Research Article Design, Synthesis, Characterization, and ...

Research ArticleDesign Synthesis Characterization and ComputationalStudies on Benzamide Substituted Mannich Bases as NovelPotential Antibacterial Agents

Suman Bala Neha Sharma Anu Kajal and Sunil Kamboj

M M College of Pharmacy Maharishi Markandeshwar University Mullana Ambala Haryana 133207 India

Correspondence should be addressed to Suman Bala sumankmj7gmailcom

Received 16 August 2013 Accepted 8 October 2013 Published 19 January 2014

Academic Editors A Guijarro and A Marra

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

A series of benzamide substituted Mannich bases (1ndash7) were synthesized The synthesized derivatives were authenticated by TLCUV-Visible FTIR NMR and mass spectroscopic techniques and further screened for in vitro antibacterial activity by test tubedilution method using amoxicillin and cefixime as standard drugs The compounds 5 6 and 7 were found to be the most activeantibacterial agents among all the synthesized compounds The physicochemical similarity of the compounds with standard drugswas assessed by calculating various physicochemical properties using software programs The percent similarity of synthesizedcompounds was found to be good and compound 1 was found to have higher percentage of similarity The compounds weresubjected to QSAR by multilinear regression using Analyze it version 30 software and four statistically sound models weredeveloped with 1198772 (0963ndash0997) 1198772adj (0529ndash0982) and 119876

2 (0998ndash0999) with good F (235ndash6556) values

1 Introduction

The infectious diseases are widely managed by the antimi-crobial agents but increase in resistance of microorganismstowards antimicrobial agents in the past few years has becomea serious health care problem and this has led to the necessityof designing of some novel potent and safe antimicrobialagents against resistant microbial strains The compoundshaving Mannich bases are found to have broad spectrumactivity against all strains resistant to other drugs Mannichbases have gained importance due to their application inantibacterial activity [1ndash3]

Mannich bases are the end products of Mannich reactionwith basic moiety of beta amino ketone [4 5] Mannichbases are formed by the condensation of a compound withactive hydrogen(s)with an amine (primary or secondary) andformaldehyde (any aldehyde) [6]

Computational studies are the starting point which canbe used to predict the experimental data of entirely knownmolecule or to explore reaction mechanisms and so forthThere are several areas of computational studies and one of

them is identification of correlations between chemical struc-tures and properties and is known as QSAR Quantitativestructural activity relationship uses molecular parameters toquantify a pharmacological or chemical property for a set ofmolecules [7 8]

In the present work novel series of seven benzamidesubstitutedMannich bases are prepared and further screenedfor the antibacterial activity against Gram negative bacteria(Escherichia coli Pseudomonas aeruginosa) and Gram pos-itive bacteria (Enterococcus faecalis Staphylococcus aureus)Computational studies includingQSAR andmolecular struc-tural similarity studies were also performed to establish arelationship between biological activities in terms of mini-mum inhibitory concentration with various physicochemicalparameters using multilinear regression

2 Material and Method

21 Chemistry TLC plates of 3 times 15 cm coated with silicagel 119866 were used for reaction monitoring and for deter-mination of retardation factor Spots of TLC were located

Hindawi Publishing Corporatione Scientific World JournalVolume 2014 Article ID 732141 9 pageshttpdxdoiorg1011552014732141

2 The Scientific World Journal

Table 1 Physical data of synthesized benzamide substituted Mannich bases

Compound Color Solubility 120582max 119877119891value age

yield Molecular weight

1 Light brown crystals DMSO EtOH CHCl3 226 045 84 2202732 Dark brown crystals DMSO EtOH CHCl3 324 061 782 2192883 Light orange crystals DMSO EtOH CHCl3 227 078 76 3051764 Light brown crystals DMSO EtOH CHCl3 275 071 708 2262795 Colorless crystals DMSO EtOH CHCl3 253 065 916 3023786 Yellow crystals DMSO EtOH CHCl3 371 082 75 2712777 Yellow crystals DMSO EtOH CHCl3 346 073 80 316275Stationary phase silica gel Mobile phase for TLC petroleum ether ethyl acetate methanol (6 3 1) Iodine vapors as visualizing agent

by iodine chamber Melting points of newly synthesizedbenzamide substituted Mannich bases were determined ondigital melting point apparatus (Flora Perfit India) and werefounduncorrected (Table 1)The structures of the synthesizedderivatives were confirmed by spectral data The 120582max wascalculated by using double beam UV-Visible 1800 Shimadzuspectrophotometer The IR spectra were recorded on FTIR-Shimadzu spectrometer using Nujol method 1H NMR and13C NMR spectra were recorded on BRUKER AVANCE IINMR spectrometer using DMSO as solvent and TMS asinternal standard chemical shift values were expressed in120575 ppm For mass spectra solutions were made in HPLCgrade methanol and spectra were obtained with Vg-11-250J70S spectrophotometer at 70 eV using electron ionization(EI source) Chem3D Ultra (version 10) was employed forstructural similarity studies [9] QSAR studies were per-formed by multilinear regression using Analyze it version30 software

211 Synthesis A series of benzamide substituted Mannichbases were synthesized as per Figure 1

General Procedure for the Synthesis of Benzamide To 1mLof benzoyl chloride 2mL of ammonium hydroxide (30)was added This mixture was allowed to stand for 2 minutesand then 4mL water was added to it The crude product wasrecrystallized with ethanol [10]

N-(Morpholin-4-ylmethyl)benzamide (1) [11 12] Benzamide(0001M) was dissolved in ethanol To this morpholine(0001M) and (0015M) formaldehyde were added Thereaction mixture was refluxed for 1 hour and the reactionwas monitored by TLC Light brown colored crystals wereobtained after evaporating the solvent Mp 65ndash67∘C IR(Nujol) 342813 305047 282885 165523 154320 153942143265 130987 127790 105866 101279 81781 cmminus1 1HNMR (DMSO-d

6400MHz) 80 (br s 1H ndashNH) 795 (m

2H ArndashH) 751 (m 3H ArndashH) 427 (s 2H ndashCH2) 367

(s 4H ndashH of morpholine) 237 (s 4H ndashH of morpholine)13C NMR 715 (C-26) 539 (C-35) 64 (C-7) 1674 (C-9)1329 (C-11) 1276 (C-1216) 1319 (C-131415)MSmz 2201222110 (M+1) 22213 (M+2) Anal Cal for C

12H16N2O2 C

6543 H 732 N 1272 O 1453 Found C 6523 H 739 N1212 O 1433

N-(Piperazine-1-ylmethyl)benzamide (2) [13] Benzamide(0001M) was dissolved in ethanol To this piperazine(0001M) and (0015M) formaldehyde were added Thereaction mixture was refluxed for 7-8 hours and the reactionwas monitored by TLC Dark brown colored crystals wereobtained after evaporating the solvent Mp 68ndash70∘C IR(Nujol) 341415 305345 283988 164824 156723 153444143366 130683 101273 81882 cmminus1 1H NMR (DMSO-d

