCurrentMedicinal Chemistry vol 21 no 38 pp4347ndash4373 2014

[12] P Koch H Jahns V Schattel M Goettert and S LauferldquoPyridinylquinoxalines and pyridinylpyridopyrazines as leadcompounds for novel p38120572 mitogen-activated protein kinase

inhibitorsrdquo Journal of Medicinal Chemistry vol 53 no 3 pp1128ndash1137 2010

[13] C E Voogd J J van der Stel and J J J A A JacobsldquoThe mutagenic action of quindoxin carbadox olaquindoxand some other N-oxides on bacteria and yeastrdquo MutationResearchGenetic Toxicology vol 78 no 3 pp 233ndash242 1980

[14] A Jaso B Zarranz I Aldana and A Monge ldquoSynthesisof new quinoxaline-2-carboxylate 14-dioxide derivatives asanti-Mycobacterium tuberculosis agentsrdquo Journal of MedicinalChemistry vol 48 no 6 pp 2019ndash2025 2005

[15] C A Anothane R Bouhfid H Zouihri et al ldquo1-Allyl-3-methyl-3101584051015840-diphenyl-spiro-[quinoxaline-2(1H)21015840(31015840H)-[134]thia-diazole]rdquo Acta Crystallographia Section E StructureReport Online vol 66 part 12 Article ID o3227 2010

[16] M Vieira C Pinheiro R Fernandes J P Noronha and CPrudencio ldquoAntimicrobial activity of quinoxaline 14-dioxidewith 2- and 3-substituted derivativesrdquoMicrobiological Researchvol 169 no 4 pp 287ndash293 2014

[17] P V A Lakshmi T Satyanarayana and P S Reddy ldquoSyn-thesis characterization and antimicrobial activity of oxovana-dium(IV) complexes of Schiff base hydrazones containingquinoxaline moietyrdquo Chinese Journal of Chemistry vol 30 no4 pp 935ndash940 2012

[18] E C Calvaresi and P J Hergenrother ldquoGlucose conjugationfor the specific targeting and treatment of cancerrdquo ChemicalScience vol 4 no 6 pp 2319ndash2333 2013

[19] J Luginina V Rjabovs S Belyakov and M Turks ldquoA concisesynthesis of sugar isoxazole conjugatesrdquo Tetrahedron Lettersvol 54 no 39 pp 5328ndash5331 2013

[20] N M Xavier M Goulart A Neves et al ldquoSynthesis of sugarsembodying conjugated carbonyl systems and related triazolederivatives from carboxymethyl glycoside lactones Evaluationof their antimicrobial activity and toxicityrdquo Bioorganic ampMedic-inal Chemistry vol 19 no 2 pp 926ndash938 2011

[21] P Ramalingam S Ganapat and C H BabuRao ldquoIn vitroantitubercular and antimicrobial activities of 1-substitutedquinoxaline-2 3 (1H 4H)-dionesrdquo Bioorganic amp MedicinalChemistry Letters vol 20 pp 406ndash410 2010

[22] S Ganapaty P Ramalingam and C Baburao ldquoAntimicrobialand antimycobacterial activity of some quinoxalines lsquoNrsquo bridge-head heterocyclesrdquoAsian Journal of Chemistry vol 20 no 5 pp3353ndash3356 2008

[23] S Ganapaty P Ramalingam and C H BabuRao ldquoSAR studyimpact of hydrazide hydrazones and sulfonamide side chainon in vitro antimicrobial activity of quinoxalinerdquo InternationalJournal of Pharmacology and Biological Sciences vol 2 no 2 pp13ndash18 2008

[24] S Ganapaty P Ramalingam and C H BabuRao ldquoAntibac-terial antifungal and antitubercular screening of some novelcondensed bridgehead nitrogen heterocycles of quinoxalinesrdquoIndian Journal of Heterocyclic Chemistry vol 16 no 3 pp 283ndash286 2007

[25] R Peraman R V Varma and Y P Reddy ldquoRe-engineeringnalidixic acidrsquos chemical scaffold a step towards the devel-opment of novel anti-tubercular and anti-bacterial leads forresistant pathogensrdquo Bioorganic amp Medicinal Chemistry Lettersvol 25 no 19 pp 4314ndash4319 2015

