review article mannich bases: an important...

Review ArticleMannich Bases An Important Pharmacophore inPresent Scenario

Suman Bala Neha Sharma Anu Kajal Sunil Kamboj and Vipin Saini

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

Correspondence should be addressed to Suman Bala sumankmj7gmailcom

Received 8 August 2014 Accepted 8 October 2014 Published 12 November 2014

Academic Editor Patrick Bednarski

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

Mannich bases are the end products of Mannich reaction and are known as beta-amino ketone carrying compounds Mannichreaction is a carbon-carbon bond forming nucleophilic addition reaction and is a key step in synthesis of a wide variety of naturalproducts pharmaceuticals and so forth Mannich reaction is important for the construction of nitrogen containing compoundsThere is a number of aminoalkyl chain bearing Mannich bases like fluoxetine atropine ethacrynic acid trihexyphenidyl and soforthwith high curative valueThe literature studies enlighten the fact thatMannich bases are very reactive and recognized to possesspotent diverse activities like anti-inflammatory anticancer antifilarial antibacterial antifungal anticonvulsant anthelminticantitubercular analgesic anti-HIV antimalarial antipsychotic antiviral activities and so forth The biological activity of Mannichbases is mainly attributed to 120572 120573-unsaturated ketone which can be generated by deamination of hydrogen atom of the amine group

1 Introduction

Mannich bases beta-amino ketones carrying compoundsare the end products of Mannich reaction [1 2] Mannichreaction is a nucleophilic addition reaction which involvesthe condensation of a compound with active hydrogen(s)with an amine (primary or secondary) and formaldehyde(any aldehyde) [3] The schematic representation of generalMannich reaction is given in Scheme 1

Mannich bases also act as important pharmacophores orbioactive leads which are further used for synthesis of variouspotential agents of high medicinal value which possessaminoalkyl chain The examples of clinically useful Mannichbases which consist of aminoalkyl chain are cocaine fluoxe-tine atropine ethacrynic acid trihexyphenidyl procyclidineranitidine biperiden [4ndash6] and so forth Mannich bases areknown to play a vital role in the development of syntheticpharmaceutical chemistry The literature studies revealedthat Mannich bases are very reactive and can be easilyconverted to other compounds for example reduced to formphysiologically active amino alcohols [7] Mannich bases areknown to possess potent activities like anti-inflammatory[8 9] anticancer [10 11] antifilarial [8] antibacterial [1213] antifungal [13 14] anticonvulsant [15] anthelmintic

[16] antitubercular [17 18] analgesic [19] anti-HIV [17]antimalarial [20] antipsychotic [21] antiviral [22] activitiesand so forth Along with biological activities Mannich basesare also known for their uses in detergent additives [23]resins polymers surface active agents [24] and so forthProdrugs ofMannich bases of various active compounds havebeen prepared to overcome the limitations [25] Mannichbases (optically pure chiral) of 2-naphthol are employedfor catalysis (ligand accelerated and metal mediated) of theenantioselective carbon-carbon bond formation Mannichbases and their derivatives are intermediates for the synthesisof bioactive molecules [26 27] Mannich reaction is widelyused for the construction of nitrogen containing compounds[28] Mannich bases have gained importance due to theirapplication in antibacterial activity [29] and other applica-tions are in agrochemicals such as plant growth regulators

2 Biological Activities

21 Antimicrobial Activity A novel series of Mannichbases of 3-substituted-4-(5-nitro-2-furfurylidene) amino-5-mercapto-124-triazoles 1(andashn) (Figure 1) was synthesizedand screened for the antifungal activity against C albicansby employing disc diffusion method using nitrofurazone and

Hindawi Publishing CorporationInternational Journal of Medicinal ChemistryVolume 2014 Article ID 191072 15 pageshttpdxdoiorg1011552014191072

2 International Journal of Medicinal Chemistry

OH

H

+ + RO

O

RR998400

R998400

Nonenolizable aldehyde Primary or secondary amine Enolizable ketone Mannich base

R2NH

NR2

Scheme 1

NN

NR

N

S

N

O

c

d

f

h

j

n

1

1

R2 R2

R1

R1

NO2

H

Me

Me

Et

Et

Ph

3-Cl 4-F-aniline

Morpholine

3-Cl 4-F-aniline

Morpholine

3-Cl 4-F-aniline

3-Cl 4-F-aniline

Figure 1

fluconazole as standard drugs for comparison The resultsrevealed that all the compounds were found to be least activeas compared to nitrofurazone whereas compounds 1c 1d 1f1h 1j and 1n were found to have better antifungal activityas compared to fluconazole Compound 1f substituted withmethyl and chloro group has shown highest antifungalactivity with 17mm zone of inhibition which is higher thanzone of inhibition of fluconazole that is 12mmThese resultsenlighten the key role of chloro group towards antifungalactivity [30]

Mannich bases of 2-(phenyl)-2-(morpholine-4-yl)-N-phenylacetamide 2(andashg) were synthesized (Figure 2) andscreened for antimicrobial activity against various bacte-rial and fungal strains Ciprofloxacin and clotrimazolewere used as standard drugs for antibacterial and anti-fungal activities respectively From the synthesized com-pounds 2c 3-(4-chlorophenyl)-3-(morpholin-4-yl)-N-phe-nylpropanamide has shown highest antibacterial activityagainst S epidermidis with 20mm of zone of inhibition ascompared to ciprofloxacin with 15mm Compounds 2e 3-(morpholin-4-yl)-3-(4-nitrophenyl)-N-phenylpropanamideand 2f 3-(4-methoxyphenyl)-3-(morpholin-4-yl)-N-phe-nylpropanamide were found to have equipotent antibacterialactivity as compared to ciprofloxacin against K pneumoniaand nonhemolytic streptococcus respectively The com-pounds 2d and 2e were found to have equipotent antifungalactivity against M audouinii and C albicans as compared toclotrimazole The compound 2c having 4-chlorophenyl hasnot contributed to antifungal activity [31]

A series of novelMannich bases of 3-(46-disubstituted-2-thiomethylpyrimidyl)-4-amino-5-mercapto-12-4-triazoles3(andashf) (Figure 3) was synthesized and further subjected to

antibacterial activity against P aeruginosa S marcescens Saureus and E coli [32]

All the synthesized compounds have shown goodantibacterial activity against P aeruginosa whereas they werefound to be less potent against S marcescens S aureusand E coli when compared with standard drug tetracyclineCompounds 3b 3c and 3e substituted with nitro groupwere found to be highly active among all the synthesizedcompounds [32]

A new series of benzamide substituted Mannich bases4(andashg) (Figure 4) were synthesized and evaluated for antibac-terial activity against E coli P aeruginosa E faecalis andS aureus Test tube dilution method was employed forevaluation by using amoxicillin and cefixime as standarddrugs for comparison The results were recorded in terms ofminimum inhibitory concentration (MIC) The compounds4e 4f and 4g were found to be highly active among allthe synthesized compounds with comparable MIC valuesof both standard drugs amoxicillin (156 156 3125 and3125) and cefixime (625 625 125 and 625)The compound4g was found to be most active with MIC (3125 31253125 and 625) These results ensured that substitutions withsulphonamido (4e) p-nitro (4f) and dinitro (4g) groupsenhance the antibacterial activity [33]

A novel series of Mannich bases 5(andashe) (Figure 5) ofquinoline derivative (cinchophen) was carried out andscreened for the antimicrobial activity against various bac-terial and fungal strains Norfloxacin and fluconazole wereused as standard drugs for antibacterial and antifungalactivities respectively From the synthesized compounds5a 5b and 5c substituted with morpholine piperidine anddicyclohexylamine respectively have emerged out as more

International Journal of Medicinal Chemistry 3

N

NH

O

O

O

N

NH

OR

O

bcdefg

H

2 R

ClOH

OMeN(Me)2

NO2

2a 2bndashg

Figure 2

N

N

R

SN

NN

N

NS

N

abcdef

HHH

R

3

3

p-Chlorophenyl

CH2

CH3

R2

R2

R1

R1 MeMeMeMeMeMe

MeMeMe

p-Chlorophenylp-Nitrophenyl

p-Nitrophenyl

2-Nitro-45-dimethoxyphenyl


Figure 3

4

f

g

h

4 R

O

C NH RCH2 SO2NH2

NO2

O2N

O2N

ndashNH

ndashNH

ndashNH

Figure 4

N

a

b

c

C N

C N O

C N

5

R5CONHR

H2

H2

H2 C6H11

C6H11

Figure 5


R CH

NHN C

O Habcde

R

6

6

ClCN

OMeMe

Figure 6

N O

O

N NN X

O

N

R

O abcdefgh

H

HH

O

R X7

7

Cl

NH

CH2CH2CH2CH2CH2CH2

4-Me4-OMe4-Cl4-Br4-NO2

N-Me

Figure 7

potent antimicrobial agents than cinchophen and both ofthe standard drugs The compounds 5d and 5e were almostequipotent to cinchophen but did not respond to fungalstrains [34]

A series of various substituted N-[(1-piperidinoben-zyl)benzamide] (PBB) 6(andashe) (Figure 6) have been synthe-sized The antimicrobial activity of synthesized PBB wascarried out on the microorganisms S aureus B subtilisE coli and P aeruginosa by well diffusion method usingampicillin as standard drug It has been found that allthe compounds were found to be more active against allbacterial strains than ampicillin whereas compounds 6d and6e substituted with chloro and cyano group were foundto most potent There results revealed that introduction ofelectron withdrawing groups on the phenyl ring enhancesthe activity whereas electron releasing groups are less activecompared to unsubstituted phenyl ring [35]

Synthesis of novel Mannich bases (Z)-2-(5-(3-chloro-2-oxo-4-p-tolylazetidin-1-yl)quinolin-8-yloxy)-N1015840-(2-oxo-1-(piperidin-1-ylmethyl)indolin-3-ylidine)acetohydrazides7(andashh) (Figure 7) was carried out and screened for anti-bacterial activity against S aureus B cereus E coli and Paeruginosa Amoxicillin and cefaclor were used as referencedrugs Among all the synthesized compounds 7d 7e and 7fwere found to be highly active These results suggested thatsubstitution with the nitro chloro and bromo group has ledto enhanced antibacterial activity [36]