6

400MHz) 84 (br s 1H ndashNH) 798 (m 2H ArndashH) 752 (m3H ArndashH) 426 (s 2H ndashCH

2) 265 (s 4H ndashHof piperazine)

248 (s 4H ndashH of piperazine) 20 (br s 1H ndashNH) 13CNMR508 (C-26) 551 (C-35) 641 (C-7) 1682 (C-9) 1332 (C-11) 1279 (C-1216) 1309 (C-131415) MS mz 21914 22014(M+1) 22117 (M+2) Anal Cal for C

12H17N3O C 6573 H

781 N 1916 O 730 Found C 6579 H 761 N 1926 O732

N-[(4-Bromo-phenylamino)-methyl]-benzamide (3) Benza-mide (0001M) was dissolved in ethanol To this 4-bromoaniline (0001M) and (0015M) formaldehyde wereadded The reaction mixture was refluxed for 9-10 hours andthe reaction was monitored by TLC Light orange coloredcrystals were obtained after evaporating the solvent Mp66ndash69∘C IR (Nujol) 343923 305248 283452 164525153830 150261 146015 109464 101557 85257 cmminus1 1HNMR (DMSO-d

6400MHz) 82 (br s 1H ndashNH) 795 (m 2H

ArndashH) 756 (m 3H ArndashH) 721 (d 2H ArndashH) 632 (d 2HArndashH) 497 (t 2H ndashCH

2) 40 (br s 1H ndashNH) 13C NMR

386 (C-1) 308 (C-26) 296 (C-35) 479 (C-4) 578 (C-9)1682 (C-11) 1335 (C-13) 1273 (C-1418) 1297 (C-151617)MS mz 30402 30602 (M+1) 30501 (M+2) Anal Cal forC14H13BrN2O C 5510 H 429 Br 2618 N 918 O 524

Found C 5518 H 419 Br 2628 N 908 O 544

N-Phenyl-aminomethyl-benzamide (4) Benzamide (0001M)was dissolved in ethanol To this aniline (0001M) and(0015M) formaldehyde were added The reaction mixturewas refluxed for 9-10 hours and the reaction was monitoredby TLC Light brown colored crystals were obtained afterevaporating the solvent Mp 98ndash101∘C IR (Nujol) 344212

The Scientific World Journal 3

C

O

Cl C

O

HCHO

NH

R

Ethanol

O

Reflux

Benzoyl chloride Benzamide

C NH

N

O

O

C

NH

N

O

NH

C

NH

HN

O

Br

C NHH

N

O

C

O

NH

CHN

minusR

NH3

from 30 NH4OH

NH2

CH2

CH2

CH2

CH2

CH2

CH2

1

2

3

4 7

6

5

C NHHN

O

CH2 SO2NH2

HN

O

C NH CH2

O2N

O2N

NO2

R = 1∘ amine

= 2∘ amine

1ndash7

minusR998400

R998400

Figure 1 Synthesis of benzamide substituted Mannich bases (1ndash7)

305441 283659 165210 153926 150454 144028 10136482268 cmminus1 1HNMR (DMSO-d

6400MHz) 81 (br s 1H ndash

NH) 798 (m 2H ArndashH) 752 (m 3H ArndashH) 658 (m 2HArndashH) 704 (m 3H ArndashH) 496 (s 2H ndashCH

2) 42 (br s

1H ndashNH) 13C NMR 486 (C-1) 334 (C-26) 243 (C-345)578 (C-8) 1684 (C-10) 1330 (C-12) 1276 (C-1317) 1312 (C-141516) MS mz 22611 22713 (M+1) 22812 (M+2) AnalCal for C

14H14N2OC 7431 H 624 N 1238 O 707 Found

C 7438 H 604 N 1239 O 713

N-[(4-Sulfamoyl-phenylamino)-methyl]-benzamide (5) Ben-zamide (0001M) was dissolved in ethanol To this sulfanil-amide (0001M) and (0015M) formaldehyde were addedThe reaction mixture was refluxed for 10ndash12 hours and thereaction was monitored by TLC Colorless crystals wereobtained after evaporating the solvent Mp 69-70∘C IR(Nujol) 331016 305441 285469 163652 154119 153444144082 132022 113555 108018 86318 cmminus1 82 (br s 1H

ndashNH) 796 (m 2H ArndashH) 771 (d 2H ArndashH) 751 (m 3HArndashH) 671 (d 2H ArndashH) 494 (t 2H ndashCH

2) 40 (br s1H

ndashNH) 20 (br s 2H ndashNH2) 1HNMR (DMSO-d

6400MHz)

81 (br s 1H ndashNH) 798 (m 2H ArndashH) 752 (m 3H ArndashH) 658 (m 2H ArndashH) 704 (m 3H ArndashH) 496 (s 2H ndashCH2) 42 (br s 1H ndashNH) 13CNMR 584 (C-1) 157 (C-26)

295 (C-35) 486 (C-4) 574 (C-10) 1679 (C-12) 1329 (C-16)1276 (1721) 1304 (C-181920) MSmz 30509 30610 (M+1)30708 (M+2) Anal Cal for C

14H15N3O3S C 5507 H 495

N 1376 O 1572 S 1050 Found C 5513 H 475 N 1326O 1579 S 1042

N-[(2-Nitro-phenylamino)-methyl]-benzamide (6) Benzam-ide (0001M) was dissolved in ethanol To this 2-nitroaniline(0001M) and (0015M) formaldehyde were addedThe reac-tion mixture was refluxed for 10ndash12 hours and the reactionwasmonitored by TLC Yellow colored crystals were obtainedafter evaporating the solvent Mp 68ndash70∘C IR (Nujol)


Table 2 Minimum inhibitory concentration (MIC) of the synthesized benzamide substituted Mannich bases against Gram positive andGram negative bacteria

CompoundsMinimum inhibitory concentration (MIC) (120583gmL)

Gram positive bacteria Gram negative bacteriaS aureus E faecalis E coli P aeruginosa

1 125 125 125 1252 125 125 625 1253 125 25 625 6254 25 125 125 255 125 625 3125 6256 625 625 625 1257 3125 3125 3125 625Control mdash mdash mdash mdashAmoxicillin 156 156 3125 3125Cefixime 625 625 125 625

342380 305021 283105 164632 154019 152436 150936146221 109851 130655 85932 cmminus1 1H NMR (DMSO-d

6

400MHz) 84 (br s 1H ndashNH) 797 (m 1H ArndashH) 795 (m2H ArndashH) 754 (m 3H ArndashH) 743 (m 1H ArndashH) 684(m 1H ArndashH) 669 (m 1H ArndashH) 499 (s 2H ndashCH

2)

