Research Article 1,3,4-Oxadiazole Derivatives: Synthesis

Research Article134-Oxadiazole Derivatives Synthesis CharacterizationAntimicrobial Potential and Computational Studies

Suman Bala1 Sunil Kamboj1 Anu Kajal1 Vipin Saini1 and Deo Nanadan Prasad2

1 M M College of Pharmacy Maharishi Markandeshwar University Mullana Ambala Haryana 133207 India2 Shivalik College of Pharmacy Nangal Punjab 140126 India

Correspondence should be addressed to Suman Bala sumankmj7gmailcom

Received 11 February 2014 Revised 3 April 2014 Accepted 6 April 2014 Published 24 July 2014

Academic Editor Antonello Merlino

Copyright copy 2014 Suman Bala 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

We report the synthesis and biological assessment of 134-oxadiazole substituted 24 derivatives as novel potential antibacterialagents The structures of the newly synthesized derivatives were established by the combined practice of UV IR 1H NMR 13CNMR and mass spectrometry Further these synthesized derivatives were subjected to antibacterial activity against all the selectedmicrobial strains in comparison with amoxicillin and cefixime The antibacterial activity of synthesized derivatives was correlatedwith their physicochemical and structural properties by QSAR analysis using computer assisted multiple regression analysis andfour sound predictive models were generated with good 1198772 1198772adj and Fischer statistic The derivatives with potent antibacterialactivity were subjected to molecular docking studies to investigate the interactions between the active derivatives and amino acidresidues existing in the active site of peptide deformylase to assess their antibacterial potential as peptide deformylase inhibitor

1 Introduction

Oxadiazoles are the heterocyclic compounds containing oneoxygen and two nitrogen atoms in a five membered ring[1 2] possessing a diversity of useful biological effects[3]Oxadiazole is considered to be resultant from furanby replacement of two methane (ndashCH=) groups by twopyridine type nitrogen atoms (ndashN=) [2] Several methodshave been reported in the literature for the synthesis of134-oxadiazoles The commonly used synthetic route for134-oxadiazoles includes reactions of acid hydrazides (orhydrazine) with acid chloridescarboxylic acids and directcyclization of diacylhydrazines using a variety of dehydratingagents such as phosphorous oxychloride [3] thionyl chlo-ride [4] phosphorous pentaoxide [5] triflic anhydride [6]polyphosphoric acid [7] and direct reaction of acid with (N-isocyanimino-) triphenylphosphorane [8ndash11]

Researchers have already reported that gram positivebacteria are much more susceptible to antimicrobial agentsas compared to gram negative bacteria [12]These differencesmay be attributed to the fact that the cell wall in gram positivebacteria is of single layer whereas the gram negative bacteriahave multilayered cell wall Gram negative bacteria possess

an outer membrane and a unique periplasmic space whichis not found in gram positive bacteria [13] The resistanceof gram negative bacteria towards antibacterial substances isdue to more lipophilic nature of membrane which acts as abarrier for various antimicrobial compounds It was expectedthat hydrophilic compounds are unable to penetrate the cellmembranes of these bacteria Gram positive bacteria do nothave such outer membrane and complex cell wall structureAntibacterial substances can easily destroy the bacterial cellwall and cytoplasmic membrane of gram positive bacteriawhich results in leakage of the cytoplasm [14]

Peptide deformylase (PDF) is a vital and extremelyconserved enzyme belongs to a subfamily of metalloprotease[15] andhas emerged out as a target of efforts to develop novelantibacterial agents [16] It embraces iron and is responsiblefor proteinmaturation by the exclusion of theN-formyl groupfrom the terminalmethionine residue through Fe2+mediatedcatalysis which leads to inhibition of protein synthesis inbacteria [17]

Computational studies are the crucial steps in the drugdesigning There are numerous areas of computational stud-ies and one of them is identification of relationships between

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 172791 18 pageshttpdxdoiorg1011552014172791

2 BioMed Research International

chemical structures and properties and recognized as QSARQuantitative structural activity relationship practices molec-ular parameters to enumerate a pharmacological or chemicalproperty for a set of molecules [18]

Docking study is the computational routine to determineprobable binding manners of a ligand to the dynamic siteof a receptor It makes an image of the dynamic site withinteraction points known as gridThen it fits the ligand in thebinding site either by grid search or energy search [19]

In the present paper we have explored substituted 134-oxadiazole derivatives as antibacterial agentswith the supportof QSAR and molecular docking studies by targeting theenzyme peptide deformylase

2 Chemistry

The substituted aromatic acids were used as a versatilestartingmaterial for the synthesis of 134-oxadiazoles deriva-tives involving the formation of corresponding esters andhydrazides Ethyl esters were synthesized from substitutedaromatic acids by means of Fischer esterification which werefurther reacted with hydrazine hydrate in presence of ethanolto get corresponding hydrazide derivative The hydrazidederivatives then reacted with 120573-benzoyl propionic acid inthe presence of phosphorus oxychloride (cyclodehydratingagent) to get final compounds 6andashh (Figure 1)The chemistryof compounds 8andashh was already reported in our previousstudies [20]The substituted aromatic acid hydrazides from o-benzoyl benzoic acid reacted with aromatic aldehydes underslight acidic conditions to get the substituted hydrazonederivatives which were then cyclized in presence of bromineacetic acid and sodium acetate to get 134-oxadiazole deriva-tives (13andashh) (Figure 2) Reaction monitoring was done bymeans of thin layer chromatography (TLC) All the newsynthesized compounds were characterized by melting pointand spectroscopic analysis (UV-Visible IR 1H NMR 13CNMR and MS)

3 Experimental Section

31 Material and Method Reagent and solvents used wereobtained from commercial sources Analytical thin layerchromatography was carried out on TLC plates of 3 times 15 cmcoated with silica gel G for reactionmonitoring and for deter-mination of retardation factor Spots of TLC were located byiodine chamber Melting points of newly synthesized deriva-tives were determined on digital melting point apparatus(Flora Perfit India) and were found uncorrected (Table 2)The 120582max was calculated by using double beam UV-Visible1800 Shimadzu spectrophotometer and the values are givenin Table 2 The IR spectra were recorded on FTIR-Shimadzuspectrometer using Nujol method 1H NMR and 13C NMRspectra were recorded on BRUKER AVANCE II 400 NMRspectrometer operating at 400MHz and 125MHz respec-tively using CDCl

3 chemical shift values were expressed

in 120575 ppm For mass spectra solutions were made in HPLCgrade methanol and spectra were obtained with Vg-11-250J70S spectrophotometer at 70 eVusing electron ionization

(EI source) Chem 3D Ultra (version 10) was employed forstructural similarity studies QSAR studies were performedbymultiple linear regression analysis usingAnalyze-it version30 software Molegro Virtual Docker 500 software wasemployed for the molecular docking studies

32 General Procedure for the Synthesis of 1-(4-Methoxy-phenyl)-3-(5-phenyl-134-oxadiazol-2-yl)propan-1-one (6andashh) Aryl hydrazide 2a (1M) was dissolved in phosphorousoxychloride (5mL) and to it compound 5 (equimolar 1M)was added The reaction mixture after refluxing for 6-7hours was cooled to room temperature and poured ontocrushed ice On neutralization of the contents with sodiumbicarbonate solution (20) a solid mass separated out Thiswas filtered and washed with water It was crystallized byusing methanol to give 6a Similarly compounds (6bndashh)were prepared (Figure 1) [21 22] The corresponding R for6andashh is given in Table 1

321 1-(4-Methoxy-phenyl)-3-(5-phenyl-134-oxadiazol-2-yl)propan-1-one (6a) Yield 8990 yellow crystals mp (∘C)240ndash242 IR (Nujol cmminus1) 300317 (CHarom) 2818 (CHaliph)168579 (C=O) 159513 (C=N) 125566 (CndashOndashCasymm)116693 (CH bend) 101841 (CndashOndashCsymm) 93162 82360(CH bend) 1H NMR (CDCl

3 400MHz ppm) 81 (d 2H

H-p-methoxy phenyl (119869 = 7Hz) 79 (d 2H H-26-phenyl(119869 = 81Hz) 76 (d 3H H-345-phenyl (119869 = 77Hz) 71 (d2H H-p-methoxy phenyl (119869 = 73Hz) 38 (s 3H OCH

3)

31 (t 2H CH2(119869 = 64Hz) 29 (t 2H CH

2(119869 = 61Hz)

13C NMR (CDCl3) 246 (C-6) 412 (C-7) 1972 (C-8) 1365

(C-10) 1270 (C-1115) 1291 (C-1214) 1285 (C-13) 1297(C-16) 1295 (C-1721) 1142 (C-1820) 1659 (C-19) 562(C-22) MSmz 30812 30912 (M + 1) 31012 (M + 2)

322 1-(4-Methoxy-phenyl)-3-[5-(4-aminophenyl)-134-oxa-diazol-2-yl]propan-1-one (6b) Yield 830 light yellow crys-tals mp (∘C) 242-243 IR (Nujol cmminus1) 345065 (NH)299931 297038 (CH) 170314 (C=O) 169929 (C=N) 157777(NH) 128652 (CndashOndashCasymm) 1165 (CH) 105892 (CndashOndashCsymm) 92969 84269 (CH) 1H NMR (CDCl

3 400MHz

ppm) 799 (d 2H H-p-methoxy phenyl (119869 = 84Hz) 759(d 2H H-p-amino phenyl (119869 = 8Hz) 709 (d 2H H-p-methoxy phenyl (119869 = 78Hz) 649 (d 2H H-p-amino phenyl(119869 = 79Hz) 398 (s 2H NH

2) 379 (s 3H OCH

3) 310 (t

2H CH2(119869 = 66Hz) 289 (t 2H CH

2(119869 = 63Hz) 13C

NMR (CDCl3) 246 (C-6) 409 (C-7) 1975 (C-8) 1265 (C-

10) 1278 (C-1115) 1156 (C-1214) 1467 (C-13) 1297 (C-16)1296 (C-1721) 1140 (C-1820) 1662 (C-19) 558 (C-23) MSmz 32313 32412 (M + 1) 32515 (M + 2)

323 1-(4-Methoxy-phenyl)-3-[5-(4-hydroxyphenyl)-134-ox-adiazol-2-yl]propan-1-one (6c) Yield 8980 yellowpowdermp (∘C) 25500 IR (Nujol cmminus1) 365318 (OH) 304560(CHarom) 276785 (CHaliph) 167035 (C=O) 160285 (C=N)154306 (C=C) 136560 (OH) 128266 (CndashOndashCasymm) 103192(CndashOndashCsymm) 76767 (CH) 1H NMR (CDCl

3 400MHz

ppm) 79 (d 2H H-p-methoxy phenyl (119869 = 78Hz) 77

BioMed Research International 3

RCO2H + C2H5OH RCO2C2H5 + H2O

Aromatic acid Absolute ethanol Aromatic ester

H3COO O O

+Anhydrous AlCl3 H3CO OH

O OPOCl3

H3CO

O

NN

R

RCO2NHNH2

5

O

3 4

1andashh

2andashh

2andashh

(6andashh)

Conc H2SO4

NH2NH2middotH2O

Figure 1 Synthetic scheme of 1-(4-methoxy-phenyl)-3-[5-(substituted phenyl)-134-oxadiazol-2-yl]propan-1-one (6andashh)

+ O

O

O

AlCl3

O CO2H

O CONHNH2

RCHOreflux

C

ONNH R

Benzene

Phthalic anhydride

9

OCO2Et

1110

ArCHOreflux

12andashh

OO

N

N

O

R

CH3COONa

Br2CH3COOH

13andashh

EtOHConc H2SO4

NH2NH2middotH2O

Figure 2 Synthetic scheme of [2-(5-substituted-phenyl-[134]oxadiazol-2-yl)-phenyl]phenyl-methanone (13andashh)

(d 2HH-p-hydroxy phenyl (119869 = 77Hz) 70 (d 2H H-p-methoxy phenyl (119869 = 80Hz) 68 (d 2 H-p-hydroxy phenyl(119869 = 80Hz) 49 (s 1HOH) 37 (s 3HOCH

3) 30 (t 2HCH

2

(119869 = 61Hz) 28 (t 2HCH2(119869 = 60Hz) 13CNMR (CDCl

3)

247 (C-6) 406 (C-7) 1976 (C-8) 1291 (C-10) 1284 (C-1115)1162 (C-1214) 1573 (C-13) 1297 (C-16) 1296 (C-1721) 1140

(C-1820) 1665 (C-19) 560 (C-23) MS mz 32411 32513(M + 1) 32612 (M + 2)

324 1-(4-Methoxy-phenyl)-3-[5-(2-hydroxyphenyl)-134-ox-adiazol-2-yl]propan-1-one (6d) Yield 8080 yellow crys-tals mp (∘C) 25300 IR (Nujol cmminus1) 362633 (OH)


Table 1 Substituted groups (R) of different synthesized compounds

Compound R R1015840

6a H3CO COC2H4

6b NH2 H3CO COC2H4

6c OH H3CO COC2H4

6d

HO

H3CO COC2H4

6e Cl H3CO COC2H4

6f

Cl

H3CO COC2H4

6g CH3 H3CO COC2H4

6h NO2 H3CO COC2H4

8a NH CO

8b NH2 NH C

O

8c OHO

NH C

8d

HO ONH C

8e ClO

NH C

8f

Cl

NH CO

8g CH3 NH C

O


Table 1 Continued

Compound R R1015840

8h NO2 NH C

O

13a C

O

13b Cl C

O

13c NO2 C

O

13d CH3 C

O

13e OH

OCH3

C

O

13f OH C

O

13g

O2N

C

O

13h

HO

C

O

302548 292517 (CH) 169840 (C=O) 160581 (C=N)152287 (C=C) 136373 (OH) 125957 (CndashOndashCasymm) 114866(CH) 101364 (CndashOndashCsymm) 89599 81785 73877 (CH) 1HNMR (CDCl

3 400MHz ppm) 79 (d 2H H-p-methoxy

phenyl (119869 = 84Hz) 76 (m 1H H-p-hydroxy phenyl (119869 =76Hz) 73 (m 1H H-o-hydroxy phenyl (119869 = 77Hz) 71(m 3H 2H-p-methoxy phenyl and 1H-o-hydroxy phenyl)69 (m 1H H-o-hydroxy phenyl (119869 = 81Hz) 44 (s 1H OH)38 (s 3HOCH

3) 31 (t 2HCH

2(119869 = 61Hz) 29 (t 2HCH

2

(119869 = 60Hz) 13C NMR (CDCl3) 244 (C-6) 409 (C-7) 1974

(C-8) 1237 (C-10) 1558 (C-11) 1162 (C-12) 1299 (C-13)1216 (C-14) 1284 (C-15) 1296 (C-16) 1294 (C-1721) 1141(C-1820) 1664 (C-19) 562 (C-23)MSmz 32411 32513 (M+ 1) 32612 (M + 2)

325 1-(4-Methoxy-phenyl)-3-[5-(4-chlorophenyl)-134-oxa-diazol-2-yl]propan-1-one (6e) Yield 7880 yellow powdermp (∘C) 270ndash272 IR (Nujol cmminus1) 306489 (CHarom)


Table 2 Physical properties and UV-Visible analysis of synthesized 134-oxadiazole derivatives

Compound Molecular formula Molecular weight Solubility 120582max 119877119891value

6a C18H16N2O3 30833 DMSO MeOH CHCl3 263 0546b C18H17N3O3 32335 DMSO MeOH CHCl3 278 0426c C18H16N2O3 32433 DMSO MeOH CHCl3 265 0476d C18H16N2O3 32433 DMSO MeOH CHCl3 250 0686e C18H15ClN2O3 34278 DMSO MeOH CHCl3 266 0406f C18H15ClN2O3 34278 DMSO MeOH CHCl3 265 0436g C19H18N2O3 32236 DMSO MeOH CHCl3 254 0416h C18H15N3O5 35333 DMSO MeOH CHCl3 245 03513a C21H14N2O2 32635 DMSO MeOH CHCl3 281 05113b C21H13ClN2O2 36079 DMSO MeOH CHCl3 281 05813c C21H13N3O4 37135 DMSO MeOH CHCl3 283 04913d C22H16N2O2 34037 DMSO MeOH CHCl3 281 05513e C22H16N2O4 37237 DMSO MeOH CHCl3 281 06113f C21H14N2O3 34235 DMSO MeOH CHCl3 285 06013g C21H13N3O4 37135 DMSO MeOH CHCl3 285 05813h C21H14N2O3 34235 DMSO MeOH CHCl3 283 067Mobile phase for TLC petroleum ether ethyl acetate MeOH (6 3 1)

274276 (CHaliph) 161442 (C=O) 153929 (C=N) 129224 (CndashOndashCasymm) 101841 (CndashOndashCsymm) 79653 (CH) 56707 (CndashCl) 1HNMR (CDCl