A series of N-Mannich bases of isatin 8(andashe) wereprepared with 4-amino-N-carbamimidoyl benzene sulpho-namide (Figure 8) The synthesized compounds were then

screened for antibacterial activity and 4-amino-N-carba-mimidoyl benzene sulphonamide was used as referencedrug From the antibacterial screening it was found that thecompound bearing chloro group at 5-position has prominentactivity against all the bacterial strainswith lowestMICvalues[37]

A series of 4-[1H-benzimidazole-yl(substituted benzal)methyl-amino] benzoic acids 9(andashc) (Figure 9) was syn-thesized and screened for the antibacterial and antifungalactivities against S aureus B subtilis S typhi E coliA nigerand C albicans respectively Ciprofloxacin and ketoconazolewere used as standard drugs for antibacterial and antifungalactivities respectively The results were obtained in termsof MIC values The compounds 9b and 9c substituted withhydroxyl and methoxy group on aromatic ring have shownthe highest antibacterial activity whereas compound 9a sub-stituted with dimethyl amine has shown highest antifungalactivity [38]

Mannich bases of thiosemicarbazide 10(andashy) (Figure 10)were synthesized and evaluated for the antifungal activityagainst C albicans and A niger by using brain heart infu-sion (BHI) method to estimate the MIC Fluconazole wasemployed as standard drug for comparison From the resultsit was concluded that analogs with only alkyl groups haveshown comparable activity for both strains as comparedto fluconazole whereas acyl derivatives were found to bepartly active Analogs with aromatic and substituted aromaticaldehydes showed least activity while analogs with aliphaticaldehyde ketones and amines showed greater activity inC albicans compared to A niger The analogs substituted


N

O

N S C

R

O

O

R

8

8abcde

H

CH2N

NH

NH NH2

CH3

Br

NO2Cl

Figure 8

N

N

HN

R

a

b

c

9 R

9

CH3N

COOH

OH

OCH3

CH

Figure 9

NH

N

R NS

10

R2

R3

H2N

R1

Figure 10

with morpholine and aromatic ketone were found to highlyactive Compounds 10(qndasht) have shown comparable highestactivities [39]

A series of Mannich bases of isatin and its derivativeswith 2-[26-dichlorophenyl)amino] phenylacetic acid 11(andashf) (Figure 11) was synthesized All the derivatives were eval-uated for antibacterial and antifungal activities The resultsconfigured that all the synthesized compounds have shownmoderate antibacterial activity except 11b The reason formoderate activity may be due to steric hindrance in bindingof bacteria caused by bulky phenyl acetic acid group presentat nitrogen atom of isatin nucleus The compound 11b hasshown good activity against all the bacteria indicating thatthe substitution of isatin at the 3-position with a substitutedphenyl ring favors antibacterial activity compared to anunsubstituted phenyl ring at the same position All the com-pounds have shown significant antifungal activity especially

compound 11e indicating that unsubstituted phenyl ring at 3-position of isatin is desired for antifungal activity comparedto substituted phenyl ring [40]

A series of novel Mannich bases 12(andashh) of 4-amino-3-(N-phthalimido-methyl)-124-triazole-5-thione (Figure 12)was synthesized and evaluated for the antimicrobial activityagainst a variety of gram positive gram negative and fungalstrains Levofloxacin was used as standard drug The resultsrevealed that Mannich bases 12h with electron donatingsubstituents on phenyl ring showed comparable activity tolevofloxacin against E coli andK pneumonia Mannich bases12e and 12f with halogens on phenyl ring have shown activityvery close to levofloxacin against P aeruginosa Mannichbase 12b with 2-hydroxy group has shown highest antifungalactivity against C albicans The results also enlightened thefact that the presence of morpholine ring in heterocyclicmolecules increases the antimicrobial activity [41]

22 Anti-Inflammatory Activity Mannich bases of nicoti-namide were synthesized with secondary amines like mefe-namic acid 13 (Figure 13) and diclofenac 14 (Figure 14) inthe presence of formaldehyde and hydrochloric acid Anti-inflammatory activity was studied by hind paw oedemamethod using carrageenan as a phlogistic agent on Wistarrats Nicotinamide diclofenac and mefenamic acid wereused as standard drugs Both the Mannich bases showedgreater anti-inflammatory activity than the correspondingparent drugs [42]

Nicotinamide showed least anti-inflammatory activityMannich bases of diclofenac (MND) showed greater activitythan Mannich bases of mefenamic acid (MNM) The orderof anti-inflammatory activity was found as MND gt MNM


N

N

O

Nb

e

11

11

R

NR

HOOCH2C

Cl

Cl

SO2NH2

HNN

Figure 11

N

O

O

CN

NN

N

R

S

N

O

abcdefgh

R12

12

H2

CH

Phenyl2-Hydroxyphenyl3-Pyridyl3-Nitrophenyl4-Chlorophenyl4-Bromophenyl4-Pyridyl4-Methoxyphenyl

Figure 12

N

N

O

13

COOH

ClCl

NH

Figure 13

gt diclofenac gt mefenamic acid gt nicotinamide It appearsthat the synthesized Mannich bases showed synergistic anti-inflammatory activity [42]

Mannich bases of indole 15 derivatives were synthe-sized by reacting different derivatives of indole with var-ious aromatic and heterocyclic amines in the presence offormaldehyde and dimethylformamide (Figure 15) Anti-inflammatory activity was screened on albino rats of Wistarstrains by carrageenan paw induced method Diclofenacsodium was used as standard drug Carrageenan suspension09 in sodium chloride was injected in plantar region ofhind paw and paw volume was measured with the aid ofplethysmometer It was observed that the newly synthesizedMannich bases 15c 15f and 15g possessing electron with-drawing groups (nitro and chloro) exhibited better anti-inflammatory activity [43]

A series of 4-[(4-aryl) methylidene] amino-2-(sub-stituted-4-ylmethyl)-5-1-[4-(2-methylpropyl)phenyl]ethyl-24-dihydro-3H-124-triazole-3-thiones 16(andashn) (Figure 16)was synthesized from ibuprofen by a three-component

N

N

O

14

COOH

CH3

CH3

NH

Figure 14

N

H

15

15

cfg

HH

p-NO2C6H5ClC6H5NSClC6H5NSMe

R1

R1

R2

R2

NH

Figure 15

Mannich reaction The synthesized Mannich bases werescreened for their anti-inflammatory activity by usingcarrageenan induced rat paw oedema model Diclofenacand ibuprofen were used as standard drug substances TheMannich bases 16b 16f 16k and 16l carrying morpholinoand N-methylpiperazino residues were found to be mostpromising anti-inflammatory agents [44]

A series of Mannich bases of 5-methyl-2-[(2-oxo-2H-chromen-3-yl)carbonyl]-24-dihydro-3H-pyrazol-3-one17(andashj) (Figure 17) was synthesized by using conventionaland nonconventional (microwave) techniques The newlysynthesized Mannich bases were screened for their anti-inflammatory activity by means of carrageenan induced ratpaw oedema model Indomethacin was used as standarddrug substance for comparison of results Among all thecompounds 17f and 17g containing sulfonic group atpara and meta positions respectively have shown potentanti-inflammatory activity along with minimum ulcerogenicindex In the compound 17d introduction of bulky groupresulted in the extreme decrease in the activity [45]

23 Anthelmintic Activity N-Mannich bases of benzimida-zolyl substituted 1H-isoindole-13(2H)-dione 18(andashl) were


N

NN

N

S

RR

bfkl

16

16

MorpholineMorpholineMorpholineCH3

CH3

H3C

Ar

Ar

4-ClC6H4

4-CH3C6H4

4-NO2C6H4

4-NO2C6H4 1-Methylpiperazine

Figure 16

O O

N

N

O O

NH

SO

O

SO

O

O

d

f

g

17

17

Ar

Ar

OHOH

OH

OH

Figure 17

synthesized (Figure 18) All the synthesized compounds werescreened for anthelmintic activity by Watkins techniqueagainst common Indian earthworm P posthuma Piper-azine hydrochloride was used as standard drug All thesynthesized derivatives have shown significant anthelminticactivity whereas the derivatives substituted with differentgroups that is 18a (piperazino-) 18b (morpholine-) 18c(diphenylamino-) 18i (chloro) and 18jndashl (nitro and dinitro)groups showed better activity than other derivatives [46]

A novel series of eight Mannich bases 2-(3-chloro-25-dioxo-1-(4-substituted phenylamino)-8-(trichloromethyl)-167-triazaspiro[34]oct-7-en-6-yl)-N1015840-((3-methyl-5-oxo-1-(morpholinepiperidinN-methylpiperazine-1-ylmethyl)-45-dihydro-1H-pyrazol-4-yl)methylene)acetohydazides19(andashh) (Figure 19) were synthesized All the synthesizedMannich bases were evaluated for their anthelmintic activityagainst P posthuma Piperazine citrate was used as standarddrug The compound 19h containing N-methylpiperazinemoiety was found to have significant anthelmintic activity[47]

24 Anticonvulsant Activity Synthesis of two series 20 21(andashc) of Mannich bases of 15-benzodiazepines was carried outand evaluated for the anticonvulsant activity by isoniazidand thiosemicarbazide induced convulsion model (Figures20 and 21) Among all the synthesized compounds 20a withcyclohexane at position 2 and 21a with methyl group at

positions 2 and 4 were found to most active among all thesynthesized compounds The compounds 20b 20b and 21cwere found to be least active [48]

A series of various Mannich base derivatives of lamot-rigine 22(andashf) were synthesized (Figure 22) All the synthe-sized compounds were screened for anticonvulsant activityby maximal electroshock (MES) convulsion method Phe-nobarbitone sodium and lamotrigine were used as referencedrugs and reduction of time spent by animals in extensionflexion clonus and stupor phase were noted Compounds22d and 22f showed more potent anticonvulsant activitywhen compared with that of the standard drug [49]

25 Anticancer Activity A series of novel Mannich bases of2-propoxybenzylideneisonicotinohydrazide 23 (Figure 23)were screened for the cytotoxicity studies against the A549human lung adenocarcinoma Dulbeccorsquos modified eaglemedium was used for the growth of cells and supplementedwith glutamine fetal bovine serum penicillin and strepto-mycin Gemcitabine was used as standard drug The viabilityof the cells was assessed by MTT assay Cells were placed in96-well plate and after 24 h they were treated with differenttest compounds In each well MTT in phosphate buffer salinewas added and incubated and then DMSOwas added to eachwell and kept in incubator From all the compounds syn-thesized 23c and 23k exhibited potential cytotoxic activitysuperior to that of the standard drug gemcitabine [50]