421 (br s 1H ndashNH) 13CNMR 469 (C-1) 288 (C-2) 213(213) 225 (C-4) 229 (C-5) 853 (C-6) 1294 (C-151617)MS mz 27110 27210 (M+1) 27315 (M+2) Anal Cal forC14H13N3O5 C 6199 H 483 N 1549 O 1769 Found C

6191 H 480 N 1555 O 1742

N-[(24-Dinitro-phenylamino)-methyl]-benzamide (7) Ben-zamide (0001M) was dissolved in ethanol To this 24-dinitroaniline (0001M) and (0015M) formaldehyde wereadded The reaction mixture was refluxed for 10ndash12 hoursand the reaction was monitored by TLC Yellow coloredcrystals were obtained after evaporating the solvent Mp 69ndash72∘C IR (Nujol) 342680 305221 283505 164132 154519153036 150236 146621 109951 130455 86232 cmminus1 1HNMR (DMSO-d

6400MHz) 890 (m 1H ArndashH) 836 (m

1H ArndashH) 82 (br s 1H ndashNH) 795 (m 2H ArndashH) 75 (m3H ArndashH) 695 (m 1H ArndashH) 494 (s 2H ndashCH

2) 41 (br s

1H ndashNH) 13C NMR 459 (C-1) 242 (C-2) 219 (C-3) 767(C-4) 235 (C-5) 807 (C-6) 567 (C-8) 1679 (C-10) 1332 (C-15) 1279 (C-1620) 1302 (C-171819) MS mz 31609 31710(M+1) 31810 (M+2) Anal Cal for C

14H12N4O5 C 5317 H

382 N 1771 O 2529 Found C 5323 H 388 N 1772 O2518

3 Biological Evaluation

31 Antibacterial Activity The inhibition of the microbialgrowth may be utilized for demonstrating the therapeuticefficacy of the synthesized compounds The Gram nega-tive bacteria (Escherichia coli Pseudomonas aeruginosa) andGram positive bacteria (Enterococcus faecalis Staphylococcusaureus) were used for the activity

The antibacterial activity was evaluated by tube dilutionmethod which depends upon the inhibition of growth of amicrobial culture in a uniform solution of antibiotic in a fluidmedium that is favorable to its rapid growth in the absenceof the antibiotic [14] In this method minimum inhibitoryconcentration (MIC) of the test compounds was determinedThe MIC is the lowest concentration of an antimicrobialagent that inhibits the growth of the test organism [15]Test compounds and standard compounds (amoxicillin andcefixime) were dissolved in dimethyl sulfoxide to give aconcentration of 100120583gmL Double strength nutrient brothIP was used Suspension of each microorganism was madeby transferring the organism from culture to 10mL of sterilenormal saline solution

Determination of Minimum Inhibitory Concentration (MIC)One mL of sterilized media was poured into sterile testtubes One mL of 100 120583gmL test solution was transferredin one tube and serially diluted to give concentrations of50 25 125 625 312 156 and 078 120583gmL To all the tubes01mL of suspension of bacteria in saline was added and thetubes were incubated at 37∘C for 24 h The growth in thetube was observed visually for turbidity and inhibition wasdetermined by the absence of growth MIC was determinedby the lowest concentration of sample that retarded thedevelopment of turbidity The activity of the compoundscomparedwith the standard drugs (amoxicillin and cefixime)is given in Table 2 Graphical representation of minimuminhibitory concentration (MIC) of benzamide substitutedMannich bases against Gram positive and negative bacterialstrains is given in Figures 2 and 3 respectively

4 Molecular Structural Similarity Studies

Assessments of molecular structural similarity of synthesizedbenzamide substituted Mannich bases were compared tothose of standard compounds by means of physicochemical


Table 3 Calculation of various molecular properties of the synthesized benzamide substituted Mannich bases

Compound SASa (A2) MSb (A2) CSEVc (A3) Ovality MRd (cm3mol) MTIe WIf BIg MWh log 1198751 448081 22885 19150 14243 614384 3711 496 89200 220273 105232 512423 268228 22394 15040 429696 8354 1126 343784 30536 14843 538939 291721 26245 14715 308167 9773 1244 354337 302378 49434 443839 227461 19433 14019 631193 3795 496 89200 219288 083035 46420 234624 18775 14796 516276 4798 614 124234 226278 273896 483994 250613 20885 14721 482504 5338 727 164356 305176 356787 47056 247467 21278 14357 351809 6884 925 256945 271277 mdashStd1lowast 580224 331272 32088 14614 10691 15459 2353 1046550 43746 mdashStd2lowast 570267 318963 28294 15303 9792 13519 2039 748946 404350 2419aConnolly solvent accessible surface area bConnolly molecular surface area cConnolly solvent excluded volume dMolar refractivityeMolecular topological index fWiener index g Balaban index hMolecular weight Std1lowastmdashcefixime Std2lowastmdashtosufloxacin tosylate

Target compounds

302520151050

1 2 3 4 5 6 7

MIC

(120583g

mL)

Con

trol

Am

oxic

illin

Cefi

xim

e

S aureusE faecalis

Figure 2 Graphical representation of minimum inhibitory con-centration (MIC) of benzamide substituted Mannich bases againstGram positive bacterial strains

similarity between the standard drugs and new analoguesdesignedThe information was used for prediction of biolog-ical activity of important target compounds for novel drugdiscovery The physicochemical parameters were calculatedfor the synthesized compounds usingChem3DUltra (version10) and compared with the values obtained for standardcompounds (cefixime and tosufloxacin tosylate) Various setof parameters were used for calculations as given in Table 3

The distance 119889119894of a particular target compound 119894 can be

presented as

1198892

119894=

sum119899

119895=1(1 minus 119883

119894119895119883119894standard)

2

119899

(1)

where 119883119894119895

is the value of molecular parameters 119894 for com-pound 119895119883119894standard is the value of the same molecular parameter 119894

for standard drug119899 is the total number of the considered molecular param-

etersThe similarity of the compounds can be calculated as

age similarity = (1 minus 119877) times 100 (2)

30

25

20

15

10

5

0

MIC

(120583g

mL)

Target compounds

1 2 3 4 5 6 7

Con

trol

Am

oxic

illin

Cefi

xim

e

E coliP aeruginosa

Figure 3 Graphical representation of minimum inhibitory con-centration (MIC) of benzamide substituted Mannich bases againstGram negative bacterial strains

where 119877 is quadratic mean also known as the root meansquare and 119877 can be calculated as

119877 = radic1198892

119894 (3)

Assessment of structural similarities of synthesized com-pounds with standard drugs showed that all the derivativeshave good age similarity (Table 4)

5 Quantitative Structure ActivityRelationship (QSAR)

The synthesized substituted Mannich bases were subjectedto QSAR analysis by using multilinear regression For thisanalysis various physicochemical parameters were calculatedand correlated with biological activity that is antibacte-rial activity to obtain QSAR models The physicochemicalparameters were computed using Chem3D (Version 10) Ultraafter energy minimization to minimum root mean square(RMS) gradient of 0100 kcalmole A by MOPAC softwarepackage Out of all the physicochemical parameters (Table 4)


