Vol.2, No.

4 (2009), 972-980
ISSN: 0974-1496
CODEN: RJCABP
http://www.rasayanjournal.com

NAPHTHALENE DERIVATIVES : A NEW RANGE OF

ANTIMICROBIALS WITH HIGH THERAPEUTIC VALUE

Y.B. Rokade and R.Z. Sayyed*

G.R.Y. Institute of pharmacy, Borawa, Khargone, Madhya Pradesh (India)
*
P.G. Department of Microbiology, P.S.G.V.P. Mandals S. I. Patil Arts, G. B. Patel Science &
S.T.S.K.V.S. Commerce College, Shahada, Maharashtra-425409, India
*E-mail: sayyedrz@gmail.com

ABSTRACT
The discovery, development and identification of biologically active compounds has gain lot of importance in the
recent years, even though there is considerable number of adverse effects, the medicinal chemists have always tried
to design drug substance possessing maximum therapeutic application and minimum toxicity. Combinatorial
synthesis has brought lot of evolution in the recent trends of drug synthesis. Naphthalene has been identified as new
range of potent antimicrobials effective against wide range of human pathogens. They occupy a central place among
medicinally important compounds due to their diverse and interesting antibiotic properties with minimum toxicity.
Keywords: Naphthalene, antimicrobial activity.

INTRODUCTION
Naphthalene as antimicrobial agent
Several naphthalene containing drugs are available, such as nafacillin, naftifine, tolnaftate, terbinafine,
etc. which play vital role in the control of microbial infection. Several other synthetic derivatives have
also been reported which possess significant and satisfactory antimicrobial property. -naphthol
commonly used as dye possess a very good antimicrobial property 1

Chemistry of naphthalene:
1. Naphthalenes
Naphthalene is the simplest and the most important member of this class of arenas, in which two benzene
rings are fused in ortho positions.

Fig-1:Naphthalene
Physicochemical properties
Naphthalene is a colorless solid which forms shining flaked-crystal, its melting point is 82.2oC. It has
familiar odor of moth balls. It is very volatile and sublimes slowly at room temperature. Naphthalene is
insoluble in water, moderately soluble in alcohol, highly soluble in ether and benzene. It burns with a
smoky flame.
Naphthalene gives the usual aromatic electrophonic substitution reaction as shown in Fig 2.
H E
+
E

NAPHTHALENE DERIVATIVES Y.B. Rokade and R.Z. Sayyed

 Vol.2, No.4 (2009), 972-980

Fig.-2:Aromatic substitution reaction of naphthalene

2.Naphthol
The mono hydroxy derivatives of naphthalene are called naphthol
OH OH

Fig.-3a: 1-napthol Fig.-3b: 2-napthol

Preparation
Both 1 and 2 naphthols are prepared from the corresponding naphthalene sulphonic acids by fusion with
sodium hydroxide at 300oC followed by acidification.
ONa
SO3H OH

H2SO4 NaoH
0 0
40 c 300 c H2O

Fig.-4: Preparation of 1 and 2-napthol from naphthalene sulphonic acid

Physicochemical properties
They are colorless solid compounds having a melting point of 123-124oC, they are insoluble in water,
benzene and highly soluble in alcohol and ether. Naphthol gives all the chemical reactions characteristic
of phenols 2.
Review of research on naphthalene
Mkpenie et al., 3 have tested azo-2 naphthol and 2-napthol against five representative human pathogenic
microorganisms i.e. Staphylococcus aureus, Escherichia coli, bacillus subtilis, pseudomonas aeruginosa
and streptococcus faecalis. Both azo-2 naphthol and 2-napthol were found equally effective against all
the organisms tested.

N
N
OH

Fig.-5: 1-(4-methylphenylazo), 2-naphthol

The 2- naphthol and azo 2-napthol were screened for the presence of antibacterial constituents against
Staphylococcus aureus and Escherichia coli by Faizul et al., 4, they found naphthol ring as a active
principal component. A series of 2-benzylidene amino naphthothiazoles were designed and synthesized
incorporating the lipophillic naphthalene ring to render them more capable of penetrating various bio-
membranes. Schiff bases were synthesized by the reaction of naphtha [1, 2-d] thiazol-2-amine with
various substituted aromatic aldehydes. 2-(2'-Hydroxy) benzylidene aminonaphtho thiazole was
converted to its Co (II), Ni (II) and Cu (II) metal complexes upon treatment with metal salts in ethanol.
All the compounds were evaluated for their antibacterial activities by paper disc diffusion method with
Gram positive Staphylococcus aureus and Staphylococcus epidermidis and Gram negative Escherichia
coli and Pseudomonas aeruginosa. The minimum inhibitory concentrations of all the Schiff bases and
metal complexes were determined by agar streak dilution 4.
Yildiz et al.,5 synthesized 2-hydroxy-1-napthalene with 6,7-dihydro-13H dibenzo [e,n][1,4]doxomin-2,11
diamine of the ligands and screened in vitro for their antimicrobial potential against Staphylococcus
aureus, Klebsiella pneumoniae, Micrococcus luteusla, Proteus vulgaris, Pseudomonas aeruginosa,