N

N

N

O

O 18

18 18

H2C R2

R1

C

C

C

C

C

C

C

a

b

c

i

j

k

l

R1 R1R2 R2

H2 H2

H2

H2

H2

H2

H2

Piperazino-

Morpholino-

Diphenylamino-

4-Chlorophyenyl-amino

2-Nitrophenyl-amino-


24-Dinitrophenyl-amino-

Figure 18

R

NN

N

O

N

NN

N

X

O

OO H

R X

h

19

19

Cl

NH

CCl3

HN

CH3

NndashCH3

Figure 19

N

N

C

O

R

Habc

R

20

CH2H2

NO2Cl

20

Figure 20

N

N

C

O

R

21

21

Habc

R

NO2Cl

CH2H2

Figure 21


N

N

N

N

N

N

O

NO

22

22

abcdef

HC lHC lHC l

R2

R2

R2

R1R1

R1

Cl

Cl

N(Me)2N(Me)2N(Et)2N(Et)2NC4H8ONC4H8O

Figure 22

N C

O

N CH

ROR23

23

k

c

NH

Me

ndashN(Et)2

ndashN NndashMe

Figure 23

N

N N

F

O

O

N

NN

S

N

R

R

cgh

2-OH3-OH-4-MeO4-OH-MeO

24

24

Figure 24

O

N

O

O

C N

C N O

C N S

C N N

C C

NCH2 H2

H2

H2 H2

H2

H2

Me

Me

R1 R2

R2 R225 25

25MeO

MeO

a g

b h

c i

d j

e k

f l

Figure 25


S

NN

R

R

H

HF

c

f

NR2

R1

R1

OC2H5

R2

4-(2-Pyridinyl)piperazino

26

26

Pyrrolidino

Figure 26

N CH

R

R

N O

N

e

h

i

27

27

O2N

NO2

HO N(C6H5)2

NH

NH

Figure 27

ON

N

HN

R

R

Habcde

28

28

H2C

Cl

p-Clp-Bro-OHp-OH

Figure 28

N

N

O

29

NH

NH2

Figure 29

Schiff-Mannich bases of fluoroquinolones 24(Figure 24) from antibacterial analogs were synthesizedand screened for antitumor activity against L1210 CHO andHL60 cell lines The cell lines were maintained in RPMI1640 medium supplemented with fetal bovine serum Themedium containing 5 times 103 cells was seeded into 96-wellmicroplate and compounds to be tested were then addedPlates were incubated and MTT solution in PBS was addedto each well The plates were further incubated for 4 h

HN NH2

S30

OH

Figure 30

and DMSO was added to the wells containing CHO celllines Dodecylbenzenesulfonate (10) was added to cellscontaining L1210 and HL60The optimal density of each wellwasmeasured at 570 nm Among the synthesized compounds(24andash24k) 24c 24g and 24h exhibited significant cytotoxicactivity than the parent compound [51]

Twelve new Mannich bases of 6-(3-aryl-2-propenoyl)-2(3H)-benzoxazolones 25 (Figure 25) were synthesized andevaluated for cytotoxicity in human pre-B-cell leukemia cellline BV-173 using MTT-dye reduction assay The selectedcompounds were further evaluated on chronic myeloidleukemia K-562 cells The cytotoxic studies revealed thatthe compound bearing 4-methoxy function (25gndashl) at R1in B-ring causes significant decrease in potency while non-methoxy substituted analogues (25andashf) bearing bulky basicsubstituent at nitrogen were found to be more potent [52]

Some novel Mannich bases of 2-arylimidazo[21-b]benzothiazoles 26(andashh) (Figure 26) were synthesizedand evaluated for their anticancer activity The anticanceractivity was studied on HepG2 (hepatocarcinoma cell line)MCF-7 (breast carcinoma cell line) and HeLa 9 (humancervical carcinoma cell line) cell lines using MTT assay Allthe synthesized compounds have shown cytotoxic activityagainst the used cell lines The compounds 26c and 26f


O

OO

NN NH

R

Sef

R31

31

26-2F-C6H3-345-3F-C6H2-

Figure 31

O

N

O

NR

abcd

NRCH2O2N

32

32

4-Fluorophenyl2-Fluorophenyl4-Chlorophenyl2-Chlorophenyl

Figure 32

substituted with 4-(2-pyridinyl)piperazino and pyrrolidinorespectively were found to induce G2M cell cycle arrestwith downregulation of cyclin B and upregulation of Chk2protein Both compounds have shown characteristic featuresof apoptosis The compound 26f could be considered thepotential lead for its development as a novel anticancer agent[53]

26 Antioxidant Activity Ten new Mannich bases weresynthesized using (E)-2-[-2-(24-dinitrophenyl)hydrazono]methylphenol 27 (Figure 27) as a key intermediate andscreened for antioxidant activity From all the synthesizedderivatives 27(andashj) the compound 27h containing morpho-line moiety was found to be most active followed by thecompound 27i with piperazine moiety and compound 27ewith diphenylamine moiety [54]

A novel series of Mannich bases of pyrazolines 28(andashe)was synthesized (Figure 28) and evaluated for the antioxidantactivity using DPPH radical and NO radical scavengingmethods Ascorbic acid and rutin were employed as standarddrugs for comparisonThe results of both the assays suggestedthat compounds 28d and 28e have shown highest scavengingactivity The compound 28e was found to have highestantioxidant capacity as compared to both of the standarddrugs These results confirmed that phenolic compoundspossess high antioxidant ability as compared to nonphenoliccompounds [55]

TwoMannich bases of benzamide that is 1-((1H-benzod]imidazole-1-yl)methyl)urea (BIUF) 29 (Figure 29) and 1-((3-hydroxynaphthalen-2-yl)methyl)thiourea (TNTUF) 30(Figure 30) were synthesized and evaluated for the antioxi-dant activity Hydrogen peroxide radical scavenging DPPHradical scavenging and reducing power assays were usedfor antioxidant activity estimation Ascorbic acid was usedas standard drug Both of the Mannich bases were foundto be active antioxidant agents due to presence of electronreleasing amide group in them BIUF was found to more

active than TNTUF due to the presence of two N atoms inthe benzimidazole adjoined with amide group [56]

A series of novel Mannich bases of 134-oxadiazolederivatives having 14-benzodioxan 31 (Figure 31) weresynthesized All the synthesized novel compounds werescreened for their in vitro antioxidant activity by using 221015840-diphenyl-1-picrylhydrazyl radical (DPPH) 221015840-azinobis (3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTSlowast+)and ferric reducing antioxidant power (FRAP) scavengingassays [57]

All the compounds exhibited good antioxidant activitiesBHT and Trolox were used as standard compounds for thecomparison The compounds 31e and 31f with multifluorosubstitution on benzene ring showed significant radicalscavenging ability in all three scavenging assays [57]

27 Analgesic Activity A novel series of Mannich bases of5-nitro 3-substituted piperazinomethyl-2-benzoxazolinones32(andashd) (Figure 32) were prepared and studied for theanalgesic activity by p-benzoquinone induced writhing testAmong all the synthesized derivatives the compounds bear-ing electron withdrawing groups at para position such asfluoro and chloro showed potent analgesic activity [9]

Mannich bases of various 2-amino pyridine 33(Figure 33) derivatives were synthesized and screenedfor analgesic activity using acetic acid induced writhingtest and hot plate test A series of Mannich bases wereprepared by condensing 2-amino pyridine with isatinand treating the above condensed products with varioussecondary amines The analgesic activities were evaluatedusing central and peripheral analgesic assay Indomethacindiclofenac and morphine were used as reference drugsAmong the various synthesized compounds 33e 33g33h 33j 33k and 33l revealed potent analgesic activityCompounds 33f and 33g were found to be most potentagainst central and peripheral analgesic assay respectively[58]


N

N

NO

R

N

N

NO

R

Br

CH2CH2

N

N

NO

R

RNO2

CH2

a f kb g lc h md i ne j o

PiperazineDimethylamineDiethylamineIsopropylamineMorpholine

33

33(andashe)

33(kndasho)

33(fndashj)

Figure 33

NN

S

O

ONN

OS

S

R1

R1

R1

R2

R2

R2HN NH 34

34

120573-C10H7-O-CH2 Furfuryl-

Figure 34

N

NNH

N

N

O

Ar35

Figure 35

28 Antimycobacterial Activity By reacting oxadiazole de-rivatives dapsone and suitable aldehyde in the presence ofmethanol a series of new oxadiazole Mannich bases 34(andashn)(Figure 34) was synthesized The synthesized Mannich baseswere evaluated for their antimycobacterial activity againstM tuberculosis H37Rv and INH resistant M tuberculosisusing agar dilution method Among all the synthesizedcompounds compound 34d 3-2-furyl[4-(4-2-furyl[5-(2-naphthyloxymethyl)-2-thioxo-23-dihydro-134-oxadiazol-3-yl]methylaminophenylsulfonyl)-anilino]methyl-5-(2-na-phthyloxymethyl)-23-dihydro-134-oxadiazole-2-thione wasfound to be the most promising compound active againstM tuberculosis H37Rv and isoniazid (INH) resistant Mtuberculosis with minimum inhibitory concentration (MIC)of 01 120583M and 110 120583M respectively [59]

By using microwave irradiation method a series ofMannich bases of pyrazinamide was synthesized The sy-nthesized compounds were evaluated for their in vitro andin vivo antimycobacterial activity For in vivo activity Mtuberculosis H37Rv (MTB) strain was used Among all thesynthesized compounds 1-cyclopropyl-6-fluoro-14-dihy-dro-8-methoxy-7-(3-methyl-4-((pyrazine-2-carboxamido)methyl)piperazin-1-yl)-4-oxoquinoline-3 carboxylic acid 35(Figure 35) was found to be the most active compoundin vitro with MIC of 039 and 02 lgmL against MTB andmultidrug-resistant MTB respectively In the in vivo animalmodel 17 decreased the bacterial load in lung and spleentissues with 186 and 166 minus log 10 protections respectively[60]

A series of Mannich bases of 3-[p-(5-arylpyrazolin-3-yl) phenyl]syndone 36(andashj) (Figure 36) was synthesized andstudied for the antimycobacterial activity The antimycobac-terial activity of the test compounds was evaluated against thestandard strain of M tuberculosis H37Rv Streptomycin andpyrazinamidewere used as standardsThe results exposed thefact that the compounds 36c 36d 36e 36g and 36i exhibitedgood activity The promising activities are accredited tothe presence of long alkylating chains with electron donat-ing groups like hydroxyl amino methylene and ethylenethrough mesomeric effect attached to the pyrazoline moiety[61]