[26] K Bailey and A G Butterfield ldquoldquoStructure of condensationproducts between isonicotinylhydrazine and reducing sugars by13CNMR spectroscopyrdquoCanadian Journal of Chemistry vol 59no 3 pp 641ndash646 1981


[27] S Ganapaty P Ramalingam and C Baburao ldquoAntimicrobialand antimycobacterial activity of some quinoxalines rsquoNrsquo bridge-head heterocyclesrdquoAsian Journal of Chemistry vol 20 no 5 pp3353ndash3356 2008

[28] S Ganapaty P Ramalingam and CH Babu Rao ldquoSAR studyimpact of hydrazide hydrazones and sulfonamide side chainon in vitro antimicrobial activity of quinoxalinerdquo InternationalJournal of Pharmacology and Biology vol 2 no 2 pp 13ndash182008

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


NH

HN O

ONH

HN O

N NH

HN O

NN

CH

R

R-CHOaldoses

Acetic acidethanol

(2)(1)

NH2NH2

NH2

(3andashf)R =

Aldohexoses a = glucose b = mannose c = maltose d = lactose

Aldopentoses e = ribose f = xylose

Figure 1 Schematic route for synthesis of sugar conjugates of quinoxaline

bases keto and amido are reported to possess potent antimi-crobial property Among them spiro [15] 14-dioxide [16]and schiff base [17] of quinoxaline are proven to be the mostsuitable antibacterial and antitubercular leads Nonethelessthe reliability of above agents for new drug design is notoptimistic because of their structural toxicity contributed byhigh lipophilicity and resistance to metabolism

With reference to the biological safety profile of sugarconjugates derived fromnatural and synthetic agents [18ndash20]and in continuation with our earlier studies on quinoxaline[21ndash25] herein we report some saccharide (sugar) linkedquinoxaline In this work the hydrazino intermediate waspreferred to achieve sugar conjugates in order to mimicthe structural resemblance to nucleosides and other activehydrazide drugs In synthetic part quinoxaline 23 (1H4H)-diones (1) was used to prepare hydrazino quinoxa-line as an intermediate (2) then the intermediate (2) wassubsequently condensed with different sugars (aldohexosesaldopentoses and disaccharides) to afforded sugar conjugatesof quinoxaline (3andashf) Compounds were purified by columnchromatography and the purity was confirmed using TLCand HPLC technique The structure establishment was doneby IR 1HNMR and 13C NMR and mass spectral data Allsynthons including starting compounds were screened fortheir antitubercular (Mycobacterium tuberculosis H37Rv) andantibacterial (Staphylococcus aureus Escherichia coli Proteusvulgaris Pseudomonas aeroginosa and Salmonella typhi)activities Results were obtained as minimum inhibitoryconcentration (MIC) in micro molar units (120583M) As anattempt to predict the mode of action of these compoundsa prototype compound was evaluated on DNA gyrase by insilico docking analysis

2 Results and Discussion

21 Chemistry The synthetic route for sugar conjugateswas designed in two step reactions (Figure 1) The start-ing material quinoxaline 23(1H 4H)-dione 1 was obtainedas yellowish crystals from an acid catalyzed condensationreaction between ortho phenylenediamine and oxalic acidChemical reactions of synthetic scheme were performedbased on conventional heating method Reaction progresswas monitored on silica gel coated TLC plate The temper-ature of the reaction for converting compound 2 to 3andashf wascontrolled because of thermolabile nature of sugars that arevulnerable for charring at higher temperature Compounds

were found to be stable crystals except compound 2 The yield was more than 60 except for disaccharide derivatives(3c and 3d) All monosaccharide derivatives were yellowishcrystals whilst disaccharides derivatives appeared as creamywhite In TLC the retardation factors (119877

119891value) for sugar

conjugates (3andashf) were lower than compounds 1 and 2 thusindicating the more polar nature of sugar conjugates Thecalculated log119875 and C log119875 values of sugar conjugates arein good agreement with our prediction that they are morehydrophilic than parent compound (1) The melting pointof the synthesized compounds was more than 200∘C thiscould be due to the high degree of hydrogen bonding offeredby ndashOH residues of sugar moiety The physical data of thesynthesized compounds are shown in Table 1 Structure of thesynthesized compounds was established by UV IR 1HNMR13CNMR and mass spectral data Assignment of proton andcarbon to the structure was performed based on the reportby Bailey and Butterfield [26]The bathochromic shift of 120582maxfor compound 3andashf indicated the formation conjugated C=Nbond The conversion of quinoxaline-23(1H 4H)-diones 1to intermediate 2 was established by spectral characteristicssuch as (a) disappearance of coupled vibration of C=O (b)appearance of coupled band for NH