NAPHTHALENE DERIVATIVES 973 Y.B. Rokade and R.Z. Sayyed

 Vol.2, No.4 (2009), 972-980

Mycobacterium segments, Bacillus cereus, Liseria monocytogenes, Candida albicans,

Kluyeromycesfrugilis, Rhodotorularubra, debrayomyceshanseni, Hanseniaspora guilliermondi 5.
Zeynep et al., 6 studied the antimicrobial activity of certain chemically synthesized compounds. The
compound containing naphthalene moiety 6

R
S

N N
Fig.-6: Benzylidene aminonaphtho thiazole

1
R
Fig.-7: 2-hydroxy-1-napthalene with 6,7-dihydro-13H dibenzo [e,n][1,4]doxomin-2,11 diamine

The compound 2-hydroxy-1-napthalene with 6,7-dihydro-13H dibenzo [e,n] [1,4] doxomin-2,11 diamine
were studied on the Gram-negative bacteria like Escherichia coli (ATCC 25922) and Pseudomonas
aeruginosa (ATCC 27853), the Gram-positive bacteria like S. aureus (ATCC 25923), MRSA (clinical
isolate), Enterococcus faecalis (ATCC 29212) and fungi like Candida krusei (ATTC 6258) and Candida
albicans (ATCC 10231). The compound was found to have potent antibacterial and antifungal activity.
Nagaraja et al., 8 synthesis of naphthofurans derivative coupled with both quinoline and azetidine nucleus.
This compound exhibited significant antimicrobial activities 8.
1
R R

2
N R

3
R
NH
O N
O Cl
O
Fig.- 8: N-[3-Chloro-2-(2-chloroquinolin-3-yl)-4-oxoazetidin-1-yl] naphtho [2, 1-b] furan-2-Carboxamide

Nagaraja et al.,9 synthesized 2-Aryl-2,3-dihydronaphtho[2,1-b]furo[3,2-b]pyridin-4(1H)-ones were

synthesized from2-hydroxy-1-naphthonitrile 2 and characterized on the basis of chemical, analytical and
spectral data. The compounds screened for antibacterial and antifungal activity9 were found effective
against human pathogenic Gram positive and Gram negative bacteria and fungi.
R

H
N

O
O
Fig.-9: 2-Aryl-2,3-dihydronaphtho[2,1-b]furo[3,2-b]pyridin-4(1H)-ones

NAPHTHALENE DERIVATIVES 974 Y.B. Rokade and R.Z. Sayyed

 Vol.2, No.4 (2009), 972-980

R=H,Cl,Br,CH3,OCH3,NO2

Sharma et al., 10 prepared some naphthalene derivatives by incorporating azetidinyl and thiazolidinyl
moieties at its a- or b-positions such as a-(3-chloro-2-oxo-4-substituted)aryl-1-azetidinyl) naphthalenes 6
10, a-((substituted)aryl-4-oxo-1,3-thiazolidin-3-yl) naphthalenes1115, b-(3-chloro-2-oxo-4-substituted
aryl-1-azetidinyl) naphthalenes 2125, and b-(substitutedaryl-4-oxo-1,3-thiazolidin-3-yl) naphthalenes
2630. These compounds have also been screened for acute toxicity and anti-inflammatory and analgesic
activities. Compounds which showed better anti-inflammatory and analgesic activities were also
examined for their ulcerogenic liability and underwent a cyclooxygenase assay 10.
Cl
S
O R R O
O R
N N S Cl

N N

O R

Fig.-10: Synthesis of naphthalene derivatives by incorporating azetidinyl and thiazolidinyl moieties

Zeynep et al., 6 prepared several 2-(5,5,8,8-tetramethyl-5,6,7,8 tetrahydronaphtha--len-2-yl)-1H-

benzimidazole-5-carboxamidine analogues and evaluated for their antibacterial and antifungal activities
against S. aureus, Methicillin-resistant S. aureus (MRSA), C. albicans and C. krusei 6.

N
HN

N Cl
HN

Cl
Fig.-11: 2-(5,5,8,8-tetramethyl-5,6,7,8 tetrahydronaphthalen-2-yl)-1H-benzimidazole-5-carboxamidine

Goksu et al., 12 reported that 5-bromo-6methoxynapthalene-2-carboxylic acid and 5,6

dimethoxynapthalene-2-carboxylic acid were having antibacterial activity against some pathogenic
bacteria under in-vitro conditions 12.
O O

OR OR

MeO MeO
OMe Br
Fig.-12:(5,6 dimethoxynapthalene-2-carboxylic acid) (5-bromo-6methoxynapthalene-2-carboxylic acid)

Kyu Ryu et al., prepared 13 a series of 2-arylamino-5-hydroxy-naphthalene-l,4-diones, 3-arylamino-5-

methoxy-naphthalene-l,4-diones, and 2-arylamino-3chloro-5-hydroxy-naphthalene-l,4-diones and tested
for their in-vitro antifungal activity against the Candida and Aspergillus niger 13.