R

N N

N

N O

H

H

H

H

H

c

d

e

g

i

NR

NN

N

N O

H

Ph

Ominus

36

t-Butyl

CH3CH2CH2CH2minus

HN NH

NH2

(CH2)5

R998400

R99840036

Figure 36

3 Conclusion

As demonstrated by the frame of work reviewed in this paperMannich bases and their derivatives are found to have potentdiverse activities This review summarized various biologicalactivities of Mannich base derivatives in present scenarioIt can be concluded that Mannich bases have remarkablebiological potential which is remaining unexplored Howeverthis review would expectantly shed light on ways to raisethe therapeutic worth and specificity of Mannich bases Thisbioactive core has maintained the interest of researchers ingaining the most suggestive and conclusive access in thefield of variousMannich bases of medicinal importance fromlast decades and also endorsed the researchers for designof novel heterocyclicaryl derivatives for progress of newenvironment-friendly technology

Conflict of Interests

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

References

[1] Advanced Organic Chemistry Reactions Mechanisms andStructure JohnWiley amp Sons New York NY USA 3rd edition1985

[2] 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

[3] S Joshi N Khosla and P Tiwari ldquoIn vitro study of somemedic-inally important Mannich bases derived from anti-tubercularagentrdquo Bioorganic ampMedicinal Chemistry vol 12 no 3 pp 571ndash576 2004

[4] L Racane V T Kulenovic L F Jakic D W Boykin and G KZamola ldquoSynthesis of bis-substituted amidino-benzothiazolesas potential anti-HIV agentsrdquo Heterocycles vol 55 pp 2085ndash2098 2001

[5] E Kashiyama I HutchinsonM-S Chua et al ldquoAntitumor ben-zothiazoles 81 Synthesis metabolic formation and biologicalproperties of the C- and N-oxidation products of antitumor 2-(4-aminophenyl)-benzothiazolesrdquo Journal of Medicinal Chem-istry vol 42 no 20 pp 4172ndash4184 1999

[6] S R Bhusare R P Pawar and Y B Vibhute ldquoSynthesisand antibacterial activity of some new 2-(substituted phenylsulfonamido)-6-substituted benzothiazolesrdquo Indian Journal ofHeterocyclic Chemistry vol 11 no 1 pp 79ndash80 2001

[7] N Raman S Esthar and C Thangaraja ldquoA new Mannich baseand its transition metal (II) complexesmdashsynthesis structuralcharacterization and electrochemical studyrdquo Journal of Chem-ical Sciences vol 116 no 4 pp 209ndash213 2004

[8] B Kalluraya R M Chimbalkar and J C Hegde ldquoAnti-convulsant activity of nicotinylisonicotinyl substituted 124-triazol-5-thione Mannich basesrdquo Indian Journal of HeterocyclicChemistry vol 15 no 1 pp 15ndash18 2005

[9] M Koksal N Gokhan E Kupeli E Yesilada and H Erdo-gan ldquoAnalgesic and antiinflammatory activities of some newMannich bases of 5-nitro-2-benzoxazolinonesrdquo Archives ofPharmacal Research vol 30 no 4 pp 419ndash424 2007

[10] Y Ivanova G Momekov O Petrov M Karaivanova and VKalcheva ldquoCytotoxicMannich bases of 6-(3-aryl-2-propenoyl)-2(3H)-benzoxazolonesrdquo European Journal of Medicinal Chem-istry vol 42 no 11-12 pp 1382ndash1387 2007

[11] H I Gul J Vepsalainen M Gul E Erciyas and O HanninenldquoCytotoxic activities of mono and bis Mannich bases derivedfrom acetophenone against Renca and Jurkat cellsrdquo Pharmaceu-tica Acta Helvetiae vol 74 no 4 pp 393ndash398 2000

[12] M Ashok B S Holla and B Poojary ldquoConvenient one potsynthesis and antimicrobial evaluation of some new Mannichbases carrying 4-methylthiobenzyl moietyrdquo European Journal ofMedicinal Chemistry vol 42 no 8 pp 1095ndash1101 2007

[13] S N Pandeya D Sriram G Nath and E De Clercq ldquoSynthesisantibacterial antifungal and anti-HIV activities of norfloxacinMannich basesrdquo European Journal of Medicinal Chemistry vol35 no 2 pp 249ndash255 2000

[14] B N Singh S K Shukla and M Singh ldquoSynthesis andbiological activity of sulphadiazine Schiff rsquos bases of isatin andtheir N-mannich basesrdquo Asian Journal of Chemistry vol 19 no7 pp 5013ndash5018 2007

[15] S C Vashishtha G A Zello K H Nienaber et al ldquoCytotoxicand anticonvulsant aryloxyaryl Mannich bases and related


compoundsrdquo European Journal of Medicinal Chemistry vol 39no 1 pp 27ndash35 2004

[16] E Bennet-Jenkins and C Bryant ldquoNovel sources of anthel-minticsrdquo International Journal for Parasitology vol 26 no 8-9pp 937ndash947 1996

[17] D Sriram D Banerjee and P Yogeeswari ldquoEfavirenz Mannichbases synthesis anti-HIV and antitubercular activitiesrdquo Journalof Enzyme Inhibition andMedicinal Chemistry vol 24 no 1 pp1ndash5 2009

[18] J S Mulla A Y Khan S I Panchamukhi M A Khazi MB Kalashetti and I M Khazi ldquoSynthesis and antitubercularactivity ofMannich bases of imidazo [21-b] [134] thiadiazolesrdquoIndian Journal of Novel Drug Delivery vol 3 no 4 pp 289ndash2952011

[19] W Malinka P Swiatek B Filipek J Sapa A Jezierska and AKoll ldquoSynthesis analgesic activity and computational study ofnew isothiazolopyridines of Mannich base typerdquo Farmaco vol60 no 11-12 pp 961ndash968 2005

[20] G B Barlin and C Jiravinya ldquoPotential antimalarials X Di-Mannich Bases of 4-(71015840-Trifluoromethyl-1101584051015840-naphthyridin-41015840-ylamino)phenol and N-(41015840-Diethylamino-11015840-methylbutyl)-7-trifluoromethyl-15-naphthyridin-4-aminerdquo Australian Jour-nal of Chemistry vol 43 no 7 pp 1175ndash1181 1990

[21] M K Scott G E Martin D L DiStefano et al ldquoPyrrolemannich bases as potential antipsychotic agentsrdquo Journal ofMedicinal Chemistry vol 35 no 3 pp 552ndash558 1992

[22] M L Edwards HW Ritter D M Stemerick and K T StewartldquoMannich bases of 4-phenyl-3-buten-2-one a new class ofantiherpes agentrdquo Journal of Medicinal Chemistry vol 26 no3 pp 431ndash436 1983

[23] R E Karll and R J Lee ldquoProcess and compositionsrdquo US Patentno 4384138 1983

[24] F P Otto US Patent US 3 649 229 1972[25] J R Dimmock and P Kumar ldquoAnticancer and cytotoxic proper-

ties of Mannich basesrdquo Current Medicinal Chemistry vol 4 no1 pp 1ndash22 1997

[26] J-X Ji L-QQiu CWingYip andA S CChan ldquoA convenientone-step synthesis of optically active tertiary aminonaphtholand its applications in the highly enantioselective alkenylationsof aldehydesrdquo The Journal of Organic Chemistry vol 68 no 4pp 1589ndash1590 2003

[27] P-J J Huang D Youssef T S Cameron and A Jha ldquoMicro-wave-assisted synthesis of novel 2-naphthol bis-MannichBasesrdquo Arkivoc vol 2008 no 16 pp 165ndash177 2008

[28] M Arend B Westermann and N Risch ldquoModern variantsof the Mannich reactionrdquo Angewandte ChemiemdashInternationalEdition vol 37 no 8 pp 1045ndash1070 1998

[29] 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

[30] M K Shivananda and P Prakash Shet ldquoAntifungal activitystudies of some mannich bases carrying nitrofuran moietyrdquoJournal of Chemical and Pharmaceutical Research vol 3 no 2pp 303ndash307 2011

[31] A Idhayadhulla R Surendra Kumar A Jamal Abdul Nasserand A Manilal ldquoSynthesis and antimicrobial activity of somenew mannich base derivativesrdquo Journal of Chemical and Phar-maceutical Research vol 3 no 4 pp 904ndash911 2011

[32] B Lingappa K S Girisha B Kalluraya N Satheesh Raiand N S Kumari ldquoRegioselective reaction synthesis ofnovel Mannich bases derived from 3-(46-disubstituted-2-thiomethylpyrimidyl)-4-amino-5-mercapto-12-4-triazolesand their antimicrobial propertiesrdquo Indian Journal ofChemistrymdashSection B Organic and Medicinal Chemistryvol 47 no 12 pp 1858ndash1864 2008

[33] S Bala N Sharma A Kajal and S Kamboj ldquoDesign synthesischaracterization and computational studies on benzamide sub-stituted mannich bases as novel potential antibacterial agentsrdquoTheScientificWorld Journal vol 2014 Article ID 732141 9 pages2014

[34] P P Jumade S J Wadher A J Chourasia U V Kharabe DMude and P G Yeole ldquoSynthesis of newer Mannich basesof quinoline derivative for antimicrobial activityrdquo InternationalJournal of Chemical Sciences vol 7 no 3 pp 1518ndash1530 2009

[35] S Ravichandran and S S Kumar ldquoSynthesis characteri-sation and antibacterial activity of Mannich base N-[(1-piperidinobenzyl)]benzamide a structure and reactivity studyrdquoAsian Journal of Biochemical and Pharmaceutical Research vol2 no 1 pp 136ndash142 2011

[36] G Madhu K N Jayaveera L K Ravindra Nath B SantoshKumar and P Nagarjuna Reddy ldquoSynthesis and structure activ-ity relationship of new antibacterial active multi substitutedquinoline-azetidinone mannich basesrdquo Der Pharma Chemicavol 4 no 3 pp 1033ndash1040 2012

[37] U K Singh S N Pandeya A Singh B K Srivastava and MPandey ldquoSynthesis and antimicrobial activity of Schiff rsquos and N-Mannich bases of isatin and its derivatives with 4-amino-n-carbamimidoyl benzene sulphonamiderdquo International Journalof Pharmaceutical Sciences and Drug Research vol 2 no 2 pp151ndash154 2010