2 (c) the appearance

of 13C NMR signal for C=N and (d) 1H NMR for ndashNH2

The conjugate formation with sugar was established by (a)1H NMR signal at 423 and 497 ppm for anomeric CHndash ofsugar (b) 13C NMR signals within 100ndash60 ppm for sugarstructure residue and (c) the presence of broad absorptionband for ndashOH group in IR spectrum (3400ndash3600 cmminus1)The detailed spectral characteristics of the compounds areshown in Table 2 A prototype 1H NMR spectrum of glucoseconjugate is shown in Figure 2

22 Antibacterial and Antitubercular Activities Compounds(1 to 3andashf) were screened for their in vitro antibacterial andantitubercular activities using microdilution assay methodand microplate alamar blue assay (MABA) method respec-tively The obtained results were presented in Table 3 Theconcentration range used for screening was from 004 to96 120583gmL and then the obtained MIC (in 120583gmL) was con-verted to micromolar (120583M) concentration Result revealedthat compound 3e (ribose conjugate) exhibited promisingantibacterial and antitubercular activities with respectiveMIC of 207 and 065 120583M Compound 3f (xylose conjugate)was also equally effective against S aureus and E coli but notagainst other pathogens of this study Antibacterial activity





39 8 7 6 5 4 2 11011(ppm)

095

024

033

039

070

200

200

111

062

050

263

212

120

221

041









ticso

fthe

synthesiz

edcompo

unds

Snu

mber

Com

pcode

Molecular

form

ula

Molecular

weight

IR(cmminus1)

1HNMR(120575

ppm)

(DMSO

-d6CDCl3)

13CN

MR(120575

ppm)

(DMSO

-d6CDCl3)

ESIM

S

11

C 8H6N2O2

16214

3158

(NH)1685

(C=O

)16121500(C

=Cstr

etching)764

(ArC

-Hout

ofplane)

1190(sN

H)696ndash710

711ndash714

(m

quinox)

1556(C

=O)125312321154(A

rC)

162

(M+)

22

C 8H8N4O

17617

3150

(NHweak)1681(C=

O)15601500

(C=C

)759(A

rC-H

)97

0(sN

H)78

9ndash78

176

4ndash75

7(m

qu

inox)74

1(sNH)68(sN

H2)

1556(C

=O)1483(C

=N)1421

1421

13641316

1309

1288128112301224

(quino

x)

176

(M+)

33a

C 15H18N4O6

33832

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

995(sN

H)826

(sN

H)78

1ndash682

(m

Ar-H)598

(sN

H)491421(s

anom

ericCH


1602(C

=O)1487(C

=N)

142ndash122(quino

x)982(C1CH

ndashNH)735724702692


339

(M+1)

43b

C 15H18N4O6

33832

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

995(sN

H)826

(sN

H)78

1ndash682

(m

Ar-H)598

(sN

H)421

(sano

meric


1602(C

=O)1487(C

=N)

142ndash122(quino

x)982(C1CH

ndashNH)735724702692


339

(M+1)

53c

C 20H28N4O11

50045

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

1022(sN

H)833

(sN

H)79

6ndash690

(m

Ar-H)611(sN

H)522

(sano

meric

CH)423ndash319

(cpxm

altosyl)

1611

(C=O

)1489(C

=N)

1431ndash1215

(quino

x)1002(C1CH

ndashNH)72ndash70(m

altosyl)

608(ndashCH2OH)

501

(M+1)

63d

C 20H28N4O11

50045

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

104(sN

H)833

(sN

H)804ndash6

82(m

Ar-H)673

(sN

H)558

(sano

meric


1613

(C=O

)1487(C

=N)

1436ndash

1213

(quino

x)1033

(C1CH


ctosyl)612

(ndashCH2OH)

501

(M+1)

73e

C 13H16N4O5

30829

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

1013

(sN

H)847

(sN

H)79

2ndash685

(m

Ar-H)624

(sN

H)421

(sano

meric

CH)223ndash4

37(cpxribosyl)

1618

(C=O

)1505(C

=N)