3 400MHz ppm) 79 (d 2H p-methoxy

phenyl (119869 = 768Hz) 77 (d 2H p-chloro phenyl (119869 = 77Hz)75 (d 2H p-chloro phenyl (119869 = 80Hz) 71 (d 2H p-methoxyphenyl (119869 = 81Hz) 38 (s 3H OCH

3) 32 (t 2H CH

2(119869 =

61Hz) 30 (t 2H CH2(119869 = 60Hz) 13CNMR (CDCl

3) 244

(C-6) 408 (C-7) 1980 (C-8) 1346 (C-10) 1284 (C-1115)1294 (C-1214) 1338 (C-13) 1297 (C-16) 1297 (C-1721) 1140(C-1820) 1668 (C-19) 561 (C-23) MS mz 34208 34407(M + 1) 34308 (M + 2)

326 1-(4-Methoxy-phenyl)-3-[5-(2-chlorophenyl)-134-oxa-diazol-2-yl]propan-1-one (6f) Yield 7800 Yellow powdermp (∘C) 2730 IR (Nujol cmminus1) 307646 (CHarom) 274471(CHaliph) 161828 (C=O) 155655 (C=N) 105120 (CndashOndashC)82168 (CH) 59022 (CndashCl) 1H NMR (CDCl

3 400MHz

ppm) 80 (d 2HH-p-methoxy phenyl (119869 = 89Hz) 76 (m2HH-o-chloro phenyl (119869 = 81Hz) 74 (m 1H H-o-chlorophenyl) 72 (m 1H H-o-chloro phenyl) 71 (d 2H H-p-methoxy phenyl (119869 = 82Hz) 37 (s H OCH

3) 32 (t H CH

2

(119869 = 63Hz) 30 (t H CH2(119869 = 63Hz) 13C NMR (CDCl

3)

242 (C-6) 404 (C-7) 1969 (C-8) 1379 (C-10) 1274 (C-11)1343 (C-12) 1289 (C-13) 1304 (C-14) 1251 (C-15) 1289 (C-16) 1295 (C-1721) 1140 (C-1820) 1669 (C-19) 564 (C-23)MSmz 34208 34407 (M + 1) 34308 (M + 2)

327 1-(4-Methoxy-phenyl)-3-[5-(4-methylphenyl)-134-oxa-diazol-2-yl]propan-1-one (6g) Yield 7920 Brown crystalsmp (∘C) 250ndash253 IR (Nujol cmminus1) 302824 (CHarom)277942 (CHaliph) 169929 (C=O) 151412 (C=N) 130195(CndashOndashCasymm) 119008 (CndashOndashCsymm) 90847 81975 77346(CH) 1H NMR (CDCl

3 400MHz ppm) 78 (d 2H H-p-

methoxy phenyl (119869 = 84Hz) 75 (d 2H H-p-methyl phenyl

(119869 = 84Hz) 72 (d 2H H-p-methyl phenyl (119869 = 83Hz) 70(d 2H H-p-methoxy phenyl (119869 = 84Hz) 37 (s 3H OCH

3)

31 (t 2H CH2) 29 (t 2H CH

2(119869 = 62Hz) 23 (s 3H

CH3(119869 = 60Hz) 13C NMR (CDCl

3) 249 (C-6) 412 (C-

7) 1974 (C-8) 1335 (C-10) 1266 (C-1115) 1293 (C-1214)1377 (C-13) 1292 (C-16) 1294 (C-1721) 209 (C-22) 1142 (C-1820) 1665 (C-19) 560 (C-23) MSmz 32213 32314 (M +1) 32411 (M + 2)

328 1-(4-Methoxy-phenyl)-3-[5-(4-nitrophenyl)-134-oxad-iazol-2-yl]propan-1-one (6h) Yield 900 yellow crystalsmp (∘C) 25000 IR (Nujol cmminus1) 302438 2906 (CH)166264 (C=O) 163178 (C=N) 158742 (C=C) 151798(N=Oasymm) 131738 (N=Osymm) 106471 (CndashOndashC) 93933742 (CH) 1H NMR (CDCl

3 400MHz ppm) 84 (d 2H H-

p-nitro phenyl (119869 = 80Hz) 82 (d 2H H-p-methoxy phenyl(119869 = 77Hz) 78 (d 2H H-p-nitro phenyl (119869 = 78Hz) 70 (d2H H-p-methoxy phenyl (119869 = 76Hz) 37 (s 3H OCH

3) 31

(t 2H CH2(119869 = 63Hz) 29 (t 2H CH

2(119869 = 63Hz) 13C

NMR (CDCl3) 244 (C-6) 409 (C-7) 1976 (C-8) 1426 (C-

10) 1279 (C-1115) 1241 (C-1214) 1484 (C-13) 1297 (C-16)1296 (C-1721) 1140 (C-1820) 1664 (C-19) 560 (C-23) MSmz 35310 35411 (M + 1) 35511 (M + 2)

33 General Procedures for the Synthesis of [2-(5-Substituted-phenyl-[134]oxadiazol-2-yl)-phenyl]-phenyl-methanone(13andashh) A mixture of 12a (001M) anhydrous sodiumacetate (002M) and glacial acetic acid was placed inround bottomed flask equipped with separating funnelfor the addition of bromine Bromine (08mL in 5mL ofglacial acetic acid) was added slowly to it while stirringmagnetically After 2 hours of stirring the solution waspoured on crushed ice The resulting solid was separateddried and recrystallized from ethyl alcohol Similarly


compounds (13bndashh) were prepared (Figure 2) [23] Thecorresponding R for 13andashh is given in Table 1

331 2-[5-(4-Phenyl)-[134]oxadiazol-2-yl]-phenyl-phenyl-methanone (13a) Yield 7245 white crystals mp (∘C)29100 IR (Nujol cmminus1) 303017 (CH) 162792 (C=O)160092 (C=N) 151991 (C=C) 121909 (CndashOndashCasymm)104349 (CndashOndashCsymm) 92005 77924 73874 (CH) 1HNMR(CDCl

3 400MHz ppm) 83 (d 1H H-diphenyl methanone

(119869 = 84Hz) 79 (d 2H H-phenyl (119869 = 77Hz) 77 (m3H H-diphenyl methanone (119869 = 77Hz) 76 (m 1H H-diphenyl methanone) 75 (m 5H 2H-diphenyl methanoneand 3H-phenyl) 73 (m 2H diphenyl methanone) 13CNMR (CDCl

3) 1362 (C-6) 1286 (C-7) 1383 (C8) 1301

(C-9) 1287 (C-10) 1307 (C-11) 1365 (C-12) 1270 (C-1317)1290 (C-1416) 1285 (C-15) 1870 (C-18) 1378 (C-20) 1301(C-2125) 1282 (C-2224) 1322 (C-23) MS mz 3261432611 (M + 1) 32711 (M + 2)

332 2-[5-(4-Chlorophenyl)-[134]oxadiazol-2-yl]-phenyl-phenyl-methanone (13b) Yield 7660 yellow powder mp(∘C) 283ndash285 IR (Nujol cmminus1) 303403 291830 (CH)168386 (C=O) 158356 (C=N) 152184 (C=C) 125759 (CndashOndashCasymm) 117658 (CH) 105892 (CndashOndashCsymm) 92583 8117875610 (CH) 54585 (CndashCl) 1H NMR (CDCl

3 400MHz

ppm) 82 (d 1H H-diphenyl methanone) (119869 = 78Hz)78 (m 3HH-diphenyl methanone and 2H-p-chlorophenyl)76 (m 3HH-diphenyl methanone) 74 (m 2H diphenylmethanone (119869 = 78Hz) 72 (d 4H 2H-diphenyl methanoneand 2H-p-chlorophenyl) 13C NMR (CDCl

3) 1364 (C-6)

1285 (C-7) 1387 (C-8) 1305 (C-9) 1282 (C-10) 1309 (C-11)1346 (C-12) 1284 (C-1317) 1294 (C-1416) 1338 (C-15) 1872(C-18) 1374 (C-21) 1306 (C-2226) 1288 (C-2325) 1319 (C-24) MSmz 36007 36206 (M + 1) 36310 (M + 2)

333 2-[5-(4-Nitrophenyl)-[134]oxadiazol-2-yl]-phenyl-phenyl-methanone (13c) Yield 7550 brown crystals mp(∘C) 261ndash263 IR (Nujol cmminus1) 311504 292023 (CH)165107 (C=O) 162021 (C=N) 157199 (C=C) 149676(N=Oasymm) 136560 (N=Osymm) 120937 (CndashOndashCasymm)112064 (CH) 104735 (N=Osymm) 79853 (CH) 1H NMR(CDCl

3 400MHz ppm) 86 (d 2H H-p-nitrophenyl

(119869 = 77Hz) 83 (m 3H 1H-diphenyl methanone and2H-p-nitrophenyl) 79 (m 3H 1H-diphenyl methanone(119869 = 80Hz) 77 (m 3H 1H-diphenyl methanone(119869 = 77Hz) 74 (m 2H 1H-diphenyl methanone(119869 = 79Hz) 13C NMR (CDCl

3) 1360 (C-6) 1282 (C-

7) 1383 (C-8) 1309 (C-9) 1280 (C-10) 1304 (C-11) 1426(C-12) 1279 (C-1317) 1241 (C-1416) 1484 (C-15) 1869(C-18) 1379 (C-21) 1282 (C-2226) 1272 (C-2325) 1299(C-24) MSmz 37109 37206 (M + 1) 37310 (M + 2)

334 2-[5-(4-Methylphenyl)-[134]oxadiazol-2-yl]-phenyl-phenyl-methanone (13d) Yield 7550 yellow powder mp(∘C) 257ndash259 IR (Nujol cmminus1) 3000 (CH) 165596 (C=O)1563337 (C=N) 152190 (C=C) 123642 (CndashOndashCasymm)

111105 (CH) 104161 (CndashOndashCsymm) 85836 82075 (CH)1H NMR (CDCl

3 400MHz ppm) 85 (d 1H 1H-diphenyl

methanone (119869 = 78Hz) 80 (d 2H p-methyl phenyl (119869 =80Hz) 78 (m 3H diphenyl methanone (119869 = 80Hz) 76 (m3H diphenyl methanone (119869 = 79Hz) 75 (m 2H diphenylmethanone (119869 = 76Hz) 71 (d 2H p-methyl phenyl (119869 =77Hz) 24 (s 3H CH

3) 13C NMR (CDCl

3) 1369 (C-6)

1282 (C-7) 1387 (C-8) 1305 (C-9) 1282 (C-10) 1309 (C-11) 1335 (C-12) 1269 (C-1317) 1297 (C-1416) 1377 (C-15)1872 (C-18) 209 (C-20) 1374 (C-21) 1306 (C-2226) 1288(C-2325) 1319 (C-24) MSmz 34010 34112 (M + 1) 34211(M + 2)

335 2-[5-(3-Methoxy-4-hydroxyphenyl)-[134]oxadiazol-2-yl]-phenyl-phenyl-methanone (13e) Yield 7880 yellowpowder mp (∘C) 268ndash271 IR (Nujol cmminus1) 360511 (OH)307370 303223 (CH) 166271 (C=O) 155855 (C=N) 151033(C=C) 131069 (OH) 125475 (CndashOndashC) 111780 (CH) 9837483521 (CH) 1H NMR (CDCl

3 400MHz ppm) 84 (d 1H

H-diphenyl methanone (119869 = 79Hz) 79 (m 3H H-diphenylmethanone (119869 = 76Hz) 775 (m 3H H-diphenyl methanone(119869 = 77Hz) 74 (m 3H 1H-p-hydroxy-3-methoxyphenyland 2H-diphenyl methanone) 72 (s 1H 1H-p-hydroxy-3-methoxyphenyl) 69 (d 1H 1H-p-hydroxy-3-methoxyphenyl (119869 = 75Hz) 55 (s 1HOH) 37 (s 3HOCH

3) 13C NMR

(CDCl3) 1301 (C-6) 1140 (C-7) 1497 (C-8) 1429 (C-9) 1172

(C-10) 1207 (C-11) 1368 (C-12) 1279 (C-13) 1380 (C-14)1294 (C-15) 1284 (C-16) 1301 (C-17) 563 (C-18) 1881 (C-20) 1378 (C-21) 1299 (C-2327) 1285 (C-2426) 1319 (C-25)MSmz 37211 37313 (M + 1) 37412 (M + 2)

336 2-[5-(4-Hydroxyphenyl)-[134]oxadiazol-2-yl]-phen-yl-phenyl-methanone (13f) Yield 800 light yellowpowder mp (∘C) 294-295 IR (Nujol cmminus1) 362425 (OH)302438 (CH) 166714 (C=O) 158934 (C=N) 155463 (C=C)140225 (OH) 124794 (CndashOndashC) 112643 (CH) 9337086218 76960 (CH) 1H NMR (CDCl

3 400MHz ppm)

83 (d 1H H-diphenyl methanone (J = 81Hz) 79 (m5H 2H-4-hydroxy phenyl 3H-diphenyl methanone) 76(m 3H H-diphenyl methanone (119869 = 78Hz) 739 (m 2HH-diphenyl methanone (119869 = 78Hz) 73 (m 2H H-diphenylmethanone (119869 = 81Hz) 69 (d 2HH-p-hydroxy phenyl(119869 = 78 Hz) 509 (s 1HOH) 13C NMR (CDCl

3) 1369

(C-6) 1282 (C-7) 1387 (C-8) 1305 (C-9) 1282 (C-10)1309 (C-11) 1291 (C-12) 1284 (C-1317) 1162 (C-1416) 1573(C-15) 1872 (C-18) 209 (C-20) 1374 (C-21) 1306 (C-2226)1288 (C-2325) 1319 (C-24) MSmz 34210 34318 (M + 1)34411 (M + 2)

337 2-[5-(2-Nitrophenyl)-[134]oxadiazol-2-yl]-phenyl-phenyl-methanone (13g) Yield 7585 yellow crystals mp(∘C) 237ndash239 IR (Nujol cmminus1) 292035 (CH) 166850(C=O) 152287 (C=N) 151804 (C=C) 151129 (N=Oasymm)137145 (N=Osymm) 126536 (CndashOndashC) 116023 110815109851 (CH) 75806 (CH) 1H NMR (CDCl

3 400MHz

ppm) 83 (d 1H H-diphenyl methanone (119869 = 82Hz)


80 (m 2H o-nitrophenyl (119869 = 77Hz) 77 (m 4H 1H-o-nitrophenyl and 3H-diphenyl methanone) 75 (m 2H1H-o-nitrophenyl and 1H-diphenyl methanone) 74 (m 4HH-diphenyl methanone (119869 = 78Hz) 13C NMR (CDCl

3)

1316 (C-6) 1469 (C-7) 1241 (C-8) 1294 (C-9) 1351 (C-10)1279 (C-11) 1359 (C-12) 1279 (C-13) 1380 (C-14) 1294(C-15) 1284 (C-16) 1301 (C-17) 1870 (C-19) 1374 (C-21)1306 (C-2226) 1288 (C-2325) 1319 (C-24) MSmz 3711037209 (M + 1) 37310 (M + 2)

338 2-[5-(2-Hydroxyphenyl)-[134]oxadiazol-2-yl]-phen-yl-phenyl-methanone (13h) Yield 780 yellow crystalsmp(∘C) 254-255 IR (Nujol cmminus1) 338121 (OH) 298774 (CH)160285 (C=O) 159127 (C=N) 135210 (OH) 107049 (CndashOndashC) 74259 (CH) 1H NMR (CDCl

3 400MHz ppm) 85 (s

1H OH) 839 (d 1H H-diphenyl methanone (119869 = 85Hz)781 (m 3H H-diphenyl methanone (119869 = 75Hz) 761 (m5H H-diphenyl methanone and o-hydroxy phenyl) 73(m 1H H-diphenyl methanone (119869 = 82Hz) 68 (m 1Ho-hydroxy phenyl (119869 = 77Hz) 67 (m 1H o-hydroxy phenyl(119869 = 76Hz) 65 (m 1H o-hydroxy phenyl (119869 = 77Hz) 13CNMR (CDCl

3) 1237 (C-6) 1558 (C-7) 1162 (C-8) 1299

(C-9) 1216 (C-10) 1284 (C-11) 1359 (C-12) 1279 (C-13)1380 (C-14) 1294 (C-15) 1284 (C-16) 1301 (C-17) 1870(C-19) 1374 (C-21) 1306 (C-2226) 1288 (C-2325) 1319(C-24) MSmz 34210 34312 (M + 1) 34411 (M + 2)