Table 4 Assessment of structural similarity of synthesized benza-mide substituted Mannich bases with standard drugs

Compound Cefixime(1 minus 119877)100

Tosufloxacin tosylate(1 minus 119877)100

1 727 97722 84 6793 9034 52894 682 6635 952 6956 91 547 74 967

C

O

NH CH2 R

Scheme 1

the following five parameters were selected for QSAR studieslog 119875 Connolly solvent accessible surface area (SAS) molarrefractivity (MR) ovality and molecular weight (MW)Biological activity data was converted to the logarithmicvalues For antibacterial activity biological activity was takenas minuslog(MICmolecular weight of compound)

51 Statistical Analysis The statistical significance of themodels was assessed on the basis of various parameters suchas 1198772 (coefficient of correlation) 1198772adj (coefficient of deter-mination) 1198762 (cross validates 1198772) and F (Fischer statistics)considering all the parameters in the model significant onlyat 95 confidence level (119875 lt 005)

Basic structure of synthesized benzamide substitutedMannich bases is shown in Scheme 1

(I) QSAR Model for Antibacterial Activity against Escherichiacoli

pMIC = 006413 (log119875) minus 0009411 (SAS)

minus 0003046 (MW) + 8615 (Ovality)

minus 002413 (MR) minus 457

119873 = 7 1198772= 0921 119877

2

adj = 0529

Press = 000000025 1198762 = 0999

119865 = 235 119878 = 0188

(4)

Here and hereafter 1198772 is coefficient of correlation 1198772adj iscoefficient of determination 119865 is Fischer statistics 119873 isnumber of test compounds Press is predictive error sum ofsquares 1198762 is cross validated 1198772 BA is biological activityand 119878 is standard error of estimation

Table 5 Observed and predicted antibacterial activity of synthe-sized benzamide substituted Mannich bases against Escherichia coli

Compound Observed activity Predicted activity Residual1 1246051254 1398072 minus0152022 168893213 1692905 minus0003973 1684670173 1688051 minus0003384 1244104854 1145049 00990565 185979231 1810427 00493666 1688673205 1692826 minus0004157 1938562952 1922897 0015666

The observed and predicted antibacterial activity ofsynthesized benzamide substituted Mannich bases are sum-marized in Table 5 and plot of calculated and observedantibacterial activity is given in Figure 4

(II) QSAR Model for Antibacterial Activity against Staphylo-coccus aureus


+ 0003104 (MW) + 5643 (Ovality)

minus 004099 (MR) + 3876

119873 = 7 1198772= 986 119877

2

adj = 0913

Press = 000094 1198762 = 0999

119865 = 1366 119878 = 0095

(5)

The observed and predicted antibacterial activity of synthe-sized benzamide substituted Mannich bases are summarizedin Table 6 and plot of calculated and observed antibacterialactivity is given in Figure 4

(III) QSAR Model for Antibacterial Activity against Pseu-domonas aeruginosa




119873 = 7 1198772= 0997 119877

2

adj = 0982

Press = 000009 1198762 = 0998

119865 = 6556 119878 = 0034

(6)

The observed and predicted antibacterial activity of synthe-sized benzamide substituted Mannich bases are summarized


R2 = 09214

105

135

165

195

105 135 165 195

Pred

icte

d ac

tivity

Observed activity

y = 09214x + 01274

(a)

y = 09857x + 00215

R2 = 09856

09

12

15

18

09 12 15 18

Pred

icte

d ac

tivity

Observed activity

(b)

Figure 4 Plot of Predicted pMIC values against observed pMIC for QSAR model for (a) Escherichia coli and (b) Staphylococcus aureus

in Table 7 and plot of calculated and observed antibacterialactivity is given in Figure 5

(IV) QSARModel for Antibacterial Activity against Enterococ-cus faecalis


+ 0002366 (MW) + 8135 (Ovality)

minus 003458 (MR) + 151

119873 = 7 1198772= 0963 119877

2

adj = 0779

Press = 000000009 1198762 = 0998

119865 = 523 119878 = 0139

(7)


6 Result and Discussion

61 Chemistry Thestructures of synthesized derivatives weresupported by means of chromatographic and spectroscopicmethods Both analytical and spectral data (IR and 1HNMR)of all the synthesized derivatives were in full agreement withthe proposed structures The structures of the synthesizedderivatives were proven by the spectroscopic method Thestructures assigned to (1ndash7) were supported by IR spec-tra showing absorption bands at 3442ndash3310 cmminus1 due toNndashH stretching Carbonyl stretch was observed at 1655ndash1636 cmminus1 Stretching vibrations due to C=C (aromatic) were

Table 6 Observed and predicted antibacterial activity of synthe-sized benzamide substituted Mannich bases against Staphylococcusaureus

Compound Observed activity Predicted activity Residual1 1246051254 1170593 0075457822 1387902134 138014 0007762343 138360177 1386275 minus000263514 0943074858 0991585 minus004851025 1257732318 1286955 minus002922326 1688673205 1692675 minus000400227 193925838 1947837 minus00085788

observed at 1539ndash1502 cmminus1 respectively Bands at 1509ndash1502 cmminus1 appeared due to asymmetric N=O stretch Bandsat 863-817 cmminus1 indicated out-of-plane aromatic stretch Theproton NMR of these compounds revealed the presence ofdownfield singlet 80ndash89 ppm for ndashCONH A 2 protons sin-glet at 427ndash499 ppm appeared due to protons of methylenegroup All the other aliphatic and aromatic protons wereobserved within the expected regions This part concludedthe synthesis of benzamide substituted Mannich bases

62 Biological Activity

621 Antibacterial Activity The minimum inhibitory con-centrations of 5 (125 625 3125 and 625) 6 (625 625625 and 125) and 7 (3125 3125 3125 and 625) werefound to be good which is comparable with MIC of bothstandard drugs amoxicillin (156 156 3125 and 3125) andcefixime (625 625 125 and 625) No inhibitory effect wasobserved for DMSO used as control The MIC of 7 wasfound to be better than cefixime and MIC of 6 was found


09

11

13

15

17

19

09 13 17

y = 09971x + 00036R2 = 0997

Pred

icte

d ac

tivity

Observed activity

(a)

09

11

13

15

17

19

21

09 14 19 24

y = 09632x + 00534

R2 = 09632

Pred

icte

d ac

tivity

Observed activity

(b)

Figure 5 Plot of Predicted pMIC values against observed pMIC for QSAR model for (a) Pseudomonas aeruginosa and (b) Enterococcusfaecalis

Table 7 Observed and predicted antibacterial activity of synthe-sized substituted benzamide Mannich bases against Pseudomonasaeruginosa