144ndash

123(quino

x)965(C1CH

ndashNH)735718

694

(C2ndashC4)64

2(ndashCH2OH)

309

(M+1)

83f

C 13H16N4O5

30829

3450ndash3250(O

Hstr

etch

broad)1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

1034(sN

H)865

(sN

H)802ndash6

71(m

Ar-H)632

(sN

H)478

(sano

meric

CH)223ndash4

37(cpxX

ylosyl)

1621(C=

O)1500(C

=N)

143ndash121(qu

inox)

975(C1CH

ndashNH)774751709


309

(M+1)



Compcode



NH

HN O

N

HN O

OH

HHO H

HHO

H

H

OH NH

HN O

N

HN

O

OH

OH

H

H

H

H






3 Experimental



18


6CDCl

3as



using DMSO-d6CDCl











4 Conclusion






Acknowledgment


References








































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of





39 8 7 6 5 4 2 11011(ppm)

095

024

033

039

070

200

200

111

062

050

263

212

120

221

041









ticso

fthe

synthesiz

edcompo

unds

Snu

mber

Com

pcode

Molecular

form

ula

Molecular

weight

IR(cmminus1)

1HNMR(120575

ppm)

(DMSO

-d6CDCl3)

13CN

MR(120575

ppm)

(DMSO

-d6CDCl3)

ESIM

S

11

C 8H6N2O2

16214

3158

(NH)1685

(C=O

)16121500(C

=Cstr

etching)764

(ArC

-Hout

ofplane)

1190(sN

H)696ndash710

711ndash714

(m

quinox)

1556(C

=O)125312321154(A

rC)

162

(M+)

22

C 8H8N4O

17617

3150

(NHweak)1681(C=

O)15601500

(C=C

)759(A

rC-H

)97

0(sN

H)78

9ndash78

176

4ndash75

7(m

qu

inox)74

1(sNH)68(sN

H2)

1556(C

=O)1483(C

=N)1421

1421

13641316

1309

1288128112301224

(quino

x)

176

(M+)

33a

C 15H18N4O6

33832

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

995(sN

H)826

(sN

H)78

1ndash682

(m

Ar-H)598

(sN

H)491421(s

anom

ericCH


1602(C

=O)1487(C

=N)

142ndash122(quino

x)982(C1CH

ndashNH)735724702692


339

(M+1)

43b

C 15H18N4O6

33832

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

995(sN

H)826

(sN

H)78

1ndash682

(m

Ar-H)598

(sN

H)421

(sano

meric


1602(C

=O)1487(C

=N)

142ndash122(quino

x)982(C1CH

ndashNH)735724702692


339

(M+1)

53c

C 20H28N4O11

50045

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

1022(sN

H)833

(sN

H)79

6ndash690

(m

Ar-H)611(sN

H)522

(sano

meric

CH)423ndash319

(cpxm

altosyl)

1611

(C=O

)1489(C

=N)

1431ndash1215

(quino

x)1002(C1CH

ndashNH)72ndash70(m

altosyl)

608(ndashCH2OH)

501

(M+1)

63d

C 20H28N4O11

50045

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

104(sN

H)833

(sN

H)804ndash6

82(m

Ar-H)673

(sN

H)558

(sano

meric


1613

(C=O

)1487(C

=N)

1436ndash

1213

(quino

x)1033

(C1CH


ctosyl)612

(ndashCH2OH)

501

(M+1)

73e

C 13H16N4O5

30829

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

1013

(sN

H)847

(sN

H)79

2ndash685

(m

Ar-H)624

(sN

H)421

(sano

meric

CH)223ndash4

37(cpxribosyl)

1618

(C=O

)1505(C

=N)

144ndash

123(quino

x)965(C1CH

ndashNH)735718

694

(C2ndashC4)64

2(ndashCH2OH)

309

(M+1)

83f

C 13H16N4O5

30829

3450ndash3250(O

Hstr

etch

broad)1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

1034(sN

H)865

(sN

H)802ndash6

71(m

Ar-H)632

(sN

H)478

(sano

meric

CH)223ndash4

37(cpxX

ylosyl)

1621(C=

O)1500(C

=N)

143ndash121(qu

inox)

975(C1CH

ndashNH)774751709


309

(M+1)