4 Antibacterial Evaluation

41 Antibacterial Activity The antibacterial evaluation wascarried out by using agar cup-plate method The microor-ganisms Escherichia coli Pseudomonas aeruginosa Staphy-lococcus epidermidis and Staphylococcus aureus were usedfor the antibacterial evaluation Nutrient agar media wereprepared and then inoculated with fresh prepared culturemedia The inoculated media were poured into Petri dishand allowed to set Cups were made by punching the agarsurface with a sterile cork bore (8mm) Solutions containing10 125 25 50 100 200 400 800 and 1600 120583gmL ofthe test derivatives in dimethyl formamide (DMF) wereadded to each cup Amoxicillin and cefixime were taken aspositive control and DMF was taken as blank The plateswere incubated at 37∘C for 24 hours and the results wererecorded The zones of inhibition of the microbial growthproduced by different concentration of test compounds weremeasured in millimeters [24 25] The zone of inhibition datafor antibacterial compounds is summarized in Table 3

42Minimum Inhibitory Concentration (MIC) Nutrient agarwas prepared sterilized and cooled to 45∘C with gentleshaking to bring about uniform cooling It was inoculatedwith 05-06mL of culture and mixed well by gentle shakingbefore pouring into the sterilized petri dishes The pouredmaterials were allowed to set and thereafter the cups weremade by punching into the agar surface with sterile corkborer and scooping out the punched part of the agar 01mLof each test compounds was added into the cups withthe help of sterile syringe Twofold diluted solutions of the

Compounds

050100150200250300350400

6a 6b 6c 6d 6e 6f 6g 6h 13a

13b

13c

13d

13e

13f

13g

13h

Con

trol

Am

oxic

illin

Cefi

xim

e

MIC

(120583g

mL)

E coliP aeruginosa

Figure 3 Minimum inhibitory concentrations (MIC) of synthe-sized 134-oxadiazole derivatives and standard drugs against gramnegative bacterial strains

Compounds

6a 6b 6c 6d 6e 6f 6g 6h 13a

13b

13c

13d

13e

13f

13g

13h

Con

trol

Am

oxic

illin

Cefi

xim

e

MIC

(120583g

mL)

S aureusS epidermidis

400

300

200

100

0

Figure 4 Minimum inhibitory concentrations (MIC) of synthe-sized 134-oxadiazole derivatives and standard drugs against grampositive bacterial strains

compounds and reference drugs were used (65 125 2550 100 200 400 800 and 1600 120583gmL) The drug solutionswere allowed to diffuse for some time into the mediumThe plates were incubated at 30ndash35∘C for 24ndash48 hours Theincubation chamber was kept sufficiently humid MIC valueswere determined at the end of the incubation period TheMIC values for synthesized compounds are summarized inTable 4 and graphical representation of MIC of synthesized134-oxadiazole derivatives and standard drugs against gramnegative and gram positive bacterial strains are given inFigures 3 and 4 (Table 4) respectively [24 25]

43 QSAR Analysis The compounds were analyzed by mul-tiple regression analysis a QSAR approach using differentphysicochemical parameters as independent and biologicalactivity as dependent variables [26] Multiple linear regres-sion efforts to maximize the fit of the data to a QSARmodel for the biological activity by correcting each of theexisting parameters Successive regression models will begenerated in which parameters will be either added orremoved until themaximum 1199032 andminimumS are obtained


Table 3 Zone of inhibition of synthesized 134-oxadiazole derivatives against selected microbial strains

Compound Concentration (120583gmL) Zone of inhibition (mm)E coli P aeruginosa S aureus S epidermidis

6a100 1600 plusmn 020 mdash 1081 plusmn 050 1217 plusmn 016

200 2180 plusmn 015 mdash 1180 plusmn 040 1498 plusmn 022


6b100 1590 plusmn 090 mdash 1503 plusmn 010 1401 plusmn 034

200 1899 plusmn 010 1202 plusmn 018 1601 plusmn 021 1317 plusmn 017


6c100 1311 plusmn 020 mdash 1411 plusmn 011 mdash200 1401 plusmn 002 mdash 1703 plusmn 025 1101 plusmn 013


6d100 1403 plusmn 019 1203 plusmn 023 1511 plusmn 012 mdash200 1500 plusmn 011 1411 plusmn 011 1617 plusmn 017 1407 plusmn 024


6e100 2002 plusmn 009 1412 plusmn 012 1500 plusmn 010 1698 plusmn 023



6f100 1593 plusmn 040 1413 plusmn 011 1205 plusmn 023 2013 plusmn 011



6g100 1611 plusmn 011 mdash 1412 plusmn 013 1220 plusmn 020



6h100 1593 plusmn 006 mdash 1591 plusmn 090 1406 plusmn 029



13a50 2097 plusmn 017 1840 plusmn 016 1599 plusmn 014 1291 plusmn 006



13b50 1989 plusmn 011 1310 plusmn 015 2207 plusmn 021 1605 plusmn 031



13c50 2210 plusmn 009 1591 plusmn 050 2404 plusmn 007 2010 plusmn 011



13d50 1406 plusmn 011 2002 plusmn 018 1601 plusmn 021 2000 plusmn 007









13g50 1412 plusmn 013 1191 plusmn 090 1605 plusmn 026 1600 plusmn 022



13h50 2003 plusmn 015 1110 plusmn 009 1401 plusmn 032 1980 plusmn 019




Table 3 Continued


Amoxicillin200 2200 plusmn 067 mdash 1098 plusmn 010 2409 plusmn 010



Cefixime200 1600 plusmn 028 mdash mdash 1488 plusmn 012

400 1815 plusmn 017 mdash mdash 1599 plusmn 030


Values are expressed as mean plusmn standard deviation of the three replicatesDiameter of the well is not included in zone of inhibition

Table 4 Minimum inhibitory concentrations (MIC) of synthesized 134-oxadiazole derivatives

Compound MIC (120583gmL)E coli P aeruginosa S aureus S epidermidis C albicans A niger

6a 50 100 50 200 50 1006b 50 200 50 100 25 2006c 25 200 100 100 200 506d 200 200 100 200 200 1006e 25 100 25 100 200 506f 125 100 100 125 125 256g 50 100 100 50 25 256h 25 100 50 25 50 20013a 25 200 25 50 50 5013b 125 125 100 125 125 1013c 25 25 100 25 25 1013d 25 25 50 50 50 5013e 125 25 25 25 100 1013f 50 50 100 25 25 2513g 50 25 50 50 50 10013h 50 100 200 25 100 200Control mdash mdash mdash mdash mdash mdashAmoxicillin 125 200 100 125 mdash mdashCefixime 50 400 400 50 mdash mdashFluconazole mdash mdash mdash mdash 125 400

The extent of coefficients obtained in this routine specifies thevirtual contribution of the associated parameters to biologicalactivity

Biological activity data was converted to the logarithmicvalue The biological activities used in the present studieswere expressed as pMIC

50 logarithm of a reciprocal con-

centration for 50 inhibition where MIC50is the minimum

inhibitory concentration of the compounds producing 50reduction in the effect caused by bacteria (Escherichia coliPseudomonas aeruginosa Staphylococcus epidermidis andStaphylococcus aureus) is stated as a mean of at least threeexperiments for 24 compounds [26 27]

The physicochemical parameters were computed(Table 5) using Chem 3D Ultra 10 after energy minimizationto minimum root mean square (RMS) gradient of0100 kcalmole A by MOPAC software package Theparameters Log P SAS MR ovality MSA and MW wereselected in QSAR studies which are having significant effecton biological activity

44 Molecular Docking Studies Docking studies reportedhere IN were performed using software Molegro VirtualDocker 500

The newly synthesized 134-oxadiazoles derivatives werecomputationally designed and optimized to investigate theinteractions between the target compounds and the aminoacid residues of the E coli PDFNi enzyme by moleculardocking [15] Target compounds were docked into activesite of PDF (PDB code 1G2A) using MVD (version 500)software to observe the affinity for the enzyme and alsocompared their binding energies with standard drugs such asamoxicillin and cefixime

5 Results and Discussion

51 Chemistry The structures of all the newly synthesizedderivatives were confirmed by chromatographic and spectro-scopic (IR 1H-NMR 13C NMR and mass) methods Both


Table 5 Observed and predicted antibacterial activity of synthesized 134-oxadiazole derivatives against Escherichia coli and Pseudomonasaeruginosa

Compounds Observed activity Calculated activity Residuals Observed activity Calculated activity Residuals6a 139794 142696 minus002902 139794 1380355 00175856b 139794 149081 minus009287 mdash mdash mdash6c mdash mdash 169897 1693166 00058046d mdash mdash mdash 169897 1749717 minus0050756e 109691 117324 minus007633 mdash mdash mdash6f mdash mdash mdash 169897 1739458 minus0040496g 139794 128492 0113024 169897 1565732 01332388a 109691 110285 minus000594 mdash mdash mdash8b 109691 122329 minus012638 mdash mdash mdash8c 109691 101685 0080062 mdash mdash mdash8d 2 195106 0048936 2 2143298 minus014338e mdash mdash mdash mdash mdash mdash8f 169897 166784 0031132 mdash mdash mdash8g 109691 10879 0009007 139794 1417768 minus00198313a 109691 12223 minus012539 109691 1241458 minus01445513b 079588 09957 minus019982 169897 159415 01048213d 109691 113534 minus003843 139794 1422187 minus00242513e 079588 080956 minus001368 mdash mdash mdash13f 139794 103279 0365149 169897 1642724 005624613h 109691 111426 minus001735 2 1769982 0230018(mdash) Compounds are not included in QSAR model development

analytical and spectral data of all the synthesized deriva-tives were in full agreement with the proposed structuresThe characteristic C=N band (1680ndash1520 cmminus1) of mediumintensity and a medium-strong band at 1300ndash1050 cmminus1 wereidentified in each IR spectra the latter could be attributed tothe CndashOndashC vibration or heteroatom ring deformation of theoxadiazole ring 1H NMR showed characteristic doublets at(78ndash82) and 70-71) due to aromatic protons of p-methoxyphenyl for derivatives (6andashh)The presence of twomethylenegroups was confirmed by presence of doublets at (30ndash32)and (28ndash30) All the other aliphatic and aromatic protonswere observed within the expected regions 13C data alsosupported the structures of the synthesized derivatives Inthe mass spectra molecular ions of medium intensity andthe base peak usually belonged to the corresponding acyliumions and nitrile radical ions which are formed by the cleavageof heteroatom ring Both of these have been reported asa characteristic for this family This part concluded thesynthesis of 134-oxadiazole derivatives

52 Antibacterial Activity The antibacterial activity of thesynthesized derivatives was carried out by agar cup platemethod and the average radius of zone of inhibition (mm)andMIC (120583gmL) were recorded in comparison with amoxi-cillin and cefiximeThe zone of inhibition of 6e (2782plusmn0162063 plusmn 016 246 plusmn 011 and 2586 plusmn 017 at 400120583gmL)8h (2897 plusmn 016 239 plusmn 01 2604 plusmn 014 and 2691 plusmn 019 at1600 120583gmL) 13b (2895plusmn018 1811plusmn011 2616plusmn018 and269plusmn014 at 200120583gmL) 13c (2815plusmn018 2213plusmn015 2708plusmn 024 and 28 plusmn 008 at 200120583gmL) and 13e (2801 plusmn 0182217 plusmn 02 2834 plusmn 024 and 2808 plusmn 007 at 200120583gmL) was

found to be goodwhich is comparable with zone of inhibitionof amoxicillin (30plusmn01 1399plusmn023 1812plusmn012 and 3206plusmn022 at 800120583gmL) and cefixime (2218plusmn022 12 plusmn 038 1203plusmn 019 and 2003 plusmn 015 at 800120583gmL) indicated that thesederivatives have potent antibacterial activity No inhibitoryeffectwas observed forDMFAll the derivativeswere found tobe active against Pseudomonas aeruginosa and StaphylococcusaureusThezone of inhibition andMICand zone of inhibitionof all the synthesized derivatives is summarized in Table 3(Figure 3) and Table 4 (Figure 4) respectively

An introspection of the active compounds revealedthat different structural features of the compounds havemore influence on biological activity Three starting mate-rials which have been selected for design and develop-ment of novel substituted 134-oxadiazole derivatives includemethoxy benzene (anisole) N-phenyl anthranilic acid and o-benzoyl benzoic acid

(i) All these have a significant influence on increaseof lipophilicity which is responsible for the betteractivity of the tested compounds may be due to easypenetration of compounds in themicrobial cell mem-brane The inclusion of an oxadiazole moiety in thesynthesized compounds also showed high lipophilic-ity hypothesizing that this lipophilicity could facili-tate passage of these compounds through the bacterialmembrane All synthesized compounds have signifi-cant logP (octanol-water partition coefficient) whichaffect drug absorption distribution bioavailabilitydrug-receptor interactions metabolism and toxicityprofile


2

2

15

15

1

1

05

05

Observed activity

y = 08306x + 02131

R2 = 08307

Pred

icte

d ac

tivity

(a)

25

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 08255x + 0273

R2 = 08255

(b)

21

21

16

16

11

11

06

06

Pred

icte

d ac

tivity

Observed activity

y = 08891x + 01511

R2 = 08891

(c)

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 07958x + 03355

R2 = 07962

(d)

Figure 5 Plot of calculated pMIC50values against observed pMIC

50for QSAR model for (a) Escherichia coli (b) Pseudomonas aeruginosa

(c) Staphylococcus aureus and (d) Staphylococcus epidermidis

(ii) At one side of 134-oxadiazole nucleus substitutionwith phenyl ring or bulkier aromatic groups may alsooffer significant increase in the biological activity

(iii) The antimicrobial activity results indicated that thepresence of electron-withdrawing halogen groupsand nitro group at para and ortho position of thephenyl ring improved their biological activity On thebasis of biological data improvement in biologicalactivity was observed with an increase in electroneg-ativity of the molecule due to the presence of halogengroup (6e 6f 8e 8f and 13b) and nitro group (6h8h 13c and 13g)

53 QSAR Studies Multilinear regression is one of the vitalmethod of quantitative structure activity relationship whichis used for displaying linear correlation among a dependentvariable Y (biological activity MIC

50) and independent

variable X (physicochemical parameters)

531 QSAR Model for Antibacterial Activity againstEscherichia coli Consider the following

pMIC50= minus 003664 (Log119875) + 006895 (SAS)

+ 009532 (MR) minus 4489 (Ovality)minus 006354 (MSA) minus 00167 (MW) + 4831

(1)

119873 = 16 1198772= 0831

1198772

adj = 0718 Press = 0244

1198762= 08304 119865 = 736 119878 = 0164

(2)

Here and hereafter 1198772 coefficient of correlation 1198772adjcoefficient of determination119865 Fischer statistics119873 numbersof synthesized derivatives 119878 standard error of estimate Presspredictive error sum of squares 1198762 cross validated 1198772 andBA biological activity

The observed and predicted antibacterial activity of syn-thesized 134-oxadiazole derivatives against Escherichia coli


Table 6 Observed and predicted antibacterial activities of 134-oxadiazole derivatives against Staphylococcus aureus and Staphylococcusepidermidis

Compounds Staphylococcus aureus Staphylococcus epidermidisObserved activity Calculated activity Residuals Observed activity Calculated activity Residuals

6a 169897 1747218 minus004825 2 2018882 minus00188806b 2 2061071 minus006107 169897 1726729 minus00277606c 2 1875044 0124956 169897 1573922 01250486d 2 1834783 0165217 mdash mdash mdash6e 169897 2002453 minus030348 169897 1740717 minus00417506f 169897 1827713 minus012874 mdash mdash mdash6g 169897 1462069 0236901 mdash mdash mdash8a mdash mdash mdash mdash mdash mdash8b 109691 117198 minus007507 169897 1591267 01077038c 109691 1151688 minus005478 169897 1732577 minus00336108d 2 1808758 0191242 139794 1343779 00541618e 2 1885819 0114181 109691 0887520 02093908f 169897 1552991 0145979 139794 1353518 00444228g 109691 1268834 minus017192 139794 1327929 007001113a mdash mdash mdash 139794 1308439 008950113b mdash mdash mdash 079588 1030457 minus02345813d 109691 1056386 0040524 139794 1425514 minus00275713e mdash mdash mdash 109691 1227397 minus01304913f 139794 1647697 minus024976 109691 1118010 minus00211013h 169897 1611633 0087337 109691 1165225 minus006832(mdash) Compounds are not included in QSAR model development

are summarized in Table 6 and plot of observed and predictedantibacterial activity is given in Figure 5

532 QSAR Model for Antibacterial Activity against Pseu-domonas aeruginosa Consider the following

pMIC50= minus 04431 (Log119875) minus 005285 (SAS)

minus 001438 (MR) minus 3004 (Ovality)

+ 01083 (MSA) + 001097 (MW) + 2893

(3)

119873 = 12 1198772= 0825

1198772

adj = 0616 Press = 0131

1198762= 0823 119865 = 394 119878 = 0161

(4)