Compound Observed activity Predicted activity Residual1 1246051 1217519 00285322 1387902 1384015 00038873 168467 1684545 00001254 0943075 0959732 minus0016665 1558762 1568366 minus000966 1387643 1388065 minus0000427 1637533 1639689 minus000216

to be comparatively similar to cefixime While studying MICagainst bacterial strains 7was found to be most active amongall the synthesized benzamide substituted Mannich basesFrom the above results it was concluded that compoundsbearing substitutions such as sulphonamido 5 p-nitro 6 anddinitro group 7 have emerged out as potent antibacterialagents

The compounds bearing nitro groups were found to havesignificant potential against all bacterial strains This activitywas attributed to lipophilic nature of these substituents whichultimately facilitate the transportation of target compoundsacross the biological membranes to produce desired effectBoth nitro and sulphonamide groups are an efficient ndashI ndashRgroup but the nature of the latter (low log119875 value) is morehydrophilic than the former (high log119875 value) Hence thecontribution of sulphonamide group towards antibacterial

Table 8 Observed and predicted antibacterial activity of synthe-sized benzamide substituted Mannich bases against Enterococcusfaecalis

Compound Observed activity Predicted activity Residual1 1246051 1358788 minus0112742 1387902 1401507 minus001363 108261 10811 0001514 1244105 1174548 00695575 1558762 1517701 00410616 1688673 1684798 00038757 1939258 1928613 0010645

activity is comparatively less than compounds bearing nitrogroups

622 Similarity Studies Assessment of structural similaritiesof synthesized benzamide substituted Mannich bases withantibacterial drugs (cefixime and tosufloxacin tosylate) indi-cated that all the derivatives have shown good percentage ofsimilarity ranging from 5289 to 9772 and compound 1was found to have excellent percentage of similarity (gt90)with all standard drugs The structural similarity of all thecompounds with standard drugs varying from one com-pound to another This may be due to the large differencebetween the values of physicochemical parameters calculatedfor target compounds with values of parameters calculatedfor standard drugs However good structural similarity of


compounds does not always lead to good therapeutic activityas compound 1 has shown an excellent percentage of sim-ilarity (5289ndash9772) but it was found to be less active asantibacterial agent

63Quantitative StructureActivity Relationship (QSAR)Anal-ysis The results suggested that antibacterial activity washighly dependent on log119875 SAS MR ovality and MW Allthe developed models have good coefficient of correlation(0963ndash0997) coefficient of determination (0529ndash0982)and cross validated 1198772 (0998ndash0999) with Fischer statistics(235ndash6556) The derived models could be used in designingof more potent inhibitors against bacterial infection The fiveparameters correlated statistically sound QSAR models forantibacterial activity against Staphylococcus aureus Entero-coccus faecalis Escherichia coli and Pseudomonas aeruginosacould be used for the prediction of biological activitiesof unknown and unavailable compounds of this class Inthe present study an attempt has been made to designsome active antibacterial agents with lesser side effects TheQSAR results have shown the dependence of antibacterialactivity of synthesized substituted benzamide Mannich basederivatives on their structural and physicochemical featuresThe results indicated that the bulkier aromatic substituentslike sulphonamido group may increase lipophilicity andgive better antibacterial activity The presence of electronwithdrawing group like ndashNO

2in the compound resulted

in enhanced biological activity by improving lipophilicityThis lipophilicity could facilitate penetration or passage ofthese compounds across the biological membrane easily forbeneficial therapeutic effect

7 Conclusion

In antibacterial activity the compounds 5 6 and 7 wereobserved as good antibacterial agents and compound 7 wasfound to be the most active against all the selected bacterialstrainsThe compound 1was found to have excellent percent-age of similarity (gt90) with all standard drugs The resultssuggested that antibacterial activity is highly dependent onphysicochemical parameters such as log119875 Connolly solventaccessible surface area (SAS)molar refractivity (MR) ovalityand molecular weight (MW) The derived model could beused in the future for designing of more potent inhibitors ofbacterial infection

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] K C Chaluvaraju and B K Ishwar ldquoSynthesis and antimicro-bial activities of amino benzylated mannich bases of pyrazi-namiderdquo International Journal of ChemTech Research vol 2 no3 pp 1368ndash1371 2010

[2] K C Chaluvaraju and K Ishwar Bhat ldquoBiological evaluationof aminobenzylated mannich bases of P- fluoro benzaldehyderdquoInternational Journal of PharmTech Research vol 3 no 4 pp1904ndash1908 2011

[3] B S Holla M K Shivananda M S Shenoy and G AntonyldquoStudies on arylfuran derivatives Part VII Synthesis and char-acterization of some Mannich bases carrying halophenylfurylmoieties as promising antibacterial agentsrdquo Farmaco vol 53 no8-9 pp 531ndash535 1998

[4] J March Advanced Organic Chemistry Reactions Mechanismsand Structure Wiley New York NY USA 3rd ed edition 1985

[5] V J Belinelo G T Reis G M Stefani D L Ferreira-Alvesand D Pilo-Veloso ldquoSynthesis of 61205727120573-dihydroxyvouacapan-17120573-oic acid derivatives Part IV mannich base derivatives andits activities on the electrically stimulated guinea-pig ileumpreparationrdquo Journal of the Brazilian Chemical Society vol 13no 6 pp 830ndash837 2002

[6] S Joshi N Khosla and P Tiwari ldquoIn vitro study of somemedic-inally important Mannich bases derived from antitubercularagentrdquo Bioorganic and Medicinal Chemistry vol 12 no 3 pp571ndash576 2004

[7] X-H Wang Y Tang Q Xie and Z-B Qiu ldquoQSAR study of4-phenylpiperidine derivatives as 120583 opioid agonists by neuralnetworkmethodrdquoEuropean Journal ofMedicinal Chemistry vol41 no 2 pp 226ndash232 2006

[8] K B Lipkowitz and D B Boyd Reviews on ComputationalChemistry vol 1 2007

[9] N Nikolova and J Jaworska ldquoApproaches to measure chemicalsimilaritymdasha reviewrdquoQSAR and Combinatorial Science vol 22no 9-10 pp 1006ndash1026 2004

[10] M Malhotra M Arora A Samad K Sahu P Phogat and ADeep ldquoSynthesis and evaluation of some novel derivatives of2-propoxybenzylideneisonicotinohydrazide for their potentialantimicrobial activityrdquo Journal of Serbian Chemical Society vol77 no 5 pp 589ndash597 2012

[11] A R Katritzky C N Fali W Bao and M Qi ldquoMonoacylami-nals by the benzotriazole-assisted aminoalkylation of amidesrdquoSynthesis vol 10 pp 1421ndash1423 1998

[12] H Bundgaard and M Johansen ldquoProdrugs as drug deliverysystems IV N-Mannich bases as potential novel prodrugs foramides ureides amines and other NH-acidic compoundsrdquoJournal of Pharmaceutical Sciences vol 69 no 1 pp 44ndash461980