[38] M Vijey Aanandhi A K Verma R Sujatha and R KamalRaj ldquoSynthesis and characterization of novel mannich basesof benzimidazole derivatives for antibacterial and antifungalactivityrdquo International Journal of Pharmacy and PharmaceuticalSciences vol 5 no 2 pp 295ndash297 2013

[39] S A Pishawikar and H N More ldquoSynthesis docking and in-vitro screening of mannich bases of thiosemicarbazide for anti-fungal activityrdquo Arabian Journal of Chemistry 2013

[40] V Ravichandran S Mohan and K S Kumar ldquoSynthesisand antimicrobial activity of Mannich bases of isatin andits derivatives with 2-[(26-dichlorophenyl)amino]phenylaceticacidrdquo ARKIVOC vol 2007 no 14 pp 51ndash57 2007

[41] U Yunus M H Bhatti N Rahman N Mussarat S Asgharand B Masood ldquoSynthesis characterization and biologicalactivity of novel Schiff and Mannich bases of 4-amino-3-(N-phthalimidomethyl)-124-triazole-5-thionerdquo Journal of Chem-istry vol 2013 Article ID 638520 8 pages 2013

[42] R Babbar D P Pathak N Jain and S Jain ldquoSynthesis and anti-inflammatory activity of Mannich bases of Nicotinamide withdiclofenac and mefenamic acidrdquo Der Pharma Chemica vol 4no 5 pp 2024ndash2028 2012

[43] P Lohitha D Giles C Sreedhar et al ldquoSynthesis and phar-macological evaluation of schiffs and Mannich bases of indolederivativesrdquo RUGHS Journal of Pharmaceutical Sciences vol 1no 1 pp 70ndash78 2011

[44] K V Sujith J N Rao P Shetty and B Kalluraya ldquoRegioselectivereaction synthesis and pharmacological study of Mannichbases containing ibuprofen moietyrdquo European Journal of Medic-inal Chemistry vol 44 no 9 pp 3697ndash3702 2009


[45] K K Sivakumar A Rajasekaran P Senthilkumar and P PWattamwar ldquoConventional and microwave assisted synthesisof pyrazolone Mannich bases possessing anti-inflammatoryanalgesic ulcerogenic effect and antimicrobial propertiesrdquoBioorganic and Medicinal Chemistry Letters vol 24 no 13 pp2940ndash2944 2014

[46] R Rita and P Shrivastva ldquoSynthesis and characterization ofsomeN-Mannich bases as potential antimicrobial anthelminticand insecticidal agentsrdquoChemical Science Transaction vol 1 no2 pp 431ndash439 2012

[47] K R Raju A Guru Prasad B Kumar L Rao and K RRavindranath ldquoSynthesis andmedicinal evaluation of Mannichbases carrying azetidinone moietyrdquo Journal of Clinical andAnalytical Medicine pp 1ndash5 2014

[48] N S Pandeya and N Rajput ldquoSynthesis and anticonvul-sant activity of various Mannich and Schiff bases of 15-benzodiazepinesrdquo International Journal of Medicinal Chemistryvol 2012 Article ID 237965 10 pages 2012

[49] A A Kulkarni S B Wankhede N D Dhawale P B YadavV V Deore and I D Gonjari ldquoSynthesis characterizationand biological behavior of some Schiff rsquos and Mannich basederivatives of LamotriginerdquoArabian Journal of Chemistry 2013

[50] 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 the Serbian Chemical Societyvol 77 no 5 pp 589ndash597 2012

[51] G Hua T Caoa H Wenlong et al ldquoDesign synthesis andantitumor activities of fluoroquinolone C-3 heterocycles ( IV)S-triazole Schiff-Mannich bases derived from ofloxacinrdquo ActaPharmaceutica Sinica B vol 2 no 3 pp 312ndash317 2012


[53] R M Kumbhare K Vijay Kumar M J Ramaiah et alldquoSynthesis and biological evaluation of novel Mannich basesof 2-arylimidazo[21-b]benzothiazoles as potential anti-canceragentsrdquo European Journal of Medicinal Chemistry vol 46 no 9pp 4258ndash4266 2011

[54] M Malhotra R Sharma M Sanduja R Kumar E Jain and ADeep ldquoSynthesis characterization and evaluation of Mannichbases as potent antifungal and hydrogen peroxide scavengingagentsrdquo Acta Poloniae Pharmaceutica Drug Research vol 69no 2 pp 355ndash361 2012

[55] P C Jagadish N Soni and A Verma ldquoDesign synthesis andin vitro antioxidant activity of 135-trisubstituted-2-pyrazolinesderivativesrdquo Journal of Chemistry vol 2013 Article ID 7657686 pages 2013

[56] K Chakkaravarthi K Gokulakrishnan T Suman and DTamilvendan ldquoSynthesize spectral antimicrobial and antioxi-dant studies of diamidemannich base derivativesrdquo InternationalJournal of Pharmacy and Pharmaceutical Sciences vol 6 no 1pp 492ndash495 2013

[57] L Ma Y Xiao C Li et al ldquoSynthesis and antioxidant activity ofnovel Mannich base of 134-oxadiazole derivatives possessing14-benzodioxanrdquo Bioorganic and Medicinal Chemistry vol 21no 21 pp 6763ndash6770 2013

[58] CKKumar and SN Pandeya ldquoSynthesis characterization andanalgesic activity of various pyridine derivativesrdquo InternationalJournal of Ayurveda and Pharmacy vol 2 no 6 pp 1763ndash17672011

[59] M A Ali and M Shaharyar ldquoOxadiazole mannich bases syn-thesis and antimycobacterial activityrdquo Bioorganic andMedicinalChemistry Letters vol 17 no 12 pp 3314ndash3316 2007

[60] D Sriram P Yogeeswari and S P Reddy ldquoSynthesis ofpyrazinamideMannich bases and its antitubercular propertiesrdquoBioorganic and Medicinal Chemistry Letters vol 16 no 8 pp2113ndash2116 2006

[61] T Taj R R Kamble T M Gireesh and R K HunnurldquoFacile syntheses of Mannich bases of 3-[p-(5-arylpyrazolin-3-yl)phenyl] sydnones as anti-tubercular and anti-microbialagents under ionic liquidtetrabutylammonium bromide cat-alytic conditionsrdquo Journal of the Serbian Chemical Society vol76 no 8 pp 1069ndash1079 2011

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


OH

H

+ + RO

O

RR998400

R998400

Nonenolizable aldehyde Primary or secondary amine Enolizable ketone Mannich base

R2NH

NR2

Scheme 1

NN

NR

N

S

N

O

c

d

f

h

j

n

1

1

R2 R2

R1

R1

NO2

H

Me

Me

Et

Et

Ph

3-Cl 4-F-aniline

Morpholine

3-Cl 4-F-aniline

Morpholine

3-Cl 4-F-aniline

3-Cl 4-F-aniline

Figure 1

fluconazole as standard drugs for comparison The resultsrevealed that all the compounds were found to be least activeas compared to nitrofurazone whereas compounds 1c 1d 1f1h 1j and 1n were found to have better antifungal activityas compared to fluconazole Compound 1f substituted withmethyl and chloro group has shown highest antifungalactivity with 17mm zone of inhibition which is higher thanzone of inhibition of fluconazole that is 12mmThese resultsenlighten the key role of chloro group towards antifungalactivity [30]

Mannich bases of 2-(phenyl)-2-(morpholine-4-yl)-N-phenylacetamide 2(andashg) were synthesized (Figure 2) andscreened for antimicrobial activity against various bacte-rial and fungal strains Ciprofloxacin and clotrimazolewere used as standard drugs for antibacterial and anti-fungal activities respectively From the synthesized com-pounds 2c 3-(4-chlorophenyl)-3-(morpholin-4-yl)-N-phe-nylpropanamide has shown highest antibacterial activityagainst S epidermidis with 20mm of zone of inhibition ascompared to ciprofloxacin with 15mm Compounds 2e 3-(morpholin-4-yl)-3-(4-nitrophenyl)-N-phenylpropanamideand 2f 3-(4-methoxyphenyl)-3-(morpholin-4-yl)-N-phe-nylpropanamide were found to have equipotent antibacterialactivity as compared to ciprofloxacin against K pneumoniaand nonhemolytic streptococcus respectively The com-pounds 2d and 2e were found to have equipotent antifungalactivity against M audouinii and C albicans as compared toclotrimazole The compound 2c having 4-chlorophenyl hasnot contributed to antifungal activity [31]

A series of novelMannich bases of 3-(46-disubstituted-2-thiomethylpyrimidyl)-4-amino-5-mercapto-12-4-triazoles3(andashf) (Figure 3) was synthesized and further subjected to

antibacterial activity against P aeruginosa S marcescens Saureus and E coli [32]

All the synthesized compounds have shown goodantibacterial activity against P aeruginosa whereas they werefound to be less potent against S marcescens S aureusand E coli when compared with standard drug tetracyclineCompounds 3b 3c and 3e substituted with nitro groupwere found to be highly active among all the synthesizedcompounds [32]

A new series of benzamide substituted Mannich bases4(andashg) (Figure 4) were synthesized and evaluated for antibac-terial activity against E coli P aeruginosa E faecalis andS aureus Test tube dilution method was employed forevaluation by using amoxicillin and cefixime as standarddrugs for comparison The results were recorded in terms ofminimum inhibitory concentration (MIC) The compounds4e 4f and 4g were found to be highly active among allthe synthesized compounds with comparable MIC valuesof both standard drugs amoxicillin (156 156 3125 and3125) and cefixime (625 625 125 and 625)The compound4g was found to be most active with MIC (3125 31253125 and 625) These results ensured that substitutions withsulphonamido (4e) p-nitro (4f) and dinitro (4g) groupsenhance the antibacterial activity [33]

A novel series of Mannich bases 5(andashe) (Figure 5) ofquinoline derivative (cinchophen) was carried out andscreened for the antimicrobial activity against various bac-terial and fungal strains Norfloxacin and fluconazole wereused as standard drugs for antibacterial and antifungalactivities respectively From the synthesized compounds5a 5b and 5c substituted with morpholine piperidine anddicyclohexylamine respectively have emerged out as more