The observed and predicted antibacterial activities ofsynthesized 134-oxadiazole derivatives against Pseudomonasaeruginosa are summarized in Table 6 and plot of observedand predicted antibacterial activity is given in Figure 5

533 QSARModel for Antibacterial Activity against Staphylo-coccus aureus Consider the following

pMIC50= 0007502 (Log119875) minus 001653 (SAS)


+ 007769 (MSA) minus 001452 (MW) + 1304

(5)

119873 = 16 1198772= 0889

1198772

adj = 0815 Press = 0170

1198762= 08887 119865 = 1202 119878 = 0137

(6)

The observed and predicted antibacterial activities of syn-thesized 134-oxadiazole derivatives against Staphylococcusaureus are summarized in Table 7 and plot of observed andpredicted antibacterial activities is given in Figure 5

534 QSARModel for Antibacterial Activity against Staphylo-coccus epidermidis Consider the following


+ 0004048 (MR) minus 6152 (Ovality)

minus 007843 (MSA) + 002144 (MW) + 6999

(7)

119873 = 16 1198772= 0796

1198772

adj = 0654 Press = 0394

1198762= 0792 119865 = 574 119878 = 0209

(8)

The observed and predicted antibacterial activities of syn-thesized 134-oxadiazole derivatives against Staphylococcusepidermidis are summarized in Table 7 and plot of observedand predicted antibacterial activities is given in Figure 5


Table 7 Ligand-receptor interaction of synthesized 134-oxadiazole derivatives with peptide deformylase

Compound Docking score (binding energy) Distance (A) Amino acid Group involved in interaction with receptor

6e minus77213 263 Lys 150 Oxygen of oxadiazole ring253 Lys 150 Nitrogen of oxadiazole ring

6f minus135787 272 Lys 150 Nitrogen of oxadiazole ring288 Lys 150 Oxygen of oxadiazole ring

8e minus146825 346 Lys 150 Nitrogen of oxadiazole ring427 Lys 150 Nitrogen of oxadiazole ring

8f minus138439350 Lys 150 Oxygen of oxadiazole ring321 Lys 150 Nitrogen of oxadiazole ring321 Lys 150 Nitrogen of oxadiazole ring

8h minus151632340 Lys 150 Oxygen of oxadiazole ring341 Lys 150 Nitrogen of oxadiazole ring319 Lys 150 Nitrogen of oxadiazole ring

13b minus8830 319 Arg 97 Oxygen of oxadiazole ring

13c minus96604331 Lys 150 Nitrogen of oxadiazole ring349 Lys 150 Oxygen of oxadiazole ring269 Arg 97 Nitrogen of nitro group

13e minus15344295 Lys 157 Oxygen of hydroxyl group202 Arg 153 Oxygen of methoxy group326 Lys 150 Oxygen of oxadiazole ring

13g minus81702 206 Arg 153 Oxygen of nitro group305 Arg 153 Oxygen of oxadiazole ring

Amoxicillin minus128027 354 Arg 153 Oxygen of ndashCOOH groupCefixime minus153288 276 Lys 150 Nitrogen of 120573-lactam

Ala 98(B)

Leu 99(B)

Arg 97(B)

Glu 87(B)

Lys 150(B)

Glu 88(B)

Arg 97(B)

Leu 99(B)

Lys 150(B)

Ala 98(B)

(6e998400)

(6f 998400)

Arg 97

(6e)

(6f)

Tyr 145

Arg 153

Leu 145

Lys 150

Val 100263

253

Leu 95

Ser 147

Leu 149

Ala 88

Ile 154

Leu 146

Leu 99

Lys 150 Arg 153

Ala 98 288

272

Glu 87

A

A

A

A

Figure 6 Binding modes of 6e and 6f (6e 6f as docking view and 6e1015840 6f1015840 as interaction view) with peptide deformylase where bluegreenlines and red lines represent hydrogen bonding and favourable steric interactions respectively


(8e998400)

Lys 150(B)

Lys 160(B)

Lys 160(B)

Arg 153(B)

(8h998400)

(8e)

(8f)

(8h)

Lys 150346427

Leu 146

Lys 150

Arg 153

Ala 98

321321

350

Lys 150

319341

340

Arg 153

Arg 97

98

Cl

(8f 998400)

A A

A

AA

AA

A

Figure 7 Binding modes of 8e 8f and 8h (8e 8f and 8h as docking views 8e1015840 8f1015840 and 8h1015840 as interaction views) with peptide deformylasewhere bluegreen lines and red lines represent hydrogen bonding and favourable steric interactions respectively

Plot of predicted pMIC50values against observed pMIC

50

for QSAR model of all bacterial strains is given in Figure 5From the above mentioned QSAR models the following

observations can be drawn

(i) The biological activity has shown dependence onLogP SAS MR ovality MSA and MW

(ii) The aromatic substituents like methoxy benzene (6andashh) N-phenyl anthranilic acid (8andashh) and o-benzoylbenzoic acid (13andashh) in addition to 134-oxadiazolemoiety which resulted in increased lipophilicity leadsto better biological activity

(iii) Also the presence of electron withdrawing group atpara and ortho positions in the compounds resultedin enhanced biological activities

(iv) The results suggested that the antimicrobial activitywas highly dependent on LogP SAS MR ovalityMSA and MW

(v) The derived models could be used in designing ofmore potent inhibitors against microbial infections

(vi) Six parameter correlation equations for antimicrobialactivity having good values of correlation coefficient(r2) and minimum standard error of estimate (S)developed against E coli P aeruginosa S aureus


Lys 157(B)

Lys 157(B)

Lys 157(B)

Lys 150(B)

Arg 153(B)

Arg 153(B)

Arg 153(B)

Gln 96(B)

Arg 97(B)

(13b998400)

(13c998400)(13c)

(13e998400)(13e)

(13g998400)(13g)

152 A

295 A252 A

206 A

360 A

189 A

Lys 157 B

Lys 157 B

Lys 157

Ile 154 B

Lys 150 B

Lys 150

Arg 153 B

Arg 153 B

Arg 153

Glu 95

Arg 97

Gln15

Gln 96

Ser

156

Lys 150Glu 87 Ala 98Leu 149

153

157

(13b)

Figure 8 Binding modes of 13b 13c 13e and 13g (13b 13c 13e and 13g as docking views 13b1015840 13c1015840 13e1015840 and 13g1015840 as interaction views) withpeptide deformylase where bluegreen lines and red lines represent hydrogen bonding and favourable steric interactions respectively


Arg 153(B)

Lys 150(B)

Lys 150(B)

Arg 153(B)

(cefixime998400)

(amoxicillin998400)

Ala 98

Ala 98

(amoxicillin)

(cefixime)

354 A

276 A

Arg 153

Arg 153

Lys 150

Lys 57

Lys 150

Ile 154

Ile 154

Leu 146

Leu 146

Figure 9 Binding modes of amoxicillin and cefixime (amoxicillin and cefixime as docking views amoxicillinrsquo and cefiximersquo as interactionviews) with peptide deformylase where bluegreen lines and red lines represent hydrogen bonding and favourable steric interactionsrespectively

and S epidermidis could be used for the predictionof biological activities of unknown and unavailablecompounds of this class

54 Molecular Docking Studies The results of docking studyof synthesized 134-oxadiazole derivatives (Table 7) (Figures6 7 8 and 9) with peptide deformylase depicted the hydro-gen bonding interactions with Lys 150 (6e 6f 8e 8f 8h 13cand 13e) Lys 157 (13e) Arg 97 (13b and 13c) and Arg 153(13e and 13g) The amino acids Lys 150 and Arg 153 wereinvolved in interaction with the standard drugs (cefiximeand amoxicillin) as well as the synthesized 134-oxadiazolederivatives The docking score of derivatives 6f 8e 8f 8hand 13e was found to be higher than amoxicillin and 13e wasfound to have the highest dock scoring derivative than that ofamoxicillin and cefixime

In synthesized 134-oxadiazole derivatives replacementof free carboxylic group by oxadiazole nucleus enhancedthe receptor interaction by formation of numerous hydro-gen bonds and favourable steric interactions with peptidedeformylaseThese results could be used for the developmentof novel potent and effective antimicrobial agents

The carbonyl nitro and 134-oxadiazole functionalities(acting as acceptor) whereas ndashNHndash and hydroxyl group(acting as donor) in the synthesized derivatives have playedvery imperative position in ligand-receptor interaction forthe creation of numerous hydrogen bonds Insertion of

electron withdrawing 134-oxadiazole offers an upgraded120587-electron delocalization across the donor-acceptor linksand affords significant electron transportation Results alsorevealed that the hydrogen bond distance is important indocking studiesThedistancemore than 32 A indicates feeblehydrogen bonding between ligand and receptor 26 Andash32 Arepresents virtuous hydrogen bonding and less than 25 Aindicates robust bonding Almost all the active derivativesshowed good hydrogen bonding with enzymes

6 Conclusion

Among all the synthesized derivatives 6e 6f 13b 86 8f 8h13c and 13e were observed as the best antibacterial agentsagainst all the selectedmicrobial strainsWhile studyingMICagainst bacterial strains compound 13bwith p-chloro and 13ewithm-methoxy and p-hydroxyl substitutions were found tobe the most active among all the derivatives In developedQSAR models six physicochemical parameters (LogP SASMR ovality MSA and MW) were instituted to be importantfor the antibacterial activity All the developed models havegood coefficient of correlation (0796ndash0885) coefficient ofdetermination (0616ndash0815) and cross validated 1198772 (0792ndash0888) with good Fischer statistics (394ndash1202) Among allthe synthesized compounds 13e was found to be most potentpeptide deformylase inhibitor with the highest dock score(minus15344) than that of amoxicillin and cefixime


Conflict of Interests

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

Acknowledgment

The authors are thankful to M M College of Pharmacy MM University Mullana Ambala for providing support andfacility to carry out research

References

[1] P Sengupta M Mal S Mandal J Singh and T K MaityldquoEvaluation of antibacterial and antifungal activity of some1 3 4 oxadiazolesrdquo Iranian Journal of Pharmacology andTherapeutics vol 7 no 2 pp 165ndash167 2008

[2] N Bhardwaj S K Saraf P Sharma and P Kumar ldquoSynthesesevaluation and characterization of some 1 3 4-oxadiazoles asantimicrobial agentsrdquo E-Journal of Chemistry vol 6 no 4 pp1133ndash1138 2009

[3] A A Kadi N R El-Brollosy O A Al-Deeb E E Habib TM Ibrahim and A A El-Emam ldquoSynthesis antimicrobialand anti-inflammatory activities of novel 2-(1-adamantyl)-5-substituted-134-oxadiazoles and 2-(1-adamantylamino)-5-substituted-134-thiadiazolesrdquo European Journal of MedicinalChemistry vol 42 no 2 pp 235ndash242 2007

[4] V Mickevicius R Vaickelioniene and B Sapijanskaite ldquoSyn-thesis of substituted 134-oxadiazole derivativesrdquo Chemistry ofHeterocyclic Compounds vol 45 no 2 pp 215ndash218 2009

[5] F Bentiss andM Lagrenee ldquoAnew synthesis of symmetrical 25-disubstituted 134-oxadiazolesrdquo Journal of Heterocyclic Chem-istry vol 36 no 4 pp 1029ndash1032 1999

[6] S Liras M P Allen and B E Segelstein ldquoA mild method forthe preparation of 134-oxadiazoles triflic anhydride promotedcyclization of diacylhydrazinesrdquo Synthetic Communications vol30 no 3 pp 437ndash443 2000

[7] D Gomes C P Borges and J C Pinto ldquoStudy of the syn-thesis of poly(441015840-diphenylether-134-oxadiazole) in solutionsof poly(phosphoric acid)rdquo Polymer vol 42 no 3 pp 851ndash8652001

[8] A Souldozi and A Ramazani ldquoThe reaction of (N-isocyanimi-no)triphenylphosphorane with benzoic acid derivatives a novelsynthesis of 2-aryl-134-oxadiazole derivativesrdquo TetrahedronLetters vol 48 no 9 pp 1549ndash1551 2007

[9] A Ramazani B Abdian F Z Nasrabadi and M RouhanildquoThe reaction of N-isocyaniminotriphenylphosphorane withbiacetyl in the presence of (E)-cinnamic acids synthesis offully substituted 134-oxadiazole derivatives via intramolecularaza -wittig reactions of in situ generated iminophosphoranesrdquoPhosphorus Sulfur and Silicon and the Related Elements vol 188no 5 pp 642ndash648 2013

[10] A Ramazani F Zeinalia Nasrabadi and Y Ahmadi ldquoOne-potfour-component synthesis of fully substituted 134-oxadiazolederivatives from (Isocyanoimino)triphenylphosphorane a pri-mary amine an aromatic carboxylic acid and chloroacetonerdquoHelvetica Chimica Acta vol 94 no 6 pp 1024ndash1029 2011

[11] A Ramazani and A Souldozi ldquoIminophosphorane-mediatedone-pot synthesis of 134-oxadiazole derivativesrdquo Arkivoc vol2008 no 16 pp 235ndash242 2008

[12] R Franski ldquoBiological activities of the compounds bearing134-oxa(thia)diazole ringrdquo Asian Journal of Chemistry vol 17no 4 pp 2063ndash2075 2005

[13] J Parekh and S Chanda ldquoIn vitro antimicrobial activity of Trapanatans L fruit rind extracted in different solventsrdquo AfricanJournal of Biotechnology vol 6 no 6 pp 766ndash770 2007

[14] X Yao M Jericho D Pink and T Beveridge ldquoThickness andelasticity of gram-negative murein sacculi measured by atomicforce microscopyrdquo Journal of Bacteriology vol 181 no 22 pp6865ndash6875 1999

[15] D Kalemba and A Kunicka ldquoAntibacterial and antifungalproperties of essential oilsrdquo Current Medicinal Chemistry vol10 no 10 pp 813ndash829 2003

[16] R S Kumar R V Pradeepchandran and K N JayaveeraldquoComputer aided discovery of benzimidazole derivatives onpeptide deformylase as antimicrobial agent using HEXrdquo Euro-pean Journal of Chemistry vol 2 pp 558ndash560 2011

[17] R S Kumar R V Pradeepchandran and K N JayaveeraldquoDocking studies of benzimidazole derivatives on peptidedeformylase and heptosyltransferase waac as antibacterialagentrdquo International Journal of Pharmaceutical Research andInnovation vol 4 pp 1ndash5 2011

[18] C D Selassie History of Quantitative Structure Activity Rela-tionships Burgerrsquos Medicinal Chemistry and Drug DiscoveryedJohn Wiley amp Sons 6th edition 2003

[19] P P Mahulikar U D Patil A P Nikum and P S NagleldquoSynthesis antimicrobial and antifungal activity evaluationof 26-diaryl-4-SEC-aminonicotinonitriles and 4-sec-amino-6-aryl-2-(pyridin-2-YL)pyridine-3-carbonitriles ie Bipyridinesand their docking studyrdquo The Journal of Pharmacy vol 5 no3 pp 1383ndash1386 2012

[20] S Bala S Kamboj V Saini and D N Prasad ldquoSynthesischaracterization computational studies and evaluation of novelsubstituted 1 3 4-oxadiazolesrdquo International Journal of Phar-macy and Pharmaceutical Sciences vol 4 pp 131ndash135 2012

[21] A Husain and P Ahuja ldquoSynthesis and biological evaluation of-aroylpropionic acid based 134-oxadiazolesrdquo Indian Journal ofPharmaceutical Sciences vol 71 no 1 pp 62ndash66 2009

[22] A Husain M S Y Khan S M Hasan and M M Alamldquo2-Arylidene-4-(4-phenoxy-phenyl)but-3-en-4-olides synthe-sis reactions and biological activityrdquo European Journal ofMedicinal Chemistry vol 40 no 12 pp 1394ndash1404 2005

[23] H RajakM D Kharya and PMishra ldquoSynthesis of some noveloxadiazole and oxadiazoline analogues for their antiinflamma-tory activityrdquo Yakugaku Zasshi vol 127 no 10 pp 1757ndash17642007

[24] J G Cappucino and N Sherman Microbiology A LaboratoryManual Addison Wesley Longman New York NY USA 4thedition 1999

[25] Pharmacopoeia of India (The Indian Pharmacopoeia) Con-troller of Publications New Delhi India 1985

[26] G La Regina R Silvestri V Gatti et al ldquoSynthesis structure-activity relationships and molecular modeling studies of newindole inhibitors of monoamine oxidases A and Brdquo Bioorganicand Medicinal Chemistry vol 16 no 22 pp 9729ndash9740 2008

[27] W S Han J K Lee J-S Lee H-G Hahn and C N YoonldquoStudy of thiazoline derivatives for the design of optimalfungicidal compounds usingmultiple linear regression (MLR)rdquoBulletin of the Korean Chemical Society vol 33 no 5 pp 1703ndash1706 2012