[13] Patented Span ES 418775 A1 19760301 1976[14] J G Cappucino andN Sherman ldquoMicrobiologymdashA laboratory

Manualrdquo p 263 Addison Wesley Longman New York NYUSA 4th edition 1999

[15] Pharmacopoeia of India (the Indian Pharmacopoeia) Controllerof Publications New Delhi India 1985

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy


Carbohydrate Chemistry

International Journal of


Journal of

Chemistry


Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


Table 1 Physical data of synthesized benzamide substituted Mannich bases

Compound Color Solubility 120582max 119877119891value age

yield Molecular weight

1 Light brown crystals DMSO EtOH CHCl3 226 045 84 2202732 Dark brown crystals DMSO EtOH CHCl3 324 061 782 2192883 Light orange crystals DMSO EtOH CHCl3 227 078 76 3051764 Light brown crystals DMSO EtOH CHCl3 275 071 708 2262795 Colorless crystals DMSO EtOH CHCl3 253 065 916 3023786 Yellow crystals DMSO EtOH CHCl3 371 082 75 2712777 Yellow crystals DMSO EtOH CHCl3 346 073 80 316275Stationary phase silica gel Mobile phase for TLC petroleum ether ethyl acetate methanol (6 3 1) Iodine vapors as visualizing agent

by iodine chamber Melting points of newly synthesizedbenzamide substituted Mannich bases were determined ondigital melting point apparatus (Flora Perfit India) and werefounduncorrected (Table 1)The structures of the synthesizedderivatives were confirmed by spectral data The 120582max wascalculated by using double beam UV-Visible 1800 Shimadzuspectrophotometer The IR spectra were recorded on FTIR-Shimadzu spectrometer using Nujol method 1H NMR and13C NMR spectra were recorded on BRUKER AVANCE IINMR spectrometer using DMSO as solvent and TMS asinternal standard chemical shift values were expressed in120575 ppm For mass spectra solutions were made in HPLCgrade methanol and spectra were obtained with Vg-11-250J70S spectrophotometer at 70 eV using electron ionization(EI source) Chem3D Ultra (version 10) was employed forstructural similarity studies [9] QSAR studies were per-formed by multilinear regression using Analyze it version30 software

211 Synthesis A series of benzamide substituted Mannichbases were synthesized as per Figure 1

General Procedure for the Synthesis of Benzamide To 1mLof benzoyl chloride 2mL of ammonium hydroxide (30)was added This mixture was allowed to stand for 2 minutesand then 4mL water was added to it The crude product wasrecrystallized with ethanol [10]

N-(Morpholin-4-ylmethyl)benzamide (1) [11 12] Benzamide(0001M) was dissolved in ethanol To this morpholine(0001M) and (0015M) formaldehyde were added Thereaction mixture was refluxed for 1 hour and the reactionwas monitored by TLC Light brown colored crystals wereobtained after evaporating the solvent Mp 65ndash67∘C IR(Nujol) 342813 305047 282885 165523 154320 153942143265 130987 127790 105866 101279 81781 cmminus1 1HNMR (DMSO-d

6400MHz) 80 (br s 1H ndashNH) 795 (m

2H ArndashH) 751 (m 3H ArndashH) 427 (s 2H ndashCH2) 367

(s 4H ndashH of morpholine) 237 (s 4H ndashH of morpholine)13C NMR 715 (C-26) 539 (C-35) 64 (C-7) 1674 (C-9)1329 (C-11) 1276 (C-1216) 1319 (C-131415)MSmz 2201222110 (M+1) 22213 (M+2) Anal Cal for C

12H16N2O2 C

6543 H 732 N 1272 O 1453 Found C 6523 H 739 N1212 O 1433

N-(Piperazine-1-ylmethyl)benzamide (2) [13] Benzamide(0001M) was dissolved in ethanol To this piperazine(0001M) and (0015M) formaldehyde were added Thereaction mixture was refluxed for 7-8 hours and the reactionwas monitored by TLC Dark brown colored crystals wereobtained after evaporating the solvent Mp 68ndash70∘C IR(Nujol) 341415 305345 283988 164824 156723 153444143366 130683 101273 81882 cmminus1 1H NMR (DMSO-d

6

400MHz) 84 (br s 1H ndashNH) 798 (m 2H ArndashH) 752 (m3H ArndashH) 426 (s 2H ndashCH

2) 265 (s 4H ndashHof piperazine)

248 (s 4H ndashH of piperazine) 20 (br s 1H ndashNH) 13CNMR508 (C-26) 551 (C-35) 641 (C-7) 1682 (C-9) 1332 (C-11) 1279 (C-1216) 1309 (C-131415) MS mz 21914 22014(M+1) 22117 (M+2) Anal Cal for C

12H17N3O C 6573 H

781 N 1916 O 730 Found C 6579 H 761 N 1926 O732

N-[(4-Bromo-phenylamino)-methyl]-benzamide (3) Benza-mide (0001M) was dissolved in ethanol To this 4-bromoaniline (0001M) and (0015M) formaldehyde wereadded The reaction mixture was refluxed for 9-10 hours andthe reaction was monitored by TLC Light orange coloredcrystals were obtained after evaporating the solvent Mp66ndash69∘C IR (Nujol) 343923 305248 283452 164525153830 150261 146015 109464 101557 85257 cmminus1 1HNMR (DMSO-d

6400MHz) 82 (br s 1H ndashNH) 795 (m 2H

ArndashH) 756 (m 3H ArndashH) 721 (d 2H ArndashH) 632 (d 2HArndashH) 497 (t 2H ndashCH

2) 40 (br s 1H ndashNH) 13C NMR

386 (C-1) 308 (C-26) 296 (C-35) 479 (C-4) 578 (C-9)1682 (C-11) 1335 (C-13) 1273 (C-1418) 1297 (C-151617)MS mz 30402 30602 (M+1) 30501 (M+2) Anal Cal forC14H13BrN2O C 5510 H 429 Br 2618 N 918 O 524

Found C 5518 H 419 Br 2628 N 908 O 544

N-Phenyl-aminomethyl-benzamide (4) Benzamide (0001M)was dissolved in ethanol To this aniline (0001M) and(0015M) formaldehyde were added The reaction mixturewas refluxed for 9-10 hours and the reaction was monitoredby TLC Light brown colored crystals were obtained afterevaporating the solvent Mp 98ndash101∘C IR (Nujol) 344212


C

O

Cl C

O

HCHO

NH

R

Ethanol

O

Reflux


C NH

N

O

O

C

NH

N

O

NH

C

NH

HN

O

Br

C NHH

N

O

C

O

NH

CHN

minusR

NH3

from 30 NH4OH

NH2

CH2

CH2

CH2

CH2

CH2

CH2

1

2

3

4 7

6

5

C NHHN

O

CH2 SO2NH2

HN

O

C NH CH2

O2N

O2N

NO2

R = 1∘ amine

= 2∘ amine

1ndash7

minusR998400

R998400





2) 42 (br s


14H14N2OC 7431 H 624 N 1238 O 707 Found

C 7438 H 604 N 1239 O 713



2) 40 (br s1H


6400MHz)