N

NH

O

O

O

N

NH

OR

O

bcdefg

H

2 R

ClOH

OMeN(Me)2

NO2

2a 2bndashg

Figure 2

N

N

R

SN

NN

N

NS

N

abcdef

HHH

R

3

3

p-Chlorophenyl

CH2

CH3

R2

R2

R1

R1 MeMeMeMeMeMe

MeMeMe


p-Nitrophenyl



Figure 3

4

f

g

h

4 R

O

C NH RCH2 SO2NH2

NO2

O2N

O2N

ndashNH

ndashNH

ndashNH

Figure 4

N

a

b

c

C N

C N O

C N

5

R5CONHR

H2

H2

H2 C6H11

C6H11

Figure 5


R CH

NHN C

O Habcde

R

6

6

ClCN

OMeMe

Figure 6

N O

O

N NN X

O

N

R

O abcdefgh

H

HH

O

R X7

7

Cl

NH

CH2CH2CH2CH2CH2CH2


N-Me

Figure 7









N

O

N S C

R

O

O

R

8

8abcde

H

CH2N

NH

NH NH2

CH3

Br

NO2Cl

Figure 8

N

N

HN

R

a

b

c

9 R

9

CH3N

COOH

OH

OCH3

CH

Figure 9

NH

N

R NS

10

R2

R3

H2N

R1

Figure 10








N

N

O

Nb

e

11

11

R

NR

HOOCH2C

Cl

Cl

SO2NH2

HNN

Figure 11

N

O

O

CN

NN

N

R

S

N

O

abcdefgh

R12

12

H2

CH


Figure 12

N

N

O

13

COOH

ClCl

NH

Figure 13




N

N

O

14

COOH

CH3

CH3

NH

Figure 14

N

H

15

15

cfg

HH


R1

R1

R2

R2

NH

Figure 15





N

NN

N

S

RR

bfkl

16

16


CH3

H3C

Ar

Ar

4-ClC6H4

4-CH3C6H4

4-NO2C6H4


Figure 16

O O

N

N

O O

NH

SO

O

SO

O

O

d

f

g

17

17

Ar

Ar

OHOH

OH

OH

Figure 17








N

N

N

O

O 18

18 18

H2C R2

R1

C

C

C

C

C

C

C

a

b

c

i

j

k

l

R1 R1R2 R2

H2 H2

H2

H2

H2

H2

H2

Piperazino-

Morpholino-

Diphenylamino-





Figure 18

R

NN

N

O

N

NN

N

X

O

OO H

R X

h

19

19

Cl

NH

CCl3

HN

CH3

NndashCH3

Figure 19

N

N

C

O

R

Habc

R

20

CH2H2

NO2Cl

20

Figure 20

N

N

C

O

R

21

21

Habc

R

NO2Cl

CH2H2

Figure 21


N

N

N

N

N

N

O

NO

22

22

abcdef

HC lHC lHC l

R2

R2

R2

R1R1

R1

Cl

Cl


Figure 22

N C

O

N CH

ROR23

23

k

c

NH

Me

ndashN(Et)2

ndashN NndashMe

Figure 23

N

N N

F

O

O

N

NN

S

N

R

R

cgh


24

24

Figure 24

O

N

O

O

C N

C N O

C N S

C N N

C C

NCH2 H2

H2

H2 H2

H2

H2

Me

Me

R1 R2

R2 R225 25

25MeO

MeO

a g

b h

c i

d j

e k

f l

Figure 25


S

NN

R

R

H

HF

c

f

NR2

R1

R1

OC2H5

R2


26

26

Pyrrolidino

Figure 26

N CH

R

R

N O

N

e

h

i

27

27

O2N

NO2

HO N(C6H5)2

NH

NH

Figure 27

ON

N

HN

R

R

Habcde

28

28

H2C

Cl

p-Clp-Bro-OHp-OH

Figure 28

N

N

O

29

NH

NH2

Figure 29


HN NH2

S30

OH

Figure 30





O

OO

NN NH

R

Sef

R31

31

26-2F-C6H3-345-3F-C6H2-

Figure 31

O

N

O

NR

abcd

NRCH2O2N

32

32


Figure 32











N

N

NO

R

N

N

NO

R

Br

CH2CH2

N

N

NO

R

RNO2

CH2



33

33(andashe)

33(kndasho)

33(fndashj)

Figure 33

NN

S

O

ONN

OS

S

R1

R1

R1

R2

R2

R2HN NH 34

34


Figure 34

N

NNH

N

N

O

Ar35

Figure 35





R

N N

N

N O

H

H

H

H

H

c

d

e

g

i

NR

NN

N

N O

H

Ph

Ominus

36

t-Butyl

CH3CH2CH2CH2minus

HN NH

NH2

(CH2)5

R998400

R99840036

Figure 36

3 Conclusion




References










































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

NH

O

O

O

N

NH

OR

O

bcdefg

H

2 R

ClOH

OMeN(Me)2

NO2

2a 2bndashg

Figure 2

N

N

R

SN

NN

N

NS

N

abcdef

HHH

R

3

3

p-Chlorophenyl

CH2

CH3

R2

R2

R1

R1 MeMeMeMeMeMe

MeMeMe


p-Nitrophenyl



Figure 3

4

f

g

h

4 R

O

C NH RCH2 SO2NH2

NO2

O2N

O2N

ndashNH

ndashNH

ndashNH

Figure 4

N

a

b

c

C N

C N O

C N

5

R5CONHR

H2

H2

H2 C6H11

C6H11

Figure 5


R CH

NHN C

O Habcde

R

6

6

ClCN

OMeMe

Figure 6

N O

O

N NN X

O

N

R

O abcdefgh

H

HH

O

R X7

7

Cl

NH

CH2CH2CH2CH2CH2CH2


N-Me

Figure 7









N

O

N S C

R

O

O

R

8

8abcde

H

CH2N

NH

NH NH2

CH3

Br

NO2Cl

Figure 8

N

N

HN

R

a

b

c

9 R

9

CH3N

COOH

OH

OCH3

CH

Figure 9

NH

N

R NS

10

R2

R3

H2N

R1

Figure 10








N

N

O

Nb

e

11

11

R

NR

HOOCH2C

Cl

Cl

SO2NH2

HNN

Figure 11

N

O

O

CN

NN

N

R

S

N

O

abcdefgh

R12

12

H2

CH


Figure 12

N

N

O

13

COOH

ClCl

NH

Figure 13




N

N

O

14

COOH

CH3

CH3

NH

Figure 14

N

H

15

15

cfg

HH


R1

R1

R2

R2

NH

Figure 15





N

NN

N

S

RR

bfkl

16

16


CH3

H3C

Ar

Ar

4-ClC6H4

4-CH3C6H4

4-NO2C6H4


Figure 16

O O

N

N

O O

NH

SO

O

SO

O

O

d

f

g

17

17

Ar

Ar

OHOH

OH

OH

Figure 17








N

N

N

O

O 18

18 18

H2C R2

R1

C

C

C

C

C

C

C

a

b

c

i

j

k

l

R1 R1R2 R2

H2 H2

H2

H2

H2

H2

H2

Piperazino-

Morpholino-

Diphenylamino-





Figure 18

R

NN

N

O

N

NN

N

X

O

OO H

R X

h

19

19

Cl

NH

CCl3

HN

CH3

NndashCH3

Figure 19

N

N

C

O

R

Habc

R

20

CH2H2

NO2Cl

20

Figure 20

N

N

C

O

R

21

21

Habc

R

NO2Cl

CH2H2

Figure 21


N

N

N

N

N

N

O

NO

22

22

abcdef

HC lHC lHC l

R2

R2

R2

R1R1

R1

Cl

Cl


Figure 22

N C

O

N CH

ROR23

23

k

c

NH

Me

ndashN(Et)2

ndashN NndashMe

Figure 23

N

N N

F

O

O

N

NN

S

N

R

R

cgh


24

24

Figure 24

O

N

O

O

C N

C N O

C N S

C N N

C C

NCH2 H2

H2

H2 H2

H2

H2

Me

Me

R1 R2

R2 R225 25

25MeO

MeO

a g

b h

c i

d j

e k

f l

Figure 25


S

NN

R

R

H

HF

c

f

NR2

R1

R1

OC2H5

R2


26

26

Pyrrolidino

Figure 26

N CH

R

R

N O

N

e

h

i

27

27

O2N

NO2

HO N(C6H5)2

NH

NH

Figure 27

ON

N

HN

R

R

Habcde

28

28

H2C

Cl

p-Clp-Bro-OHp-OH

Figure 28

N

N

O

29

NH

NH2

Figure 29


HN NH2

S30

OH

Figure 30





O

OO

NN NH

R

Sef

R31

31

26-2F-C6H3-345-3F-C6H2-

Figure 31

O

N

O

NR

abcd

NRCH2O2N

32

32


Figure 32











N

N

NO

R

N

N

NO

R

Br

CH2CH2

N

N

NO

R

RNO2

CH2



33

33(andashe)

33(kndasho)

33(fndashj)