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


chemical structures and properties and recognized as QSARQuantitative structural activity relationship practices molec-ular parameters to enumerate a pharmacological or chemicalproperty for a set of molecules [18]

Docking study is the computational routine to determineprobable binding manners of a ligand to the dynamic siteof a receptor It makes an image of the dynamic site withinteraction points known as gridThen it fits the ligand in thebinding site either by grid search or energy search [19]

In the present paper we have explored substituted 134-oxadiazole derivatives as antibacterial agentswith the supportof QSAR and molecular docking studies by targeting theenzyme peptide deformylase

2 Chemistry

The substituted aromatic acids were used as a versatilestartingmaterial for the synthesis of 134-oxadiazoles deriva-tives involving the formation of corresponding esters andhydrazides Ethyl esters were synthesized from substitutedaromatic acids by means of Fischer esterification which werefurther reacted with hydrazine hydrate in presence of ethanolto get corresponding hydrazide derivative The hydrazidederivatives then reacted with 120573-benzoyl propionic acid inthe presence of phosphorus oxychloride (cyclodehydratingagent) to get final compounds 6andashh (Figure 1)The chemistryof compounds 8andashh was already reported in our previousstudies [20]The substituted aromatic acid hydrazides from o-benzoyl benzoic acid reacted with aromatic aldehydes underslight acidic conditions to get the substituted hydrazonederivatives which were then cyclized in presence of bromineacetic acid and sodium acetate to get 134-oxadiazole deriva-tives (13andashh) (Figure 2) Reaction monitoring was done bymeans of thin layer chromatography (TLC) All the newsynthesized compounds were characterized by melting pointand spectroscopic analysis (UV-Visible IR 1H NMR 13CNMR and MS)

3 Experimental Section

31 Material and Method Reagent and solvents used wereobtained from commercial sources Analytical thin layerchromatography was carried out on TLC plates of 3 times 15 cmcoated with silica gel G for reactionmonitoring and for deter-mination of retardation factor Spots of TLC were located byiodine chamber Melting points of newly synthesized deriva-tives were determined on digital melting point apparatus(Flora Perfit India) and were found uncorrected (Table 2)The 120582max was calculated by using double beam UV-Visible1800 Shimadzu spectrophotometer and the values are givenin Table 2 The IR spectra were recorded on FTIR-Shimadzuspectrometer using Nujol method 1H NMR and 13C NMRspectra were recorded on BRUKER AVANCE II 400 NMRspectrometer operating at 400MHz and 125MHz respec-tively using CDCl

3 chemical shift values were expressed

in 120575 ppm For mass spectra solutions were made in HPLCgrade methanol and spectra were obtained with Vg-11-250J70S spectrophotometer at 70 eVusing electron ionization

(EI source) Chem 3D Ultra (version 10) was employed forstructural similarity studies QSAR studies were performedbymultiple linear regression analysis usingAnalyze-it version30 software Molegro Virtual Docker 500 software wasemployed for the molecular docking studies

32 General Procedure for the Synthesis of 1-(4-Methoxy-phenyl)-3-(5-phenyl-134-oxadiazol-2-yl)propan-1-one (6andashh) Aryl hydrazide 2a (1M) was dissolved in phosphorousoxychloride (5mL) and to it compound 5 (equimolar 1M)was added The reaction mixture after refluxing for 6-7hours was cooled to room temperature and poured ontocrushed ice On neutralization of the contents with sodiumbicarbonate solution (20) a solid mass separated out Thiswas filtered and washed with water It was crystallized byusing methanol to give 6a Similarly compounds (6bndashh)were prepared (Figure 1) [21 22] The corresponding R for6andashh is given in Table 1

321 1-(4-Methoxy-phenyl)-3-(5-phenyl-134-oxadiazol-2-yl)propan-1-one (6a) Yield 8990 yellow crystals mp (∘C)240ndash242 IR (Nujol cmminus1) 300317 (CHarom) 2818 (CHaliph)168579 (C=O) 159513 (C=N) 125566 (CndashOndashCasymm)116693 (CH bend) 101841 (CndashOndashCsymm) 93162 82360(CH bend) 1H NMR (CDCl

3 400MHz ppm) 81 (d 2H

H-p-methoxy phenyl (119869 = 7Hz) 79 (d 2H H-26-phenyl(119869 = 81Hz) 76 (d 3H H-345-phenyl (119869 = 77Hz) 71 (d2H H-p-methoxy phenyl (119869 = 73Hz) 38 (s 3H OCH

3)

31 (t 2H CH2(119869 = 64Hz) 29 (t 2H CH

2(119869 = 61Hz)

13C NMR (CDCl3) 246 (C-6) 412 (C-7) 1972 (C-8) 1365

(C-10) 1270 (C-1115) 1291 (C-1214) 1285 (C-13) 1297(C-16) 1295 (C-1721) 1142 (C-1820) 1659 (C-19) 562(C-22) MSmz 30812 30912 (M + 1) 31012 (M + 2)

322 1-(4-Methoxy-phenyl)-3-[5-(4-aminophenyl)-134-oxa-diazol-2-yl]propan-1-one (6b) Yield 830 light yellow crys-tals mp (∘C) 242-243 IR (Nujol cmminus1) 345065 (NH)299931 297038 (CH) 170314 (C=O) 169929 (C=N) 157777(NH) 128652 (CndashOndashCasymm) 1165 (CH) 105892 (CndashOndashCsymm) 92969 84269 (CH) 1H NMR (CDCl

3 400MHz

ppm) 799 (d 2H H-p-methoxy phenyl (119869 = 84Hz) 759(d 2H H-p-amino phenyl (119869 = 8Hz) 709 (d 2H H-p-methoxy phenyl (119869 = 78Hz) 649 (d 2H H-p-amino phenyl(119869 = 79Hz) 398 (s 2H NH

2) 379 (s 3H OCH

3) 310 (t

2H CH2(119869 = 66Hz) 289 (t 2H CH

2(119869 = 63Hz) 13C

NMR (CDCl3) 246 (C-6) 409 (C-7) 1975 (C-8) 1265 (C-

10) 1278 (C-1115) 1156 (C-1214) 1467 (C-13) 1297 (C-16)1296 (C-1721) 1140 (C-1820) 1662 (C-19) 558 (C-23) MSmz 32313 32412 (M + 1) 32515 (M + 2)

323 1-(4-Methoxy-phenyl)-3-[5-(4-hydroxyphenyl)-134-ox-adiazol-2-yl]propan-1-one (6c) Yield 8980 yellowpowdermp (∘C) 25500 IR (Nujol cmminus1) 365318 (OH) 304560(CHarom) 276785 (CHaliph) 167035 (C=O) 160285 (C=N)154306 (C=C) 136560 (OH) 128266 (CndashOndashCasymm) 103192(CndashOndashCsymm) 76767 (CH) 1H NMR (CDCl

3 400MHz

ppm) 79 (d 2H H-p-methoxy phenyl (119869 = 78Hz) 77




H3COO O O


O OPOCl3

H3CO

O

NN

R

RCO2NHNH2

5

O

3 4

1andashh

2andashh

2andashh

(6andashh)

Conc H2SO4

NH2NH2middotH2O


+ O

O

O

AlCl3

O CO2H

O CONHNH2

RCHOreflux

C

ONNH R

Benzene

Phthalic anhydride

9

OCO2Et

1110

ArCHOreflux

12andashh

OO

N

N

O

R

CH3COONa

Br2CH3COOH

13andashh

EtOHConc H2SO4

NH2NH2middotH2O



3) 30 (t 2HCH

2


3)

247 (C-6) 406 (C-7) 1976 (C-8) 1291 (C-10) 1284 (C-1115)1162 (C-1214) 1573 (C-13) 1297 (C-16) 1296 (C-1721) 1140

(C-1820) 1665 (C-19) 560 (C-23) MS mz 32411 32513(M + 1) 32612 (M + 2)




Compound R R1015840

6a H3CO COC2H4

6b NH2 H3CO COC2H4

6c OH H3CO COC2H4

6d

HO

H3CO COC2H4

6e Cl H3CO COC2H4

6f

Cl

H3CO COC2H4

6g CH3 H3CO COC2H4

6h NO2 H3CO COC2H4

8a NH CO

8b NH2 NH C

O

8c OHO

NH C

8d

HO ONH C

8e ClO

NH C

8f

Cl

NH CO

8g CH3 NH C

O


Table 1 Continued

Compound R R1015840

8h NO2 NH C

O

13a C

O

13b Cl C

O

13c NO2 C

O

13d CH3 C

O

13e OH

OCH3

C

O

13f OH C

O

13g

O2N

C

O

13h

HO

C

O




3) 31 (t 2HCH

2(119869 = 61Hz) 29 (t 2HCH

2

(119869 = 60Hz) 13C NMR (CDCl3) 244 (C-6) 409 (C-7) 1974










3) 32 (t 2H CH

2(119869 =


3) 244



3 400MHz


3) 32 (t H CH

2


3)



3 400MHz ppm) 78 (d 2H H-p-



3)

31 (t 2H CH2) 29 (t 2H CH

2(119869 = 62Hz) 23 (s 3H

CH3(119869 = 60Hz) 13C NMR (CDCl

3) 249 (C-6) 412 (C-



3 400MHz ppm) 84 (d 2H H-


3) 31

(t 2H CH2(119869 = 63Hz) 29 (t 2H CH

2(119869 = 63Hz) 13C

NMR (CDCl3) 244 (C-6) 409 (C-7) 1976 (C-8) 1426 (C-

10) 1279 (C-1115) 1241 (C-1214) 1484 (C-13) 1297 (C-16)1296 (C-1721) 1140 (C-1820) 1664 (C-19) 560 (C-23) MSmz 35310 35411 (M + 1) 35511 (M + 2)







3) 1362 (C-6) 1286 (C-7) 1383 (C8) 1301



3 400MHz


3) 1364 (C-6)





3) 1360 (C-6) 1282 (C-






3) 13C NMR (CDCl

3) 1369 (C-6)



3 400MHz ppm) 84 (d 1H


3) 13C NMR

(CDCl3) 1301 (C-6) 1140 (C-7) 1497 (C-8) 1429 (C-9) 1172



3 400MHz ppm)


3) 1369



3 400MHz




3)



3 400MHz ppm) 85 (s


3) 1237 (C-6) 1558 (C-7) 1162 (C-8) 1299





Compounds

050100150200250300350400

6a 6b 6c 6d 6e 6f 6g 6h 13a

13b

13c

13d

13e

13f

13g

13h

Con

trol

Am

oxic

illin

Cefi

xim

e

MIC

(120583g

mL)

E coliP aeruginosa


Compounds

6a 6b 6c 6d 6e 6f 6g 6h 13a

13b

13c

13d

13e

13f

13g

13h

Con

trol

Am

oxic

illin

Cefi

xim

e

MIC

(120583g

mL)


400

300

200

100

0






















































Table 3 Continued































2

2

15

15

1

1

05

05

Observed activity

y = 08306x + 02131

R2 = 08307

Pred

icte

d ac

tivity

(a)

25

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 08255x + 0273

R2 = 08255

(b)

21

21

16

16

11

11

06

06

Pred

icte

d ac

tivity

Observed activity

y = 08891x + 01511

R2 = 08891

(c)

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 07958x + 03355

R2 = 07962

(d)







50) and independent





(1)

119873 = 16 1198772= 0831

1198772

adj = 0718 Press = 0244

1198762= 08304 119865 = 736 119878 = 0164

(2)











+ 01083 (MSA) + 001097 (MW) + 2893

(3)

119873 = 12 1198772= 0825

1198772

adj = 0616 Press = 0131

1198762= 0823 119865 = 394 119878 = 0161

(4)





+ 007769 (MSA) minus 001452 (MW) + 1304

(5)

119873 = 16 1198772= 0889

1198772

adj = 0815 Press = 0170

1198762= 08887 119865 = 1202 119878 = 0137

(6)





minus 007843 (MSA) + 002144 (MW) + 6999

(7)

119873 = 16 1198772= 0796

1198772

adj = 0654 Press = 0394

1198762= 0792 119865 = 574 119878 = 0209

(8)















Ala 98(B)

Leu 99(B)

Arg 97(B)

Glu 87(B)

Lys 150(B)

Glu 88(B)

Arg 97(B)

Leu 99(B)

Lys 150(B)

Ala 98(B)

(6e998400)

(6f 998400)

Arg 97

(6e)

(6f)

Tyr 145

Arg 153

Leu 145

Lys 150

Val 100263

253

Leu 95

Ser 147

Leu 149

Ala 88

Ile 154

Leu 146

Leu 99

Lys 150 Arg 153

Ala 98 288

272

Glu 87

A

A

A

A



(8e998400)

Lys 150(B)

Lys 160(B)

Lys 160(B)

Arg 153(B)

(8h998400)

(8e)

(8f)

(8h)

Lys 150346427

Leu 146

Lys 150

Arg 153

Ala 98

321321

350

Lys 150

319341

340

Arg 153

Arg 97

98

Cl

(8f 998400)

A A

A

AA

AA

A



50










Lys 157(B)

Lys 157(B)

Lys 157(B)

Lys 150(B)

Arg 153(B)

Arg 153(B)

Arg 153(B)

Gln 96(B)

Arg 97(B)

(13b998400)

(13c998400)(13c)

(13e998400)(13e)

(13g998400)(13g)

152 A

295 A252 A

206 A

360 A

189 A

Lys 157 B

Lys 157 B

Lys 157

Ile 154 B

Lys 150 B

Lys 150

Arg 153 B

Arg 153 B

Arg 153

Glu 95

Arg 97

Gln15

Gln 96

Ser

156


153

157

(13b)



Arg 153(B)

Lys 150(B)

Lys 150(B)

Arg 153(B)

(cefixime998400)

(amoxicillin998400)

Ala 98

Ala 98

(amoxicillin)

(cefixime)

354 A

276 A

Arg 153

Arg 153

Lys 150

Lys 57

Lys 150

Ile 154

Ile 154

Leu 146

Leu 146







6 Conclusion





Acknowledgment


References



































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




H3COO O O


O OPOCl3

H3CO

O

NN

R

RCO2NHNH2

5

O

3 4

1andashh

2andashh

2andashh

(6andashh)

Conc H2SO4

NH2NH2middotH2O


+ O

O

O

AlCl3

O CO2H

O CONHNH2

RCHOreflux

C

ONNH R

Benzene

Phthalic anhydride

9

OCO2Et

1110

ArCHOreflux

12andashh

OO

N

N

O

R

CH3COONa

Br2CH3COOH

13andashh

EtOHConc H2SO4

NH2NH2middotH2O



3) 30 (t 2HCH

2


3)

247 (C-6) 406 (C-7) 1976 (C-8) 1291 (C-10) 1284 (C-1115)1162 (C-1214) 1573 (C-13) 1297 (C-16) 1296 (C-1721) 1140

(C-1820) 1665 (C-19) 560 (C-23) MS mz 32411 32513(M + 1) 32612 (M + 2)




Compound R R1015840

6a H3CO COC2H4

6b NH2 H3CO COC2H4

6c OH H3CO COC2H4

6d

HO

H3CO COC2H4

6e Cl H3CO COC2H4

6f

Cl

H3CO COC2H4

6g CH3 H3CO COC2H4

6h NO2 H3CO COC2H4

8a NH CO

8b NH2 NH C

O

8c OHO

NH C

8d

HO ONH C

8e ClO

NH C

8f

Cl

NH CO

8g CH3 NH C

O


Table 1 Continued

Compound R R1015840

8h NO2 NH C

O

13a C

O

13b Cl C

O

13c NO2 C

O

13d CH3 C

O

13e OH

OCH3

C

O

13f OH C

O

13g

O2N

C

O

13h

HO

C

O




3) 31 (t 2HCH

2(119869 = 61Hz) 29 (t 2HCH

2

(119869 = 60Hz) 13C NMR (CDCl3) 244 (C-6) 409 (C-7) 1974










3) 32 (t 2H CH

2(119869 =


3) 244



3 400MHz


3) 32 (t H CH

2


3)



3 400MHz ppm) 78 (d 2H H-p-



3)

31 (t 2H CH2) 29 (t 2H CH

2(119869 = 62Hz) 23 (s 3H

CH3(119869 = 60Hz) 13C NMR (CDCl

3) 249 (C-6) 412 (C-



3 400MHz ppm) 84 (d 2H H-


3) 31

(t 2H CH2(119869 = 63Hz) 29 (t 2H CH

2(119869 = 63Hz) 13C

NMR (CDCl3) 244 (C-6) 409 (C-7) 1976 (C-8) 1426 (C-

10) 1279 (C-1115) 1241 (C-1214) 1484 (C-13) 1297 (C-16)1296 (C-1721) 1140 (C-1820) 1664 (C-19) 560 (C-23) MSmz 35310 35411 (M + 1) 35511 (M + 2)