Compcode



NH

HN O

N

HN O

OH

HHO H

HHO

H

H

OH NH

HN O

N

HN

O

OH

OH

H

H

H

H






3 Experimental



18


6CDCl

3as



using DMSO-d6CDCl











4 Conclusion






Acknowledgment


References








































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



ticso

fthe

synthesiz

edcompo

unds

Snu

mber

Com

pcode

Molecular

form

ula

Molecular

weight

IR(cmminus1)

1HNMR(120575

ppm)

(DMSO

-d6CDCl3)

13CN

MR(120575

ppm)

(DMSO

-d6CDCl3)

ESIM

S

11

C 8H6N2O2

16214

3158

(NH)1685

(C=O

)16121500(C

=Cstr

etching)764

(ArC

-Hout

ofplane)

1190(sN

H)696ndash710

711ndash714

(m

quinox)

1556(C

=O)125312321154(A

rC)

162

(M+)

22

C 8H8N4O

17617

3150

(NHweak)1681(C=

O)15601500

(C=C

)759(A

rC-H

)97

0(sN

H)78

9ndash78

176

4ndash75

7(m

qu

inox)74

1(sNH)68(sN

H2)

1556(C

=O)1483(C

=N)1421

1421

13641316

1309

1288128112301224

(quino

x)

176

(M+)

33a

C 15H18N4O6

33832

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

995(sN

H)826

(sN

H)78

1ndash682

(m

Ar-H)598

(sN

H)491421(s

anom

ericCH


1602(C

=O)1487(C

=N)

142ndash122(quino

x)982(C1CH

ndashNH)735724702692


339

(M+1)

43b

C 15H18N4O6

33832

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

995(sN

H)826

(sN

H)78

1ndash682

(m

Ar-H)598

(sN

H)421

(sano

meric


1602(C

=O)1487(C

=N)

142ndash122(quino

x)982(C1CH

ndashNH)735724702692


339

(M+1)

53c

C 20H28N4O11

50045

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

1022(sN

H)833

(sN

H)79

6ndash690

(m

Ar-H)611(sN

H)522

(sano

meric

CH)423ndash319

(cpxm

altosyl)

1611

(C=O

)1489(C

=N)

1431ndash1215

(quino

x)1002(C1CH

ndashNH)72ndash70(m

altosyl)

608(ndashCH2OH)

501

(M+1)

63d

C 20H28N4O11

50045

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

104(sN

H)833

(sN

H)804ndash6

82(m

Ar-H)673

(sN

H)558

(sano

meric


1613

(C=O

)1487(C

=N)

1436ndash

1213

(quino

x)1033

(C1CH


ctosyl)612

(ndashCH2OH)

501

(M+1)

73e

C 13H16N4O5

30829

3450ndash3250(O

Hstr

etch

broad)

1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

1013

(sN

H)847

(sN

H)79

2ndash685

(m

Ar-H)624

(sN

H)421

(sano

meric

CH)223ndash4

37(cpxribosyl)

1618

(C=O

)1505(C

=N)

144ndash

123(quino

x)965(C1CH

ndashNH)735718

694

(C2ndashC4)64

2(ndashCH2OH)

309

(M+1)

83f

C 13H16N4O5

30829

3450ndash3250(O

Hstr

etch

broad)1683

(C=O

)1615

(C=N

)1072

(OHbend

)762(A

rC-H

deform

)

1034(sN

H)865

(sN

H)802ndash6

71(m

Ar-H)632

(sN

H)478

(sano

meric

CH)223ndash4

37(cpxX

ylosyl)

1621(C=

O)1500(C

=N)

143ndash121(qu

inox)

975(C1CH

ndashNH)774751709


309

(M+1)



Compcode



NH

HN O

N

HN O

OH

HHO H

HHO

H

H

OH NH

HN O

N

HN

O

OH

OH

H

H

H

H






3 Experimental



18


6CDCl

3as



using DMSO-d6CDCl











4 Conclusion






Acknowledgment


References








































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



Compcode



NH

HN O

N

HN O

OH

HHO H

HHO

H

H

OH NH

HN O

N

HN

O

OH

OH

H

H

H

H






3 Experimental



18


6CDCl

3as



using DMSO-d6CDCl











4 Conclusion






Acknowledgment


References








































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


using DMSO-d6CDCl











4 Conclusion






Acknowledgment


References








































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of





Acknowledgment


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

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