14H15N3O3S C 5507 H 495

N 1376 O 1572 S 1050 Found C 5513 H 475 N 1326O 1579 S 1042








6


2)


6191 H 480 N 1555 O 1742




2) 41 (br s


14H12N4O5 C 5317 H

382 N 1771 O 2529 Found C 5323 H 388 N 1772 O2518










Target compounds

302520151050

1 2 3 4 5 6 7

MIC

(120583g

mL)

Con

trol

Am

oxic

illin

Cefi

xim

e

S aureusE faecalis




presented as

1198892

119894=

sum119899

119895=1(1 minus 119883

119894119895119883119894standard)

2

119899

(1)

where 119883119894119895





30

25

20

15

10

5

0

MIC

(120583g

mL)

Target compounds

1 2 3 4 5 6 7

Con

trol

Am

oxic

illin

Cefi

xim

e

E coliP aeruginosa



119877 = radic1198892

119894 (3)








1 727 97722 84 6793 9034 52894 682 6635 952 6956 91 547 74 967

C

O

NH CH2 R

Scheme 1








119873 = 7 1198772= 0921 119877

2

adj = 0529

Press = 000000025 1198762 = 0999

119865 = 235 119878 = 0188

(4)







+ 0003104 (MW) + 5643 (Ovality)

minus 004099 (MR) + 3876

119873 = 7 1198772= 986 119877

2

adj = 0913

Press = 000094 1198762 = 0999

119865 = 1366 119878 = 0095

(5)






119873 = 7 1198772= 0997 119877

2

adj = 0982

Press = 000009 1198762 = 0998

119865 = 6556 119878 = 0034

(6)



R2 = 09214

105

135

165

195

105 135 165 195

Pred

icte

d ac

tivity

Observed activity

y = 09214x + 01274

(a)

y = 09857x + 00215

R2 = 09856

09

12

15

18

09 12 15 18

Pred

icte

d ac

tivity

Observed activity

(b)





+ 0002366 (MW) + 8135 (Ovality)

minus 003458 (MR) + 151

119873 = 7 1198772= 0963 119877

2

adj = 0779

Press = 000000009 1198762 = 0998

119865 = 523 119878 = 0139

(7)










09

11

13

15

17

19

09 13 17

y = 09971x + 00036R2 = 0997

Pred

icte

d ac

tivity

Observed activity

(a)

09

11

13

15

17

19

21

09 14 19 24

y = 09632x + 00534

R2 = 09632

Pred

icte

d ac

tivity

Observed activity

(b)















7 Conclusion




Acknowledgment


References

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


C

O

Cl C

O

HCHO

NH

R

Ethanol

O

Reflux


C NH

N

O

O

C

NH

N

O

NH

C

NH

HN

O

Br

C NHH

N

O

C

O

NH

CHN

minusR

NH3

from 30 NH4OH

NH2

CH2

CH2

CH2

CH2

CH2

CH2

1

2

3

4 7

6

5

C NHHN

O

CH2 SO2NH2

HN

O

C NH CH2

O2N

O2N

NO2

R = 1∘ amine

= 2∘ amine

1ndash7

minusR998400

R998400





2) 42 (br s


14H14N2OC 7431 H 624 N 1238 O 707 Found

C 7438 H 604 N 1239 O 713



2) 40 (br s1H


6400MHz)



14H15N3O3S C 5507 H 495

N 1376 O 1572 S 1050 Found C 5513 H 475 N 1326O 1579 S 1042








6


2)


6191 H 480 N 1555 O 1742




2) 41 (br s


14H12N4O5 C 5317 H

382 N 1771 O 2529 Found C 5323 H 388 N 1772 O2518










Target compounds

302520151050

1 2 3 4 5 6 7

MIC

(120583g

mL)

Con

trol

Am

oxic

illin

Cefi

xim

e

S aureusE faecalis




presented as

1198892

119894=

sum119899

119895=1(1 minus 119883

119894119895119883119894standard)

2

119899

(1)

where 119883119894119895





30

25

20

15

10

5

0

MIC

(120583g

mL)

Target compounds

1 2 3 4 5 6 7

Con

trol

Am

oxic

illin

Cefi

xim

e

E coliP aeruginosa



119877 = radic1198892

119894 (3)








1 727 97722 84 6793 9034 52894 682 6635 952 6956 91 547 74 967

C

O

NH CH2 R

Scheme 1








119873 = 7 1198772= 0921 119877

2

adj = 0529

Press = 000000025 1198762 = 0999

119865 = 235 119878 = 0188

(4)







+ 0003104 (MW) + 5643 (Ovality)

minus 004099 (MR) + 3876

119873 = 7 1198772= 986 119877

2

adj = 0913

Press = 000094 1198762 = 0999

119865 = 1366 119878 = 0095

(5)






119873 = 7 1198772= 0997 119877

2

adj = 0982

Press = 000009 1198762 = 0998

119865 = 6556 119878 = 0034

(6)



R2 = 09214

105

135

165

195

105 135 165 195

Pred

icte

d ac

tivity

Observed activity

y = 09214x + 01274

(a)

y = 09857x + 00215

R2 = 09856

09

12

15

18

09 12 15 18

Pred

icte

d ac

tivity

Observed activity

(b)





+ 0002366 (MW) + 8135 (Ovality)

minus 003458 (MR) + 151

119873 = 7 1198772= 0963 119877

2

adj = 0779

Press = 000000009 1198762 = 0998

119865 = 523 119878 = 0139

(7)










09

11

13

15

17

19

09 13 17

y = 09971x + 00036R2 = 0997

Pred

icte

d ac

tivity

Observed activity

(a)

09

11

13

15

17

19

21

09 14 19 24

y = 09632x + 00534

R2 = 09632

Pred

icte

d ac

tivity

Observed activity

(b)















7 Conclusion




Acknowledgment


References

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of







6


2)


6191 H 480 N 1555 O 1742




2) 41 (br s


14H12N4O5 C 5317 H

382 N 1771 O 2529 Found C 5323 H 388 N 1772 O2518










Target compounds

302520151050

1 2 3 4 5 6 7

MIC

(120583g

mL)

Con

trol

Am

oxic

illin

Cefi

xim

e

S aureusE faecalis




presented as

1198892

119894=

sum119899

119895=1(1 minus 119883

119894119895119883119894standard)

2

119899

(1)

where 119883119894119895





30

25

20

15

10

5

0

MIC

(120583g

mL)

Target compounds

1 2 3 4 5 6 7

Con

trol

Am

oxic

illin

Cefi

xim

e

E coliP aeruginosa



119877 = radic1198892

119894 (3)