3) 1362 (C-6) 1286 (C-7) 1383 (C8) 1301



3 400MHz


3) 1364 (C-6)





3) 1360 (C-6) 1282 (C-






3) 13C NMR (CDCl

3) 1369 (C-6)



3 400MHz ppm) 84 (d 1H


3) 13C NMR

(CDCl3) 1301 (C-6) 1140 (C-7) 1497 (C-8) 1429 (C-9) 1172



3 400MHz ppm)


3) 1369



3 400MHz




3)



3 400MHz ppm) 85 (s


3) 1237 (C-6) 1558 (C-7) 1162 (C-8) 1299





Compounds

050100150200250300350400

6a 6b 6c 6d 6e 6f 6g 6h 13a

13b

13c

13d

13e

13f

13g

13h

Con

trol

Am

oxic

illin

Cefi

xim

e

MIC

(120583g

mL)

E coliP aeruginosa


Compounds

6a 6b 6c 6d 6e 6f 6g 6h 13a

13b

13c

13d

13e

13f

13g

13h

Con

trol

Am

oxic

illin

Cefi

xim

e

MIC

(120583g

mL)


400

300

200

100

0






















































Table 3 Continued































2

2

15

15

1

1

05

05

Observed activity

y = 08306x + 02131

R2 = 08307

Pred

icte

d ac

tivity

(a)

25

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 08255x + 0273

R2 = 08255

(b)

21

21

16

16

11

11

06

06

Pred

icte

d ac

tivity

Observed activity

y = 08891x + 01511

R2 = 08891

(c)

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 07958x + 03355

R2 = 07962

(d)







50) and independent





(1)

119873 = 16 1198772= 0831

1198772

adj = 0718 Press = 0244

1198762= 08304 119865 = 736 119878 = 0164

(2)











+ 01083 (MSA) + 001097 (MW) + 2893

(3)

119873 = 12 1198772= 0825

1198772

adj = 0616 Press = 0131

1198762= 0823 119865 = 394 119878 = 0161

(4)





+ 007769 (MSA) minus 001452 (MW) + 1304

(5)

119873 = 16 1198772= 0889

1198772

adj = 0815 Press = 0170

1198762= 08887 119865 = 1202 119878 = 0137

(6)





minus 007843 (MSA) + 002144 (MW) + 6999

(7)

119873 = 16 1198772= 0796

1198772

adj = 0654 Press = 0394

1198762= 0792 119865 = 574 119878 = 0209

(8)















Ala 98(B)

Leu 99(B)

Arg 97(B)

Glu 87(B)

Lys 150(B)

Glu 88(B)

Arg 97(B)

Leu 99(B)

Lys 150(B)

Ala 98(B)

(6e998400)

(6f 998400)

Arg 97

(6e)

(6f)

Tyr 145

Arg 153

Leu 145

Lys 150

Val 100263

253

Leu 95

Ser 147

Leu 149

Ala 88

Ile 154

Leu 146

Leu 99

Lys 150 Arg 153

Ala 98 288

272

Glu 87

A

A

A

A



(8e998400)

Lys 150(B)

Lys 160(B)

Lys 160(B)

Arg 153(B)

(8h998400)

(8e)

(8f)

(8h)

Lys 150346427

Leu 146

Lys 150

Arg 153

Ala 98

321321

350

Lys 150

319341

340

Arg 153

Arg 97

98

Cl

(8f 998400)

A A

A

AA

AA

A



50










Lys 157(B)

Lys 157(B)

Lys 157(B)

Lys 150(B)

Arg 153(B)

Arg 153(B)

Arg 153(B)

Gln 96(B)

Arg 97(B)

(13b998400)

(13c998400)(13c)

(13e998400)(13e)

(13g998400)(13g)

152 A

295 A252 A

206 A

360 A

189 A

Lys 157 B

Lys 157 B

Lys 157

Ile 154 B

Lys 150 B

Lys 150

Arg 153 B

Arg 153 B

Arg 153

Glu 95

Arg 97

Gln15

Gln 96

Ser

156


153

157

(13b)



Arg 153(B)

Lys 150(B)

Lys 150(B)

Arg 153(B)

(cefixime998400)

(amoxicillin998400)

Ala 98

Ala 98

(amoxicillin)

(cefixime)

354 A

276 A

Arg 153

Arg 153

Lys 150

Lys 57

Lys 150

Ile 154

Ile 154

Leu 146

Leu 146







6 Conclusion





Acknowledgment


References



































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



Compound R R1015840

6a H3CO COC2H4

6b NH2 H3CO COC2H4

6c OH H3CO COC2H4

6d

HO

H3CO COC2H4

6e Cl H3CO COC2H4

6f

Cl

H3CO COC2H4

6g CH3 H3CO COC2H4

6h NO2 H3CO COC2H4

8a NH CO

8b NH2 NH C

O

8c OHO

NH C

8d

HO ONH C

8e ClO

NH C

8f

Cl

NH CO

8g CH3 NH C

O


Table 1 Continued

Compound R R1015840

8h NO2 NH C

O

13a C

O

13b Cl C

O

13c NO2 C

O

13d CH3 C

O

13e OH

OCH3

C

O

13f OH C

O

13g

O2N

C

O

13h

HO

C

O




3) 31 (t 2HCH

2(119869 = 61Hz) 29 (t 2HCH

2

(119869 = 60Hz) 13C NMR (CDCl3) 244 (C-6) 409 (C-7) 1974










3) 32 (t 2H CH

2(119869 =


3) 244



3 400MHz


3) 32 (t H CH

2


3)



3 400MHz ppm) 78 (d 2H H-p-



3)

31 (t 2H CH2) 29 (t 2H CH

2(119869 = 62Hz) 23 (s 3H

CH3(119869 = 60Hz) 13C NMR (CDCl

3) 249 (C-6) 412 (C-



3 400MHz ppm) 84 (d 2H H-


3) 31

(t 2H CH2(119869 = 63Hz) 29 (t 2H CH

2(119869 = 63Hz) 13C

NMR (CDCl3) 244 (C-6) 409 (C-7) 1976 (C-8) 1426 (C-

10) 1279 (C-1115) 1241 (C-1214) 1484 (C-13) 1297 (C-16)1296 (C-1721) 1140 (C-1820) 1664 (C-19) 560 (C-23) MSmz 35310 35411 (M + 1) 35511 (M + 2)







3) 1362 (C-6) 1286 (C-7) 1383 (C8) 1301



3 400MHz


3) 1364 (C-6)





3) 1360 (C-6) 1282 (C-






3) 13C NMR (CDCl

3) 1369 (C-6)



3 400MHz ppm) 84 (d 1H


3) 13C NMR

(CDCl3) 1301 (C-6) 1140 (C-7) 1497 (C-8) 1429 (C-9) 1172



3 400MHz ppm)


3) 1369



3 400MHz




3)



3 400MHz ppm) 85 (s


3) 1237 (C-6) 1558 (C-7) 1162 (C-8) 1299





Compounds

050100150200250300350400

6a 6b 6c 6d 6e 6f 6g 6h 13a

13b

13c

13d

13e

13f

13g

13h

Con

trol

Am

oxic

illin

Cefi

xim

e

MIC

(120583g

mL)

E coliP aeruginosa


Compounds

6a 6b 6c 6d 6e 6f 6g 6h 13a

13b

13c

13d

13e

13f

13g

13h

Con

trol

Am

oxic

illin

Cefi

xim

e

MIC

(120583g

mL)


400

300

200

100

0






















































Table 3 Continued































2

2

15

15

1

1

05

05

Observed activity

y = 08306x + 02131

R2 = 08307

Pred

icte

d ac

tivity

(a)

25

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 08255x + 0273

R2 = 08255

(b)

21

21

16

16

11

11

06

06

Pred

icte

d ac

tivity

Observed activity

y = 08891x + 01511

R2 = 08891

(c)

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 07958x + 03355

R2 = 07962

(d)







50) and independent





(1)

119873 = 16 1198772= 0831

1198772

adj = 0718 Press = 0244

1198762= 08304 119865 = 736 119878 = 0164

(2)











+ 01083 (MSA) + 001097 (MW) + 2893

(3)

119873 = 12 1198772= 0825

1198772

adj = 0616 Press = 0131

1198762= 0823 119865 = 394 119878 = 0161

(4)





+ 007769 (MSA) minus 001452 (MW) + 1304

(5)

119873 = 16 1198772= 0889

1198772

adj = 0815 Press = 0170

1198762= 08887 119865 = 1202 119878 = 0137

(6)





minus 007843 (MSA) + 002144 (MW) + 6999

(7)

119873 = 16 1198772= 0796

1198772

adj = 0654 Press = 0394

1198762= 0792 119865 = 574 119878 = 0209

(8)















Ala 98(B)

Leu 99(B)

Arg 97(B)

Glu 87(B)

Lys 150(B)

Glu 88(B)

Arg 97(B)

Leu 99(B)

Lys 150(B)

Ala 98(B)

(6e998400)

(6f 998400)

Arg 97

(6e)

(6f)

Tyr 145

Arg 153

Leu 145

Lys 150

Val 100263

253

Leu 95

Ser 147

Leu 149

Ala 88

Ile 154

Leu 146

Leu 99

Lys 150 Arg 153

Ala 98 288

272

Glu 87

A

A

A

A



(8e998400)

Lys 150(B)

Lys 160(B)

Lys 160(B)

Arg 153(B)

(8h998400)

(8e)

(8f)

(8h)

Lys 150346427

Leu 146

Lys 150

Arg 153

Ala 98

321321

350

Lys 150

319341

340

Arg 153

Arg 97

98

Cl

(8f 998400)

A A

A

AA

AA

A



50










Lys 157(B)

Lys 157(B)

Lys 157(B)

Lys 150(B)

Arg 153(B)

Arg 153(B)

Arg 153(B)

Gln 96(B)

Arg 97(B)

(13b998400)

(13c998400)(13c)

(13e998400)(13e)

(13g998400)(13g)

152 A

295 A252 A

206 A

360 A

189 A

Lys 157 B

Lys 157 B

Lys 157

Ile 154 B

Lys 150 B

Lys 150

Arg 153 B

Arg 153 B

Arg 153

Glu 95

Arg 97

Gln15

Gln 96

Ser

156


153

157

(13b)



Arg 153(B)

Lys 150(B)

Lys 150(B)

Arg 153(B)

(cefixime998400)

(amoxicillin998400)

Ala 98

Ala 98

(amoxicillin)

(cefixime)

354 A

276 A

Arg 153

Arg 153

Lys 150

Lys 57

Lys 150

Ile 154

Ile 154

Leu 146

Leu 146







6 Conclusion





Acknowledgment


References



































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


Table 1 Continued

Compound R R1015840

8h NO2 NH C

O

13a C

O

13b Cl C

O

13c NO2 C

O

13d CH3 C

O

13e OH

OCH3

C

O

13f OH C

O

13g

O2N

C

O

13h

HO

C

O




3) 31 (t 2HCH

2(119869 = 61Hz) 29 (t 2HCH

2

(119869 = 60Hz) 13C NMR (CDCl3) 244 (C-6) 409 (C-7) 1974










3) 32 (t 2H CH

2(119869 =


3) 244



3 400MHz


3) 32 (t H CH

2


3)



3 400MHz ppm) 78 (d 2H H-p-



3)

31 (t 2H CH2) 29 (t 2H CH

2(119869 = 62Hz) 23 (s 3H

CH3(119869 = 60Hz) 13C NMR (CDCl

3) 249 (C-6) 412 (C-



3 400MHz ppm) 84 (d 2H H-


3) 31

(t 2H CH2(119869 = 63Hz) 29 (t 2H CH

2(119869 = 63Hz) 13C

NMR (CDCl3) 244 (C-6) 409 (C-7) 1976 (C-8) 1426 (C-

10) 1279 (C-1115) 1241 (C-1214) 1484 (C-13) 1297 (C-16)1296 (C-1721) 1140 (C-1820) 1664 (C-19) 560 (C-23) MSmz 35310 35411 (M + 1) 35511 (M + 2)







3) 1362 (C-6) 1286 (C-7) 1383 (C8) 1301



3 400MHz


3) 1364 (C-6)





3) 1360 (C-6) 1282 (C-






3) 13C NMR (CDCl

3) 1369 (C-6)



3 400MHz ppm) 84 (d 1H


3) 13C NMR

(CDCl3) 1301 (C-6) 1140 (C-7) 1497 (C-8) 1429 (C-9) 1172



3 400MHz ppm)


3) 1369



3 400MHz




3)



3 400MHz ppm) 85 (s


3) 1237 (C-6) 1558 (C-7) 1162 (C-8) 1299





Compounds

050100150200250300350400

6a 6b 6c 6d 6e 6f 6g 6h 13a

13b

13c

13d

13e

13f

13g

13h

Con

trol

Am

oxic

illin

Cefi

xim

e

MIC

(120583g

mL)

E coliP aeruginosa


Compounds

6a 6b 6c 6d 6e 6f 6g 6h 13a

13b

13c

13d

13e

13f

13g

13h

Con

trol

Am

oxic

illin

Cefi

xim

e

MIC

(120583g

mL)


400

300

200

100

0






















































Table 3 Continued































2

2

15

15

1

1

05

05

Observed activity

y = 08306x + 02131

R2 = 08307

Pred

icte

d ac

tivity

(a)

25

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 08255x + 0273

R2 = 08255

(b)

21

21

16

16

11

11

06

06

Pred

icte

d ac

tivity

Observed activity

y = 08891x + 01511

R2 = 08891

(c)

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 07958x + 03355

R2 = 07962

(d)







50) and independent





(1)

119873 = 16 1198772= 0831

1198772

adj = 0718 Press = 0244

1198762= 08304 119865 = 736 119878 = 0164

(2)











+ 01083 (MSA) + 001097 (MW) + 2893

(3)

119873 = 12 1198772= 0825

1198772

adj = 0616 Press = 0131

1198762= 0823 119865 = 394 119878 = 0161

(4)





+ 007769 (MSA) minus 001452 (MW) + 1304

(5)

119873 = 16 1198772= 0889

1198772

adj = 0815 Press = 0170

1198762= 08887 119865 = 1202 119878 = 0137

(6)





minus 007843 (MSA) + 002144 (MW) + 6999

(7)

119873 = 16 1198772= 0796

1198772

adj = 0654 Press = 0394

1198762= 0792 119865 = 574 119878 = 0209

(8)















Ala 98(B)

Leu 99(B)

Arg 97(B)

Glu 87(B)

Lys 150(B)

Glu 88(B)

Arg 97(B)

Leu 99(B)

Lys 150(B)

Ala 98(B)

(6e998400)

(6f 998400)

Arg 97

(6e)

(6f)

Tyr 145

Arg 153

Leu 145

Lys 150

Val 100263

253

Leu 95

Ser 147

Leu 149

Ala 88

Ile 154

Leu 146

Leu 99

Lys 150 Arg 153

Ala 98 288

272

Glu 87

A

A

A

A



(8e998400)

Lys 150(B)

Lys 160(B)

Lys 160(B)

Arg 153(B)

(8h998400)

(8e)

(8f)

(8h)

Lys 150346427

Leu 146

Lys 150

Arg 153

Ala 98

321321

350

Lys 150

319341

340

Arg 153

Arg 97

98

Cl

(8f 998400)

A A

A

AA

AA

A



50










Lys 157(B)

Lys 157(B)

Lys 157(B)

Lys 150(B)

Arg 153(B)

Arg 153(B)

Arg 153(B)

Gln 96(B)

Arg 97(B)

(13b998400)

(13c998400)(13c)

(13e998400)(13e)

(13g998400)(13g)

152 A

295 A252 A

206 A

360 A

189 A

Lys 157 B

Lys 157 B

Lys 157

Ile 154 B

Lys 150 B

Lys 150

Arg 153 B

Arg 153 B

Arg 153

Glu 95

Arg 97

Gln15

Gln 96

Ser

156


153

157

(13b)



Arg 153(B)

Lys 150(B)

Lys 150(B)

Arg 153(B)

(cefixime998400)

(amoxicillin998400)

Ala 98

Ala 98

(amoxicillin)

(cefixime)

354 A

276 A

Arg 153

Arg 153

Lys 150

Lys 57

Lys 150

Ile 154

Ile 154

Leu 146

Leu 146







6 Conclusion





Acknowledgment


References



































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology








3) 32 (t 2H CH

2(119869 =


3) 244



3 400MHz


3) 32 (t H CH

2


3)



3 400MHz ppm) 78 (d 2H H-p-



3)