Figure 33

NN

S

O

ONN

OS

S

R1

R1

R1

R2

R2

R2HN NH 34

34


Figure 34

N

NNH

N

N

O

Ar35

Figure 35





R

N N

N

N O

H

H

H

H

H

c

d

e

g

i

NR

NN

N

N O

H

Ph

Ominus

36

t-Butyl

CH3CH2CH2CH2minus

HN NH

NH2

(CH2)5

R998400

R99840036

Figure 36

3 Conclusion




References










































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


R CH

NHN C

O Habcde

R

6

6

ClCN

OMeMe

Figure 6

N O

O

N NN X

O

N

R

O abcdefgh

H

HH

O

R X7

7

Cl

NH

CH2CH2CH2CH2CH2CH2


N-Me

Figure 7









N

O

N S C

R

O

O

R

8

8abcde

H

CH2N

NH

NH NH2

CH3

Br

NO2Cl

Figure 8

N

N

HN

R

a

b

c

9 R

9

CH3N

COOH

OH

OCH3

CH

Figure 9

NH

N

R NS

10

R2

R3

H2N

R1

Figure 10








N

N

O

Nb

e

11

11

R

NR

HOOCH2C

Cl

Cl

SO2NH2

HNN

Figure 11

N

O

O

CN

NN

N

R

S

N

O

abcdefgh

R12

12

H2

CH


Figure 12

N

N

O

13

COOH

ClCl

NH

Figure 13




N

N

O

14

COOH

CH3

CH3

NH

Figure 14

N

H

15

15

cfg

HH


R1

R1

R2

R2

NH

Figure 15





N

NN

N

S

RR

bfkl

16

16


CH3

H3C

Ar

Ar

4-ClC6H4

4-CH3C6H4

4-NO2C6H4


Figure 16

O O

N

N

O O

NH

SO

O

SO

O

O

d

f

g

17

17

Ar

Ar

OHOH

OH

OH

Figure 17








N

N

N

O

O 18

18 18

H2C R2

R1

C

C

C

C

C

C

C

a

b

c

i

j

k

l

R1 R1R2 R2

H2 H2

H2

H2

H2

H2

H2

Piperazino-

Morpholino-

Diphenylamino-





Figure 18

R

NN

N

O

N

NN

N

X

O

OO H

R X

h

19

19

Cl

NH

CCl3

HN

CH3

NndashCH3

Figure 19

N

N

C

O

R

Habc

R

20

CH2H2

NO2Cl

20

Figure 20

N

N

C

O

R

21

21

Habc

R

NO2Cl

CH2H2

Figure 21


N

N

N

N

N

N

O

NO

22

22

abcdef

HC lHC lHC l

R2

R2

R2

R1R1

R1

Cl

Cl


Figure 22

N C

O

N CH

ROR23

23

k

c

NH

Me

ndashN(Et)2

ndashN NndashMe

Figure 23

N

N N

F

O

O

N

NN

S

N

R

R

cgh


24

24

Figure 24

O

N

O

O

C N

C N O

C N S

C N N

C C

NCH2 H2

H2

H2 H2

H2

H2

Me

Me

R1 R2

R2 R225 25

25MeO

MeO

a g

b h

c i

d j

e k

f l

Figure 25


S

NN

R

R

H

HF

c

f

NR2

R1

R1

OC2H5

R2


26

26

Pyrrolidino

Figure 26

N CH

R

R

N O

N

e

h

i

27

27

O2N

NO2

HO N(C6H5)2

NH

NH

Figure 27

ON

N

HN

R

R

Habcde

28

28

H2C

Cl

p-Clp-Bro-OHp-OH

Figure 28

N

N

O

29

NH

NH2

Figure 29


HN NH2

S30

OH

Figure 30





O

OO

NN NH

R

Sef

R31

31

26-2F-C6H3-345-3F-C6H2-

Figure 31

O

N

O

NR

abcd

NRCH2O2N

32

32


Figure 32











N

N

NO

R

N

N

NO

R

Br

CH2CH2

N

N

NO

R

RNO2

CH2



33

33(andashe)

33(kndasho)

33(fndashj)

Figure 33

NN

S

O

ONN

OS

S

R1

R1

R1

R2

R2

R2HN NH 34

34


Figure 34

N

NNH

N

N

O

Ar35

Figure 35





R

N N

N

N O

H

H

H

H

H

c

d

e

g

i

NR

NN

N

N O

H

Ph

Ominus

36

t-Butyl

CH3CH2CH2CH2minus

HN NH

NH2

(CH2)5

R998400

R99840036

Figure 36

3 Conclusion




References










































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

O

N S C

R

O

O

R

8

8abcde

H

CH2N

NH

NH NH2

CH3

Br

NO2Cl

Figure 8

N

N

HN

R

a

b

c

9 R

9

CH3N

COOH

OH

OCH3

CH

Figure 9

NH

N

R NS

10

R2

R3

H2N

R1

Figure 10








N

N

O

Nb

e

11

11

R

NR

HOOCH2C

Cl

Cl

SO2NH2

HNN

Figure 11

N

O

O

CN

NN

N

R

S

N

O

abcdefgh

R12

12

H2

CH


Figure 12

N

N

O

13

COOH

ClCl

NH

Figure 13




N

N

O

14

COOH

CH3

CH3

NH

Figure 14

N

H

15

15

cfg

HH


R1

R1

R2

R2

NH

Figure 15





N

NN

N

S

RR

bfkl

16

16


CH3

H3C

Ar

Ar

4-ClC6H4

4-CH3C6H4

4-NO2C6H4


Figure 16

O O

N

N

O O

NH

SO

O

SO

O

O

d

f

g

17

17

Ar

Ar

OHOH

OH

OH

Figure 17








N

N

N

O

O 18

18 18

H2C R2

R1

C

C

C

C

C

C

C

a

b

c

i

j

k

l

R1 R1R2 R2

H2 H2

H2

H2

H2

H2

H2

Piperazino-

Morpholino-

Diphenylamino-





Figure 18

R

NN

N

O

N

NN

N

X

O

OO H

R X

h

19

19

Cl

NH

CCl3

HN

CH3

NndashCH3

Figure 19

N

N

C

O

R

Habc

R

20

CH2H2

NO2Cl

20

Figure 20

N

N

C

O

R

21

21

Habc

R

NO2Cl

CH2H2

Figure 21


N

N

N

N

N

N

O

NO

22

22

abcdef

HC lHC lHC l

R2

R2

R2

R1R1

R1

Cl

Cl


Figure 22

N C

O

N CH

ROR23

23

k

c

NH

Me

ndashN(Et)2

ndashN NndashMe

Figure 23

N

N N

F

O

O

N

NN

S

N

R

R

cgh


24

24

Figure 24

O

N

O

O

C N

C N O

C N S

C N N

C C

NCH2 H2

H2

H2 H2

H2

H2

Me

Me

R1 R2

R2 R225 25

25MeO

MeO

a g

b h

c i

d j

e k

f l

Figure 25


S

NN

R

R

H

HF

c

f

NR2

R1

R1

OC2H5

R2


26

26

Pyrrolidino

Figure 26

N CH

R

R

N O

N

e

h

i

27

27

O2N

NO2

HO N(C6H5)2

NH

NH

Figure 27

ON

N

HN

R

R

Habcde

28

28

H2C

Cl

p-Clp-Bro-OHp-OH

Figure 28

N

N

O

29

NH

NH2

Figure 29


HN NH2

S30

OH

Figure 30





O

OO

NN NH

R

Sef

R31

31

26-2F-C6H3-345-3F-C6H2-

Figure 31

O

N

O

NR

abcd

NRCH2O2N

32

32


Figure 32











N

N

NO

R

N

N

NO

R

Br

CH2CH2

N

N

NO

R

RNO2

CH2



33

33(andashe)

33(kndasho)

33(fndashj)

Figure 33

NN

S

O

ONN

OS

S

R1

R1

R1

R2

R2

R2HN NH 34

34


Figure 34

N

NNH

N

N

O

Ar35

Figure 35





R

N N

N

N O

H

H

H

H

H

c

d

e

g

i

NR

NN

N

N O

H

Ph

Ominus

36

t-Butyl

CH3CH2CH2CH2minus

HN NH

NH2

(CH2)5

R998400

R99840036

Figure 36

3 Conclusion




References










































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

N

O

Nb

e

11

11

R

NR

HOOCH2C

Cl

Cl

SO2NH2

HNN

Figure 11

N

O

O

CN

NN

N

R

S

N

O

abcdefgh

R12

12

H2

CH


Figure 12

N

N

O

13

COOH

ClCl

NH

Figure 13




N

N

O

14

COOH

CH3

CH3

NH

Figure 14

N

H

15

15

cfg

HH


R1

R1

R2

R2

NH

Figure 15





N

NN

N

S

RR

bfkl

16

16


CH3

H3C

Ar

Ar

4-ClC6H4

4-CH3C6H4

4-NO2C6H4


Figure 16

O O

N

N

O O

NH

SO

O

SO

O

O

d

f

g

17

17

Ar

Ar

OHOH

OH

OH

Figure 17








N

N

N

O

O 18

18 18

H2C R2

R1

C

C

C

C

C

C

C

a

b

c

i

j

k

l

R1 R1R2 R2

H2 H2

H2

H2

H2

H2

H2

Piperazino-

Morpholino-

Diphenylamino-





Figure 18

R

NN

N

O

N

NN

N

X

O

OO H

R X

h

19

19

Cl

NH

CCl3

HN

CH3

NndashCH3

Figure 19

N

N

C

O

R

Habc

R

20

CH2H2

NO2Cl

20

Figure 20

N

N

C

O

R

21

21

Habc

R

NO2Cl

CH2H2

Figure 21


N

N

N

N

N

N

O

NO

22

22

abcdef

HC lHC lHC l

R2

R2

R2

R1R1

R1

Cl

Cl


Figure 22

N C

O

N CH

ROR23

23

k

c

NH

Me

ndashN(Et)2

ndashN NndashMe

Figure 23

N

N N

F

O

O

N

NN

S

N

R

R

cgh


24

24

Figure 24

O

N

O

O

C N

C N O

C N S

C N N

C C

NCH2 H2

H2

H2 H2

H2

H2

Me

Me

R1 R2

R2 R225 25

25MeO

MeO

a g

b h

c i

d j

e k

f l

Figure 25


S

NN

R

R

H

HF

c

f

NR2

R1

R1

OC2H5

R2


26

26

Pyrrolidino

Figure 26

N CH

R

R

N O

N

e

h

i

27

27

O2N

NO2

HO N(C6H5)2

NH

NH

Figure 27

ON

N

HN

R

R

Habcde

28

28

H2C

Cl

p-Clp-Bro-OHp-OH

Figure 28

N

N

O

29

NH

NH2

Figure 29


HN NH2

S30

OH

Figure 30





O

OO

NN NH

R

Sef

R31

31

26-2F-C6H3-345-3F-C6H2-

Figure 31

O

N

O

NR

abcd

NRCH2O2N

32

32


Figure 32











N

N

NO

R

N

N

NO

R

Br

CH2CH2

N

N

NO

R

RNO2

CH2



33

33(andashe)

33(kndasho)

33(fndashj)