1 727 97722 84 6793 9034 52894 682 6635 952 6956 91 547 74 967

C

O

NH CH2 R

Scheme 1








119873 = 7 1198772= 0921 119877

2

adj = 0529

Press = 000000025 1198762 = 0999

119865 = 235 119878 = 0188

(4)







+ 0003104 (MW) + 5643 (Ovality)

minus 004099 (MR) + 3876

119873 = 7 1198772= 986 119877

2

adj = 0913

Press = 000094 1198762 = 0999

119865 = 1366 119878 = 0095

(5)






119873 = 7 1198772= 0997 119877

2

adj = 0982

Press = 000009 1198762 = 0998

119865 = 6556 119878 = 0034

(6)



R2 = 09214

105

135

165

195

105 135 165 195

Pred

icte

d ac

tivity

Observed activity

y = 09214x + 01274

(a)

y = 09857x + 00215

R2 = 09856

09

12

15

18

09 12 15 18

Pred

icte

d ac

tivity

Observed activity

(b)





+ 0002366 (MW) + 8135 (Ovality)

minus 003458 (MR) + 151

119873 = 7 1198772= 0963 119877

2

adj = 0779

Press = 000000009 1198762 = 0998

119865 = 523 119878 = 0139

(7)










09

11

13

15

17

19

09 13 17

y = 09971x + 00036R2 = 0997

Pred

icte

d ac

tivity

Observed activity

(a)

09

11

13

15

17

19

21

09 14 19 24

y = 09632x + 00534

R2 = 09632

Pred

icte

d ac

tivity

Observed activity

(b)















7 Conclusion




Acknowledgment


References

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of




Target compounds

302520151050

1 2 3 4 5 6 7

MIC

(120583g

mL)

Con

trol

Am

oxic

illin

Cefi

xim

e

S aureusE faecalis




presented as

1198892

119894=

sum119899

119895=1(1 minus 119883

119894119895119883119894standard)

2

119899

(1)

where 119883119894119895





30

25

20

15

10

5

0

MIC

(120583g

mL)

Target compounds

1 2 3 4 5 6 7

Con

trol

Am

oxic

illin

Cefi

xim

e

E coliP aeruginosa



119877 = radic1198892

119894 (3)








1 727 97722 84 6793 9034 52894 682 6635 952 6956 91 547 74 967

C

O

NH CH2 R

Scheme 1








119873 = 7 1198772= 0921 119877

2

adj = 0529

Press = 000000025 1198762 = 0999

119865 = 235 119878 = 0188

(4)







+ 0003104 (MW) + 5643 (Ovality)

minus 004099 (MR) + 3876

119873 = 7 1198772= 986 119877

2

adj = 0913

Press = 000094 1198762 = 0999

119865 = 1366 119878 = 0095

(5)






119873 = 7 1198772= 0997 119877

2

adj = 0982

Press = 000009 1198762 = 0998

119865 = 6556 119878 = 0034

(6)



R2 = 09214

105

135

165

195

105 135 165 195

Pred

icte

d ac

tivity

Observed activity

y = 09214x + 01274

(a)

y = 09857x + 00215

R2 = 09856

09

12

15

18

09 12 15 18

Pred

icte

d ac

tivity

Observed activity

(b)





+ 0002366 (MW) + 8135 (Ovality)

minus 003458 (MR) + 151

119873 = 7 1198772= 0963 119877

2

adj = 0779

Press = 000000009 1198762 = 0998

119865 = 523 119878 = 0139

(7)










09

11

13

15

17

19

09 13 17

y = 09971x + 00036R2 = 0997

Pred

icte

d ac

tivity

Observed activity

(a)

09

11

13

15

17

19

21

09 14 19 24

y = 09632x + 00534

R2 = 09632

Pred

icte

d ac

tivity

Observed activity

(b)















7 Conclusion




Acknowledgment


References

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of





1 727 97722 84 6793 9034 52894 682 6635 952 6956 91 547 74 967

C

O

NH CH2 R

Scheme 1








119873 = 7 1198772= 0921 119877

2

adj = 0529

Press = 000000025 1198762 = 0999

119865 = 235 119878 = 0188

(4)







+ 0003104 (MW) + 5643 (Ovality)

minus 004099 (MR) + 3876

119873 = 7 1198772= 986 119877

2

adj = 0913

Press = 000094 1198762 = 0999

119865 = 1366 119878 = 0095

(5)






119873 = 7 1198772= 0997 119877

2

adj = 0982

Press = 000009 1198762 = 0998

119865 = 6556 119878 = 0034

(6)



R2 = 09214

105

135

165

195

105 135 165 195

Pred

icte

d ac

tivity

Observed activity

y = 09214x + 01274

(a)

y = 09857x + 00215

R2 = 09856

09

12

15

18

09 12 15 18

Pred

icte

d ac

tivity

Observed activity

(b)





+ 0002366 (MW) + 8135 (Ovality)

minus 003458 (MR) + 151

119873 = 7 1198772= 0963 119877

2

adj = 0779

Press = 000000009 1198762 = 0998

119865 = 523 119878 = 0139

(7)










09

11

13

15

17

19

09 13 17

y = 09971x + 00036R2 = 0997

Pred

icte

d ac

tivity

Observed activity

(a)

09

11

13

15

17

19

21

09 14 19 24

y = 09632x + 00534

R2 = 09632

Pred

icte

d ac

tivity

Observed activity

(b)















7 Conclusion




Acknowledgment


References

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


R2 = 09214

105

135

165

195

105 135 165 195

Pred

icte

d ac

tivity

Observed activity

y = 09214x + 01274

(a)

y = 09857x + 00215

R2 = 09856

09

12

15

18

09 12 15 18

Pred

icte

d ac

tivity

Observed activity

(b)





+ 0002366 (MW) + 8135 (Ovality)

minus 003458 (MR) + 151

119873 = 7 1198772= 0963 119877

2

adj = 0779

Press = 000000009 1198762 = 0998

119865 = 523 119878 = 0139

(7)










09

11

13

15

17

19

09 13 17

y = 09971x + 00036R2 = 0997

Pred

icte

d ac

tivity

Observed activity

(a)

09

11

13

15

17

19

21

09 14 19 24

y = 09632x + 00534

R2 = 09632

Pred

icte

d ac

tivity

Observed activity

(b)















7 Conclusion




Acknowledgment


References

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


09

11

13

15

17

19

09 13 17

y = 09971x + 00036R2 = 0997

Pred

icte

d ac

tivity

Observed activity

(a)

09

11

13

15

17

19

21

09 14 19 24

y = 09632x + 00534

R2 = 09632

Pred

icte

d ac

tivity

Observed activity

(b)















7 Conclusion




Acknowledgment


References

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of






7 Conclusion




Acknowledgment


References

























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of










Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

Research Article Design, Synthesis, Characterization, and ...

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