31 (t 2H CH2) 29 (t 2H CH

2(119869 = 62Hz) 23 (s 3H

CH3(119869 = 60Hz) 13C NMR (CDCl

3) 249 (C-6) 412 (C-



3 400MHz ppm) 84 (d 2H H-


3) 31

(t 2H CH2(119869 = 63Hz) 29 (t 2H CH

2(119869 = 63Hz) 13C

NMR (CDCl3) 244 (C-6) 409 (C-7) 1976 (C-8) 1426 (C-

10) 1279 (C-1115) 1241 (C-1214) 1484 (C-13) 1297 (C-16)1296 (C-1721) 1140 (C-1820) 1664 (C-19) 560 (C-23) MSmz 35310 35411 (M + 1) 35511 (M + 2)







3) 1362 (C-6) 1286 (C-7) 1383 (C8) 1301



3 400MHz


3) 1364 (C-6)





3) 1360 (C-6) 1282 (C-






3) 13C NMR (CDCl

3) 1369 (C-6)



3 400MHz ppm) 84 (d 1H


3) 13C NMR

(CDCl3) 1301 (C-6) 1140 (C-7) 1497 (C-8) 1429 (C-9) 1172



3 400MHz ppm)


3) 1369



3 400MHz




3)



3 400MHz ppm) 85 (s


3) 1237 (C-6) 1558 (C-7) 1162 (C-8) 1299





Compounds

050100150200250300350400

6a 6b 6c 6d 6e 6f 6g 6h 13a

13b

13c

13d

13e

13f

13g

13h

Con

trol

Am

oxic

illin

Cefi

xim

e

MIC

(120583g

mL)

E coliP aeruginosa


Compounds

6a 6b 6c 6d 6e 6f 6g 6h 13a

13b

13c

13d

13e

13f

13g

13h

Con

trol

Am

oxic

illin

Cefi

xim

e

MIC

(120583g

mL)


400

300

200

100

0






















































Table 3 Continued































2

2

15

15

1

1

05

05

Observed activity

y = 08306x + 02131

R2 = 08307

Pred

icte

d ac

tivity

(a)

25

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 08255x + 0273

R2 = 08255

(b)

21

21

16

16

11

11

06

06

Pred

icte

d ac

tivity

Observed activity

y = 08891x + 01511

R2 = 08891

(c)

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 07958x + 03355

R2 = 07962

(d)







50) and independent





(1)

119873 = 16 1198772= 0831

1198772

adj = 0718 Press = 0244

1198762= 08304 119865 = 736 119878 = 0164

(2)











+ 01083 (MSA) + 001097 (MW) + 2893

(3)

119873 = 12 1198772= 0825

1198772

adj = 0616 Press = 0131

1198762= 0823 119865 = 394 119878 = 0161

(4)





+ 007769 (MSA) minus 001452 (MW) + 1304

(5)

119873 = 16 1198772= 0889

1198772

adj = 0815 Press = 0170

1198762= 08887 119865 = 1202 119878 = 0137

(6)





minus 007843 (MSA) + 002144 (MW) + 6999

(7)

119873 = 16 1198772= 0796

1198772

adj = 0654 Press = 0394

1198762= 0792 119865 = 574 119878 = 0209

(8)















Ala 98(B)

Leu 99(B)

Arg 97(B)

Glu 87(B)

Lys 150(B)

Glu 88(B)

Arg 97(B)

Leu 99(B)

Lys 150(B)

Ala 98(B)

(6e998400)

(6f 998400)

Arg 97

(6e)

(6f)

Tyr 145

Arg 153

Leu 145

Lys 150

Val 100263

253

Leu 95

Ser 147

Leu 149

Ala 88

Ile 154

Leu 146

Leu 99

Lys 150 Arg 153

Ala 98 288

272

Glu 87

A

A

A

A



(8e998400)

Lys 150(B)

Lys 160(B)

Lys 160(B)

Arg 153(B)

(8h998400)

(8e)

(8f)

(8h)

Lys 150346427

Leu 146

Lys 150

Arg 153

Ala 98

321321

350

Lys 150

319341

340

Arg 153

Arg 97

98

Cl

(8f 998400)

A A

A

AA

AA

A



50










Lys 157(B)

Lys 157(B)

Lys 157(B)

Lys 150(B)

Arg 153(B)

Arg 153(B)

Arg 153(B)

Gln 96(B)

Arg 97(B)

(13b998400)

(13c998400)(13c)

(13e998400)(13e)

(13g998400)(13g)

152 A

295 A252 A

206 A

360 A

189 A

Lys 157 B

Lys 157 B

Lys 157

Ile 154 B

Lys 150 B

Lys 150

Arg 153 B

Arg 153 B

Arg 153

Glu 95

Arg 97

Gln15

Gln 96

Ser

156


153

157

(13b)



Arg 153(B)

Lys 150(B)

Lys 150(B)

Arg 153(B)

(cefixime998400)

(amoxicillin998400)

Ala 98

Ala 98

(amoxicillin)

(cefixime)

354 A

276 A

Arg 153

Arg 153

Lys 150

Lys 57

Lys 150

Ile 154

Ile 154

Leu 146

Leu 146







6 Conclusion





Acknowledgment


References



































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






3) 1362 (C-6) 1286 (C-7) 1383 (C8) 1301



3 400MHz


3) 1364 (C-6)





3) 1360 (C-6) 1282 (C-






3) 13C NMR (CDCl

3) 1369 (C-6)



3 400MHz ppm) 84 (d 1H


3) 13C NMR

(CDCl3) 1301 (C-6) 1140 (C-7) 1497 (C-8) 1429 (C-9) 1172



3 400MHz ppm)


3) 1369



3 400MHz




3)



3 400MHz ppm) 85 (s


3) 1237 (C-6) 1558 (C-7) 1162 (C-8) 1299





Compounds

050100150200250300350400

6a 6b 6c 6d 6e 6f 6g 6h 13a

13b

13c

13d

13e

13f

13g

13h

Con

trol

Am

oxic

illin

Cefi

xim

e

MIC

(120583g

mL)

E coliP aeruginosa


Compounds

6a 6b 6c 6d 6e 6f 6g 6h 13a

13b

13c

13d

13e

13f

13g

13h

Con

trol

Am

oxic

illin

Cefi

xim

e

MIC

(120583g

mL)


400

300

200

100

0






















































Table 3 Continued































2

2

15

15

1

1

05

05

Observed activity

y = 08306x + 02131

R2 = 08307

Pred

icte

d ac

tivity

(a)

25

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 08255x + 0273

R2 = 08255

(b)

21

21

16

16

11

11

06

06

Pred

icte

d ac

tivity

Observed activity

y = 08891x + 01511

R2 = 08891

(c)

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 07958x + 03355

R2 = 07962

(d)







50) and independent





(1)

119873 = 16 1198772= 0831

1198772

adj = 0718 Press = 0244

1198762= 08304 119865 = 736 119878 = 0164

(2)











+ 01083 (MSA) + 001097 (MW) + 2893

(3)

119873 = 12 1198772= 0825

1198772

adj = 0616 Press = 0131

1198762= 0823 119865 = 394 119878 = 0161

(4)





+ 007769 (MSA) minus 001452 (MW) + 1304

(5)

119873 = 16 1198772= 0889

1198772

adj = 0815 Press = 0170

1198762= 08887 119865 = 1202 119878 = 0137

(6)





minus 007843 (MSA) + 002144 (MW) + 6999

(7)

119873 = 16 1198772= 0796

1198772

adj = 0654 Press = 0394

1198762= 0792 119865 = 574 119878 = 0209

(8)















Ala 98(B)

Leu 99(B)

Arg 97(B)

Glu 87(B)

Lys 150(B)

Glu 88(B)

Arg 97(B)

Leu 99(B)

Lys 150(B)

Ala 98(B)

(6e998400)

(6f 998400)

Arg 97

(6e)

(6f)

Tyr 145

Arg 153

Leu 145

Lys 150

Val 100263

253

Leu 95

Ser 147

Leu 149

Ala 88

Ile 154

Leu 146

Leu 99

Lys 150 Arg 153

Ala 98 288

272

Glu 87

A

A

A

A



(8e998400)

Lys 150(B)

Lys 160(B)

Lys 160(B)

Arg 153(B)

(8h998400)

(8e)

(8f)

(8h)

Lys 150346427

Leu 146

Lys 150

Arg 153

Ala 98

321321

350

Lys 150

319341

340

Arg 153

Arg 97

98

Cl

(8f 998400)

A A

A

AA

AA

A



50










Lys 157(B)

Lys 157(B)

Lys 157(B)

Lys 150(B)

Arg 153(B)

Arg 153(B)

Arg 153(B)

Gln 96(B)

Arg 97(B)

(13b998400)

(13c998400)(13c)

(13e998400)(13e)

(13g998400)(13g)

152 A

295 A252 A

206 A

360 A

189 A

Lys 157 B

Lys 157 B

Lys 157

Ile 154 B

Lys 150 B

Lys 150

Arg 153 B

Arg 153 B

Arg 153

Glu 95

Arg 97

Gln15

Gln 96

Ser

156


153

157

(13b)



Arg 153(B)

Lys 150(B)

Lys 150(B)

Arg 153(B)

(cefixime998400)

(amoxicillin998400)

Ala 98

Ala 98

(amoxicillin)

(cefixime)

354 A

276 A

Arg 153

Arg 153

Lys 150

Lys 57

Lys 150

Ile 154

Ile 154

Leu 146

Leu 146







6 Conclusion





Acknowledgment


References



































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



3)



3 400MHz ppm) 85 (s


3) 1237 (C-6) 1558 (C-7) 1162 (C-8) 1299





Compounds

050100150200250300350400

6a 6b 6c 6d 6e 6f 6g 6h 13a

13b

13c

13d

13e

13f

13g

13h

Con

trol

Am

oxic

illin

Cefi

xim

e

MIC

(120583g

mL)

E coliP aeruginosa


Compounds

6a 6b 6c 6d 6e 6f 6g 6h 13a

13b

13c

13d

13e

13f

13g

13h

Con

trol

Am

oxic

illin

Cefi

xim

e

MIC

(120583g

mL)


400

300

200

100

0






















































Table 3 Continued































2

2

15

15

1

1

05

05

Observed activity

y = 08306x + 02131

R2 = 08307

Pred

icte

d ac

tivity

(a)

25

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 08255x + 0273

R2 = 08255

(b)

21

21

16

16

11

11

06

06

Pred

icte

d ac

tivity

Observed activity

y = 08891x + 01511

R2 = 08891

(c)

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 07958x + 03355

R2 = 07962

(d)







50) and independent





(1)

119873 = 16 1198772= 0831

1198772

adj = 0718 Press = 0244

1198762= 08304 119865 = 736 119878 = 0164

(2)











+ 01083 (MSA) + 001097 (MW) + 2893

(3)

119873 = 12 1198772= 0825

1198772

adj = 0616 Press = 0131

1198762= 0823 119865 = 394 119878 = 0161

(4)





+ 007769 (MSA) minus 001452 (MW) + 1304

(5)

119873 = 16 1198772= 0889

1198772

adj = 0815 Press = 0170

1198762= 08887 119865 = 1202 119878 = 0137

(6)





minus 007843 (MSA) + 002144 (MW) + 6999

(7)

119873 = 16 1198772= 0796

1198772

adj = 0654 Press = 0394

1198762= 0792 119865 = 574 119878 = 0209

(8)















Ala 98(B)

Leu 99(B)

Arg 97(B)

Glu 87(B)

Lys 150(B)

Glu 88(B)

Arg 97(B)

Leu 99(B)

Lys 150(B)

Ala 98(B)

(6e998400)

(6f 998400)

Arg 97

(6e)

(6f)

Tyr 145

Arg 153

Leu 145

Lys 150

Val 100263

253

Leu 95

Ser 147

Leu 149

Ala 88

Ile 154

Leu 146

Leu 99

Lys 150 Arg 153

Ala 98 288

272

Glu 87

A

A

A

A



(8e998400)

Lys 150(B)

Lys 160(B)

Lys 160(B)

Arg 153(B)

(8h998400)

(8e)

(8f)

(8h)

Lys 150346427

Leu 146

Lys 150

Arg 153

Ala 98

321321

350

Lys 150

319341

340

Arg 153

Arg 97

98

Cl

(8f 998400)

A A

A

AA

AA

A



50










Lys 157(B)

Lys 157(B)

Lys 157(B)

Lys 150(B)

Arg 153(B)

Arg 153(B)

Arg 153(B)

Gln 96(B)

Arg 97(B)

(13b998400)

(13c998400)(13c)

(13e998400)(13e)

(13g998400)(13g)

152 A

295 A252 A

206 A

360 A

189 A

Lys 157 B

Lys 157 B

Lys 157

Ile 154 B

Lys 150 B

Lys 150

Arg 153 B

Arg 153 B

Arg 153

Glu 95

Arg 97

Gln15

Gln 96

Ser

156


153

157

(13b)



Arg 153(B)

Lys 150(B)

Lys 150(B)

Arg 153(B)

(cefixime998400)

(amoxicillin998400)

Ala 98

Ala 98

(amoxicillin)

(cefixime)

354 A

276 A

Arg 153

Arg 153

Lys 150

Lys 57

Lys 150

Ile 154

Ile 154

Leu 146

Leu 146







6 Conclusion





Acknowledgment


References



































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



















































Table 3 Continued































2

2

15

15

1

1

05

05

Observed activity

y = 08306x + 02131

R2 = 08307

Pred

icte

d ac

tivity

(a)

25

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 08255x + 0273

R2 = 08255

(b)

21

21

16

16

11

11

06

06

Pred

icte

d ac

tivity

Observed activity

y = 08891x + 01511

R2 = 08891

(c)

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 07958x + 03355

R2 = 07962

(d)







50) and independent





(1)

119873 = 16 1198772= 0831

1198772

adj = 0718 Press = 0244

1198762= 08304 119865 = 736 119878 = 0164

(2)











+ 01083 (MSA) + 001097 (MW) + 2893

(3)

119873 = 12 1198772= 0825

1198772

adj = 0616 Press = 0131

1198762= 0823 119865 = 394 119878 = 0161

(4)





+ 007769 (MSA) minus 001452 (MW) + 1304

(5)

119873 = 16 1198772= 0889

1198772

adj = 0815 Press = 0170

1198762= 08887 119865 = 1202 119878 = 0137

(6)





minus 007843 (MSA) + 002144 (MW) + 6999

(7)

119873 = 16 1198772= 0796

1198772

adj = 0654 Press = 0394

1198762= 0792 119865 = 574 119878 = 0209

(8)















Ala 98(B)

Leu 99(B)

Arg 97(B)

Glu 87(B)

Lys 150(B)

Glu 88(B)

Arg 97(B)

Leu 99(B)

Lys 150(B)

Ala 98(B)

(6e998400)

(6f 998400)

Arg 97

(6e)

(6f)

Tyr 145

Arg 153

Leu 145

Lys 150

Val 100263

253

Leu 95

Ser 147

Leu 149

Ala 88

Ile 154

Leu 146

Leu 99

Lys 150 Arg 153

Ala 98 288

272

Glu 87

A

A

A

A



(8e998400)

Lys 150(B)

Lys 160(B)

Lys 160(B)

Arg 153(B)

(8h998400)

(8e)

(8f)

(8h)

Lys 150346427

Leu 146

Lys 150

Arg 153

Ala 98

321321

350

Lys 150

319341

340

Arg 153

Arg 97

98

Cl

(8f 998400)

A A

A

AA

AA

A



50










Lys 157(B)

Lys 157(B)

Lys 157(B)

Lys 150(B)

Arg 153(B)

Arg 153(B)

Arg 153(B)

Gln 96(B)

Arg 97(B)

(13b998400)

(13c998400)(13c)

(13e998400)(13e)

(13g998400)(13g)

152 A

295 A252 A

206 A

360 A

189 A

Lys 157 B

Lys 157 B

Lys 157

Ile 154 B

Lys 150 B

Lys 150

Arg 153 B

Arg 153 B

Arg 153

Glu 95

Arg 97

Gln15

Gln 96

Ser

156


153

157

(13b)



Arg 153(B)

Lys 150(B)

Lys 150(B)

Arg 153(B)

(cefixime998400)

(amoxicillin998400)

Ala 98

Ala 98

(amoxicillin)

(cefixime)

354 A

276 A

Arg 153

Arg 153

Lys 150

Lys 57

Lys 150

Ile 154

Ile 154

Leu 146

Leu 146







6 Conclusion





Acknowledgment


References



































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


Table 3 Continued































2

2

15

15

1

1

05

05

Observed activity

y = 08306x + 02131

R2 = 08307

Pred

icte

d ac

tivity

(a)

25

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 08255x + 0273

R2 = 08255

(b)

21

21

16

16

11

11

06

06

Pred

icte

d ac

tivity

Observed activity

y = 08891x + 01511

R2 = 08891

(c)

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 07958x + 03355

R2 = 07962

(d)