Figure 33

NN

S

O

ONN

OS

S

R1

R1

R1

R2

R2

R2HN NH 34

34


Figure 34

N

NNH

N

N

O

Ar35

Figure 35





R

N N

N

N O

H

H

H

H

H

c

d

e

g

i

NR

NN

N

N O

H

Ph

Ominus

36

t-Butyl

CH3CH2CH2CH2minus

HN NH

NH2

(CH2)5

R998400

R99840036

Figure 36

3 Conclusion




References










































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

NN

N

S

RR

bfkl

16

16


CH3

H3C

Ar

Ar

4-ClC6H4

4-CH3C6H4

4-NO2C6H4


Figure 16

O O

N

N

O O

NH

SO

O

SO

O

O

d

f

g

17

17

Ar

Ar

OHOH

OH

OH

Figure 17








N

N

N

O

O 18

18 18

H2C R2

R1

C

C

C

C

C

C

C

a

b

c

i

j

k

l

R1 R1R2 R2

H2 H2

H2

H2

H2

H2

H2

Piperazino-

Morpholino-

Diphenylamino-





Figure 18

R

NN

N

O

N

NN

N

X

O

OO H

R X

h

19

19

Cl

NH

CCl3

HN

CH3

NndashCH3

Figure 19

N

N

C

O

R

Habc

R

20

CH2H2

NO2Cl

20

Figure 20

N

N

C

O

R

21

21

Habc

R

NO2Cl

CH2H2

Figure 21


N

N

N

N

N

N

O

NO

22

22

abcdef

HC lHC lHC l

R2

R2

R2

R1R1

R1

Cl

Cl


Figure 22

N C

O

N CH

ROR23

23

k

c

NH

Me

ndashN(Et)2

ndashN NndashMe

Figure 23

N

N N

F

O

O

N

NN

S

N

R

R

cgh


24

24

Figure 24

O

N

O

O

C N

C N O

C N S

C N N

C C

NCH2 H2

H2

H2 H2

H2

H2

Me

Me

R1 R2

R2 R225 25

25MeO

MeO

a g

b h

c i

d j

e k

f l

Figure 25


S

NN

R

R

H

HF

c

f

NR2

R1

R1

OC2H5

R2


26

26

Pyrrolidino

Figure 26

N CH

R

R

N O

N

e

h

i

27

27

O2N

NO2

HO N(C6H5)2

NH

NH

Figure 27

ON

N

HN

R

R

Habcde

28

28

H2C

Cl

p-Clp-Bro-OHp-OH

Figure 28

N

N

O

29

NH

NH2

Figure 29


HN NH2

S30

OH

Figure 30





O

OO

NN NH

R

Sef

R31

31

26-2F-C6H3-345-3F-C6H2-

Figure 31

O

N

O

NR

abcd

NRCH2O2N

32

32


Figure 32











N

N

NO

R

N

N

NO

R

Br

CH2CH2

N

N

NO

R

RNO2

CH2



33

33(andashe)

33(kndasho)

33(fndashj)

Figure 33

NN

S

O

ONN

OS

S

R1

R1

R1

R2

R2

R2HN NH 34

34


Figure 34

N

NNH

N

N

O

Ar35

Figure 35





R

N N

N

N O

H

H

H

H

H

c

d

e

g

i

NR

NN

N

N O

H

Ph

Ominus

36

t-Butyl

CH3CH2CH2CH2minus

HN NH

NH2

(CH2)5

R998400

R99840036

Figure 36

3 Conclusion




References










































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

N

N

O

O 18

18 18

H2C R2

R1

C

C

C

C

C

C

C

a

b

c

i

j

k

l

R1 R1R2 R2

H2 H2

H2

H2

H2

H2

H2

Piperazino-

Morpholino-

Diphenylamino-





Figure 18

R

NN

N

O

N

NN

N

X

O

OO H

R X

h

19

19

Cl

NH

CCl3

HN

CH3

NndashCH3

Figure 19

N

N

C

O

R

Habc

R

20

CH2H2

NO2Cl

20

Figure 20

N

N

C

O

R

21

21

Habc

R

NO2Cl

CH2H2

Figure 21


N

N

N

N

N

N

O

NO

22

22

abcdef

HC lHC lHC l

R2

R2

R2

R1R1

R1

Cl

Cl


Figure 22

N C

O

N CH

ROR23

23

k

c

NH

Me

ndashN(Et)2

ndashN NndashMe

Figure 23

N

N N

F

O

O

N

NN

S

N

R

R

cgh


24

24

Figure 24

O

N

O

O

C N

C N O

C N S

C N N

C C

NCH2 H2

H2

H2 H2

H2

H2

Me

Me

R1 R2

R2 R225 25

25MeO

MeO

a g

b h

c i

d j

e k

f l

Figure 25


S

NN

R

R

H

HF

c

f

NR2

R1

R1

OC2H5

R2


26

26

Pyrrolidino

Figure 26

N CH

R

R

N O

N

e

h

i

27

27

O2N

NO2

HO N(C6H5)2

NH

NH

Figure 27

ON

N

HN

R

R

Habcde

28

28

H2C

Cl

p-Clp-Bro-OHp-OH

Figure 28

N

N

O

29

NH

NH2

Figure 29


HN NH2

S30

OH

Figure 30





O

OO

NN NH

R

Sef

R31

31

26-2F-C6H3-345-3F-C6H2-

Figure 31

O

N

O

NR

abcd

NRCH2O2N

32

32


Figure 32











N

N

NO

R

N

N

NO

R

Br

CH2CH2

N

N

NO

R

RNO2

CH2



33

33(andashe)

33(kndasho)

33(fndashj)

Figure 33

NN

S

O

ONN

OS

S

R1

R1

R1

R2

R2

R2HN NH 34

34


Figure 34

N

NNH

N

N

O

Ar35

Figure 35





R

N N

N

N O

H

H

H

H

H

c

d

e

g

i

NR

NN

N

N O

H

Ph

Ominus

36

t-Butyl

CH3CH2CH2CH2minus

HN NH

NH2

(CH2)5

R998400

R99840036

Figure 36

3 Conclusion




References










































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

N

N

N

N

N

O

NO

22

22

abcdef

HC lHC lHC l

R2

R2

R2

R1R1

R1

Cl

Cl


Figure 22

N C

O

N CH

ROR23

23

k

c

NH

Me

ndashN(Et)2

ndashN NndashMe

Figure 23

N

N N

F

O

O

N

NN

S

N

R

R

cgh


24

24

Figure 24

O

N

O

O

C N

C N O

C N S

C N N

C C

NCH2 H2

H2

H2 H2

H2

H2

Me

Me

R1 R2

R2 R225 25

25MeO

MeO

a g

b h

c i

d j

e k

f l

Figure 25


S

NN

R

R

H

HF

c

f

NR2

R1

R1

OC2H5

R2


26

26

Pyrrolidino

Figure 26

N CH

R

R

N O

N

e

h

i

27

27

O2N

NO2

HO N(C6H5)2

NH

NH

Figure 27

ON

N

HN

R

R

Habcde

28

28

H2C

Cl

p-Clp-Bro-OHp-OH

Figure 28

N

N

O

29

NH

NH2

Figure 29


HN NH2

S30

OH

Figure 30





O

OO

NN NH

R

Sef

R31

31

26-2F-C6H3-345-3F-C6H2-

Figure 31

O

N

O

NR

abcd

NRCH2O2N

32

32


Figure 32











N

N

NO

R

N

N

NO

R

Br

CH2CH2

N

N

NO

R

RNO2

CH2



33

33(andashe)

33(kndasho)

33(fndashj)

Figure 33

NN

S

O

ONN

OS

S

R1

R1

R1

R2

R2

R2HN NH 34

34


Figure 34

N

NNH

N

N

O

Ar35

Figure 35





R

N N

N

N O

H

H

H

H

H

c

d

e

g

i

NR

NN

N

N O

H

Ph

Ominus

36

t-Butyl

CH3CH2CH2CH2minus

HN NH

NH2

(CH2)5

R998400

R99840036

Figure 36

3 Conclusion




References










































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


S

NN

R

R

H

HF

c

f

NR2

R1

R1

OC2H5

R2


26

26

Pyrrolidino

Figure 26

N CH

R

R

N O

N

e

h

i

27

27

O2N

NO2

HO N(C6H5)2

NH

NH

Figure 27

ON

N

HN

R

R

Habcde

28

28

H2C

Cl

p-Clp-Bro-OHp-OH

Figure 28

N

N

O

29

NH

NH2

Figure 29


HN NH2

S30

OH

Figure 30





O

OO

NN NH

R

Sef

R31

31

26-2F-C6H3-345-3F-C6H2-

Figure 31

O

N

O

NR

abcd

NRCH2O2N

32

32


Figure 32











N

N

NO

R

N

N

NO

R

Br

CH2CH2

N

N

NO

R

RNO2

CH2



33

33(andashe)

33(kndasho)

33(fndashj)

Figure 33

NN

S

O

ONN

OS

S

R1

R1

R1

R2

R2

R2HN NH 34

34


Figure 34

N

NNH

N

N

O

Ar35

Figure 35





R

N N

N

N O

H

H

H

H

H

c

d

e

g

i

NR

NN

N

N O

H

Ph

Ominus

36

t-Butyl

CH3CH2CH2CH2minus

HN NH

NH2

(CH2)5

R998400

R99840036

Figure 36

3 Conclusion




References










































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


O

OO

NN NH

R

Sef

R31

31

26-2F-C6H3-345-3F-C6H2-

Figure 31

O

N

O

NR

abcd

NRCH2O2N

32

32


Figure 32











N

N

NO

R

N

N

NO

R

Br

CH2CH2

N

N

NO

R

RNO2

CH2



33

33(andashe)

33(kndasho)

33(fndashj)

Figure 33

NN

S

O

ONN

OS

S

R1

R1

R1

R2

R2

R2HN NH 34

34


Figure 34

N

NNH

N

N

O

Ar35

Figure 35





R

N N

N

N O

H

H

H

H

H

c

d

e

g

i

NR

NN

N

N O

H

Ph

Ominus

36

t-Butyl

CH3CH2CH2CH2minus

HN NH

NH2

(CH2)5

R998400

R99840036

Figure 36

3 Conclusion




References










































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

N

NO

R

N

N

NO

R

Br

CH2CH2

N

N

NO

R

RNO2

CH2



33

33(andashe)

33(kndasho)

33(fndashj)

Figure 33

NN

S

O

ONN

OS

S

R1

R1

R1

R2

R2

R2HN NH 34

34


Figure 34

N

NNH

N

N

O

Ar35

Figure 35





R

N N

N

N O

H

H

H

H

H

c

d

e

g

i

NR

NN

N

N O

H

Ph

Ominus

36

t-Butyl

CH3CH2CH2CH2minus

HN NH

NH2

(CH2)5

R998400

R99840036

Figure 36

3 Conclusion




References










































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


R

N N

N

N O

H

H

H

H

H

c

d

e

g

i

NR

NN

N

N O

H

Ph

Ominus

36

t-Butyl

CH3CH2CH2CH2minus

HN NH

NH2

(CH2)5

R998400

R99840036

Figure 36

3 Conclusion




References










































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

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