50) and independent





(1)

119873 = 16 1198772= 0831

1198772

adj = 0718 Press = 0244

1198762= 08304 119865 = 736 119878 = 0164

(2)











+ 01083 (MSA) + 001097 (MW) + 2893

(3)

119873 = 12 1198772= 0825

1198772

adj = 0616 Press = 0131

1198762= 0823 119865 = 394 119878 = 0161

(4)





+ 007769 (MSA) minus 001452 (MW) + 1304

(5)

119873 = 16 1198772= 0889

1198772

adj = 0815 Press = 0170

1198762= 08887 119865 = 1202 119878 = 0137

(6)





minus 007843 (MSA) + 002144 (MW) + 6999

(7)

119873 = 16 1198772= 0796

1198772

adj = 0654 Press = 0394

1198762= 0792 119865 = 574 119878 = 0209

(8)















Ala 98(B)

Leu 99(B)

Arg 97(B)

Glu 87(B)

Lys 150(B)

Glu 88(B)

Arg 97(B)

Leu 99(B)

Lys 150(B)

Ala 98(B)

(6e998400)

(6f 998400)

Arg 97

(6e)

(6f)

Tyr 145

Arg 153

Leu 145

Lys 150

Val 100263

253

Leu 95

Ser 147

Leu 149

Ala 88

Ile 154

Leu 146

Leu 99

Lys 150 Arg 153

Ala 98 288

272

Glu 87

A

A

A

A



(8e998400)

Lys 150(B)

Lys 160(B)

Lys 160(B)

Arg 153(B)

(8h998400)

(8e)

(8f)

(8h)

Lys 150346427

Leu 146

Lys 150

Arg 153

Ala 98

321321

350

Lys 150

319341

340

Arg 153

Arg 97

98

Cl

(8f 998400)

A A

A

AA

AA

A



50










Lys 157(B)

Lys 157(B)

Lys 157(B)

Lys 150(B)

Arg 153(B)

Arg 153(B)

Arg 153(B)

Gln 96(B)

Arg 97(B)

(13b998400)

(13c998400)(13c)

(13e998400)(13e)

(13g998400)(13g)

152 A

295 A252 A

206 A

360 A

189 A

Lys 157 B

Lys 157 B

Lys 157

Ile 154 B

Lys 150 B

Lys 150

Arg 153 B

Arg 153 B

Arg 153

Glu 95

Arg 97

Gln15

Gln 96

Ser

156


153

157

(13b)



Arg 153(B)

Lys 150(B)

Lys 150(B)

Arg 153(B)

(cefixime998400)

(amoxicillin998400)

Ala 98

Ala 98

(amoxicillin)

(cefixime)

354 A

276 A

Arg 153

Arg 153

Lys 150

Lys 57

Lys 150

Ile 154

Ile 154

Leu 146

Leu 146







6 Conclusion





Acknowledgment


References



































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology










2

2

15

15

1

1

05

05

Observed activity

y = 08306x + 02131

R2 = 08307

Pred

icte

d ac

tivity

(a)

25

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 08255x + 0273

R2 = 08255

(b)

21

21

16

16

11

11

06

06

Pred

icte

d ac

tivity

Observed activity

y = 08891x + 01511

R2 = 08891

(c)

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 07958x + 03355

R2 = 07962

(d)







50) and independent





(1)

119873 = 16 1198772= 0831

1198772

adj = 0718 Press = 0244

1198762= 08304 119865 = 736 119878 = 0164

(2)











+ 01083 (MSA) + 001097 (MW) + 2893

(3)

119873 = 12 1198772= 0825

1198772

adj = 0616 Press = 0131

1198762= 0823 119865 = 394 119878 = 0161

(4)





+ 007769 (MSA) minus 001452 (MW) + 1304

(5)

119873 = 16 1198772= 0889

1198772

adj = 0815 Press = 0170

1198762= 08887 119865 = 1202 119878 = 0137

(6)





minus 007843 (MSA) + 002144 (MW) + 6999

(7)

119873 = 16 1198772= 0796

1198772

adj = 0654 Press = 0394

1198762= 0792 119865 = 574 119878 = 0209

(8)















Ala 98(B)

Leu 99(B)

Arg 97(B)

Glu 87(B)

Lys 150(B)

Glu 88(B)

Arg 97(B)

Leu 99(B)

Lys 150(B)

Ala 98(B)

(6e998400)

(6f 998400)

Arg 97

(6e)

(6f)

Tyr 145

Arg 153

Leu 145

Lys 150

Val 100263

253

Leu 95

Ser 147

Leu 149

Ala 88

Ile 154

Leu 146

Leu 99

Lys 150 Arg 153

Ala 98 288

272

Glu 87

A

A

A

A



(8e998400)

Lys 150(B)

Lys 160(B)

Lys 160(B)

Arg 153(B)

(8h998400)

(8e)

(8f)

(8h)

Lys 150346427

Leu 146

Lys 150

Arg 153

Ala 98

321321

350

Lys 150

319341

340

Arg 153

Arg 97

98

Cl

(8f 998400)

A A

A

AA

AA

A



50










Lys 157(B)

Lys 157(B)

Lys 157(B)

Lys 150(B)

Arg 153(B)

Arg 153(B)

Arg 153(B)

Gln 96(B)

Arg 97(B)

(13b998400)

(13c998400)(13c)

(13e998400)(13e)

(13g998400)(13g)

152 A

295 A252 A

206 A

360 A

189 A

Lys 157 B

Lys 157 B

Lys 157

Ile 154 B

Lys 150 B

Lys 150

Arg 153 B

Arg 153 B

Arg 153

Glu 95

Arg 97

Gln15

Gln 96

Ser

156


153

157

(13b)



Arg 153(B)

Lys 150(B)

Lys 150(B)

Arg 153(B)

(cefixime998400)

(amoxicillin998400)

Ala 98

Ala 98

(amoxicillin)

(cefixime)

354 A

276 A

Arg 153

Arg 153

Lys 150

Lys 57

Lys 150

Ile 154

Ile 154

Leu 146

Leu 146







6 Conclusion





Acknowledgment


References



































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


2

2

15

15

1

1

05

05

Observed activity

y = 08306x + 02131

R2 = 08307

Pred

icte

d ac

tivity

(a)

25

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 08255x + 0273

R2 = 08255

(b)

21

21

16

16

11

11

06

06

Pred

icte

d ac

tivity

Observed activity

y = 08891x + 01511

R2 = 08891

(c)

2

15

1

Pred

icte

d ac

tivity

2151

Observed activity

y = 07958x + 03355

R2 = 07962

(d)







50) and independent





(1)

119873 = 16 1198772= 0831

1198772

adj = 0718 Press = 0244

1198762= 08304 119865 = 736 119878 = 0164

(2)











+ 01083 (MSA) + 001097 (MW) + 2893

(3)

119873 = 12 1198772= 0825

1198772

adj = 0616 Press = 0131

1198762= 0823 119865 = 394 119878 = 0161

(4)





+ 007769 (MSA) minus 001452 (MW) + 1304

(5)

119873 = 16 1198772= 0889

1198772

adj = 0815 Press = 0170

1198762= 08887 119865 = 1202 119878 = 0137

(6)





minus 007843 (MSA) + 002144 (MW) + 6999

(7)

119873 = 16 1198772= 0796

1198772

adj = 0654 Press = 0394

1198762= 0792 119865 = 574 119878 = 0209

(8)















Ala 98(B)

Leu 99(B)

Arg 97(B)

Glu 87(B)

Lys 150(B)

Glu 88(B)

Arg 97(B)

Leu 99(B)

Lys 150(B)

Ala 98(B)

(6e998400)

(6f 998400)

Arg 97

(6e)

(6f)

Tyr 145

Arg 153

Leu 145

Lys 150

Val 100263

253

Leu 95

Ser 147

Leu 149

Ala 88

Ile 154

Leu 146

Leu 99

Lys 150 Arg 153

Ala 98 288

272

Glu 87

A

A

A

A



(8e998400)

Lys 150(B)

Lys 160(B)

Lys 160(B)

Arg 153(B)

(8h998400)

(8e)

(8f)

(8h)

Lys 150346427

Leu 146

Lys 150

Arg 153

Ala 98

321321

350

Lys 150

319341

340

Arg 153

Arg 97

98

Cl

(8f 998400)

A A

A

AA

AA

A



50










Lys 157(B)

Lys 157(B)

Lys 157(B)

Lys 150(B)

Arg 153(B)

Arg 153(B)

Arg 153(B)

Gln 96(B)

Arg 97(B)

(13b998400)

(13c998400)(13c)

(13e998400)(13e)

(13g998400)(13g)

152 A

295 A252 A

206 A

360 A

189 A

Lys 157 B

Lys 157 B

Lys 157

Ile 154 B

Lys 150 B

Lys 150

Arg 153 B

Arg 153 B

Arg 153

Glu 95

Arg 97

Gln15

Gln 96

Ser

156


153

157

(13b)



Arg 153(B)

Lys 150(B)

Lys 150(B)

Arg 153(B)

(cefixime998400)

(amoxicillin998400)

Ala 98

Ala 98

(amoxicillin)

(cefixime)

354 A

276 A

Arg 153

Arg 153

Lys 150

Lys 57

Lys 150

Ile 154

Ile 154

Leu 146

Leu 146







6 Conclusion





Acknowledgment


References



































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology









+ 01083 (MSA) + 001097 (MW) + 2893

(3)

119873 = 12 1198772= 0825

1198772

adj = 0616 Press = 0131

1198762= 0823 119865 = 394 119878 = 0161

(4)





+ 007769 (MSA) minus 001452 (MW) + 1304

(5)

119873 = 16 1198772= 0889

1198772

adj = 0815 Press = 0170

1198762= 08887 119865 = 1202 119878 = 0137

(6)





minus 007843 (MSA) + 002144 (MW) + 6999

(7)

119873 = 16 1198772= 0796

1198772

adj = 0654 Press = 0394

1198762= 0792 119865 = 574 119878 = 0209

(8)















Ala 98(B)

Leu 99(B)

Arg 97(B)

Glu 87(B)

Lys 150(B)

Glu 88(B)

Arg 97(B)

Leu 99(B)

Lys 150(B)

Ala 98(B)

(6e998400)

(6f 998400)

Arg 97

(6e)

(6f)

Tyr 145

Arg 153

Leu 145

Lys 150

Val 100263

253

Leu 95

Ser 147

Leu 149

Ala 88

Ile 154

Leu 146

Leu 99

Lys 150 Arg 153

Ala 98 288

272

Glu 87

A

A

A

A



(8e998400)

Lys 150(B)

Lys 160(B)

Lys 160(B)

Arg 153(B)

(8h998400)

(8e)

(8f)

(8h)

Lys 150346427

Leu 146

Lys 150

Arg 153

Ala 98

321321

350

Lys 150

319341

340

Arg 153

Arg 97

98

Cl

(8f 998400)

A A

A

AA

AA

A



50










Lys 157(B)

Lys 157(B)

Lys 157(B)

Lys 150(B)

Arg 153(B)

Arg 153(B)

Arg 153(B)

Gln 96(B)

Arg 97(B)

(13b998400)

(13c998400)(13c)

(13e998400)(13e)

(13g998400)(13g)

152 A

295 A252 A

206 A

360 A

189 A

Lys 157 B

Lys 157 B

Lys 157

Ile 154 B

Lys 150 B

Lys 150

Arg 153 B

Arg 153 B

Arg 153

Glu 95

Arg 97

Gln15

Gln 96

Ser

156


153

157

(13b)



Arg 153(B)

Lys 150(B)

Lys 150(B)

Arg 153(B)

(cefixime998400)

(amoxicillin998400)

Ala 98

Ala 98

(amoxicillin)

(cefixime)

354 A

276 A

Arg 153

Arg 153

Lys 150

Lys 57

Lys 150

Ile 154

Ile 154

Leu 146

Leu 146







6 Conclusion





Acknowledgment


References



































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology














Ala 98(B)

Leu 99(B)

Arg 97(B)

Glu 87(B)

Lys 150(B)

Glu 88(B)

Arg 97(B)

Leu 99(B)

Lys 150(B)

Ala 98(B)

(6e998400)

(6f 998400)

Arg 97

(6e)

(6f)

Tyr 145

Arg 153

Leu 145

Lys 150

Val 100263

253

Leu 95

Ser 147

Leu 149

Ala 88

Ile 154

Leu 146

Leu 99

Lys 150 Arg 153

Ala 98 288

272

Glu 87

A

A

A

A



(8e998400)

Lys 150(B)

Lys 160(B)

Lys 160(B)

Arg 153(B)

(8h998400)

(8e)

(8f)

(8h)

Lys 150346427

Leu 146

Lys 150

Arg 153

Ala 98

321321

350

Lys 150

319341

340

Arg 153

Arg 97

98

Cl

(8f 998400)

A A

A

AA

AA

A



50










Lys 157(B)

Lys 157(B)

Lys 157(B)

Lys 150(B)

Arg 153(B)

Arg 153(B)

Arg 153(B)

Gln 96(B)

Arg 97(B)

(13b998400)

(13c998400)(13c)

(13e998400)(13e)

(13g998400)(13g)

152 A

295 A252 A

206 A

360 A

189 A

Lys 157 B

Lys 157 B

Lys 157

Ile 154 B

Lys 150 B

Lys 150

Arg 153 B

Arg 153 B

Arg 153

Glu 95

Arg 97

Gln15

Gln 96

Ser

156


153

157

(13b)



Arg 153(B)

Lys 150(B)

Lys 150(B)

Arg 153(B)

(cefixime998400)

(amoxicillin998400)

Ala 98

Ala 98

(amoxicillin)

(cefixime)

354 A

276 A

Arg 153

Arg 153

Lys 150

Lys 57

Lys 150

Ile 154

Ile 154

Leu 146

Leu 146







6 Conclusion





Acknowledgment


References



































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


(8e998400)

Lys 150(B)

Lys 160(B)

Lys 160(B)

Arg 153(B)

(8h998400)

(8e)

(8f)

(8h)

Lys 150346427

Leu 146

Lys 150

Arg 153

Ala 98

321321

350

Lys 150

319341

340

Arg 153

Arg 97

98

Cl

(8f 998400)

A A

A

AA

AA

A



50










Lys 157(B)

Lys 157(B)

Lys 157(B)

Lys 150(B)

Arg 153(B)

Arg 153(B)

Arg 153(B)

Gln 96(B)

Arg 97(B)

(13b998400)

(13c998400)(13c)

(13e998400)(13e)

(13g998400)(13g)

152 A

295 A252 A

206 A

360 A

189 A

Lys 157 B

Lys 157 B

Lys 157

Ile 154 B

Lys 150 B

Lys 150

Arg 153 B

Arg 153 B

Arg 153

Glu 95

Arg 97

Gln15

Gln 96

Ser

156


153

157

(13b)



Arg 153(B)

Lys 150(B)

Lys 150(B)

Arg 153(B)

(cefixime998400)

(amoxicillin998400)

Ala 98

Ala 98

(amoxicillin)

(cefixime)

354 A

276 A

Arg 153

Arg 153

Lys 150

Lys 57

Lys 150

Ile 154

Ile 154

Leu 146

Leu 146







6 Conclusion





Acknowledgment


References



































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


Lys 157(B)

Lys 157(B)

Lys 157(B)

Lys 150(B)

Arg 153(B)

Arg 153(B)

Arg 153(B)

Gln 96(B)

Arg 97(B)

(13b998400)

(13c998400)(13c)

(13e998400)(13e)

(13g998400)(13g)

152 A

295 A252 A

206 A

360 A

189 A

Lys 157 B

Lys 157 B

Lys 157

Ile 154 B

Lys 150 B

Lys 150

Arg 153 B

Arg 153 B

Arg 153

Glu 95

Arg 97

Gln15

Gln 96

Ser

156


153

157

(13b)



Arg 153(B)

Lys 150(B)

Lys 150(B)

Arg 153(B)

(cefixime998400)

(amoxicillin998400)

Ala 98

Ala 98

(amoxicillin)

(cefixime)

354 A

276 A

Arg 153

Arg 153

Lys 150

Lys 57

Lys 150

Ile 154

Ile 154

Leu 146

Leu 146







6 Conclusion





Acknowledgment


References



































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


Arg 153(B)

Lys 150(B)

Lys 150(B)

Arg 153(B)

(cefixime998400)

(amoxicillin998400)

Ala 98

Ala 98

(amoxicillin)

(cefixime)

354 A

276 A

Arg 153

Arg 153

Lys 150

Lys 57

Lys 150

Ile 154

Ile 154

Leu 146

Leu 146







6 Conclusion





Acknowledgment


References



































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




Acknowledgment


References



































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology








Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

Documents

Research Article 1,3,4-Oxadiazole Derivatives: Synthesis