NAPHTHALENE DERIVATIVES 975 Y.B. Rokade and R.Z. Sayyed

 Vol.2, No.4 (2009), 972-980

2
1 O R
O R
1 3
2 R R
NH R

3
R NH

. OH O OCH3 O
1
O R
2
NH R

3
Cl R
OH O

Fig.-13: A series of 2-arylamino-5-hydroxy-naphthalene-l,4-diones, 3-arylamino-5-methoxy-naphthalenae-l,4-

diones,and2-arylamino-3chloro-5-hydroxy-naphthalene-l,4-diones. R1, R2, R3=H, F

Huang et al., 14, evaluated the antimicrobial potential of 18 synthetic naphthalene derivatives and tested
for their anti-inflammatory activity. They prepared naphthalene derivative prepared according to the
Mannich reaction 12.

Fig.-14: Synthetic naphthalene derivative

Ahemed et al., 15 substituted several new 1 H-benzo chromene derivatives with 2-napthols and found
them to possess enhanced biological activity against bacterial, fungal and viral pathogens of human 15.
Azarifar et al., 16 the syntheses of twenty-four 3, dinaphthalene -1-yl substituted 2-pyrazolines containing
certain groups as substituents both on the naphthalene and pyrazoline rings. The compounds were tested
in vitro for antimicrobial activity against Escherichia coli, Staphylococcus aureus, Klebsiella
pneumoniae, Proteus mirabillis, Shigella dysentry and Salmonella typhii at a temperature of 37 C
(1C). It was observed that 81% of the total samples tested showed antimicrobial activity against all the
organisms tested 16.
4
R
N N H

2 H 3
R R
1 H
R
Fig.-15: 3, dinaphthalene -1-yl substituted 2-pyrazolines

Gulay et. al., 17 synthesized new 5(1-/2-napthyloxymethyl)-1,3,4-oxadiazole-2 (3H)-thione,2-amino-5-(1-

2-napthyloxymethyl)-1,3,4-oxadiazole, (1-napthyloxy met--hyl) -1,3,4-oxadiazole-2(3H)-1,3,4-
oxadiazole-2(3H)-one derivatives from 1or/2-napthol. The antimicrobial properties of the compound were
investigated against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, Candida
albicans, C. krusi and C. parapsilosis 17. The derivatives were found effective against wide range of
pathogenic bacteria and fungi.

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 Vol.2, No.4 (2009), 972-980

H
N N

OCH2
O S

Fig.-16: 5(1-/2-napthyloxymethyl)-1, 3, 4-oxadiazole-2(3H)-thione

N N

OCH2 NH2
O

Fig.-17: 2-amino-5(1-/2-napthyloxymethyl)-1, 3,4oxadiazole

H
N N

OCH2
O O

Fig.-18: (1-/2-napthyloxymethyl)-1,3,4- oxadiazole-2(3H)-1,3, 4oxadiazole-2(3H)-one

Palaska et al.,18 synthesized sixteen 1-(2-naphthyloxyacetyl)-4-substituted-3-thiosemicarbazide, 2-(2-

naphthyloxymethyl)-substitutedamino-1,3,4-oxadiazole,2-(2-naphthyloxymethyl)-5-substitutedamino-
1,3,4, thiadiazole and 5-(2-naphthyloxymeth--yl)-4-substituted-1,2,4-triazole-3-thione derivatives. They
reported these derivatives as effective oral anti-inflammatory agents with reduced side-effects18.
O CONHNHCSNHR

Fig.-19: 1-(2-naphthyloxyaceyl)-5-substituted-3-thiosemicarbazide
N N
O NHR
O

Fig.-20: 2-(2-naphthyloxymethyl)-5-substitutedamido-1,3,4-oxadiazole
H
N N
O S
N
R
Fig.-21: 2-(2-naphthyloxymethyl)-5-substitutedamido-1,3,4-thidiazole
N N
O NHR
S

NAPHTHALENE DERIVATIVES 977 Y.B. Rokade and R.Z. Sayyed

 Vol.2, No.4 (2009), 972-980

Fig.-22: 5-(2-naphthyloxymethyl)-5-substitutedamido-1,2,4-triazole-3-thiones
R=CH3, C2H5, CH2-CH=CH2, C6H5

Bansal et al., 19 synthesized 1-acetyl-5-substitutedaryl-3-(-aminonaphthyl)-2-pyrazolines and -

(substituted aminoethyl) amido naphthalenes compounds by reaction of b-acetylamino-naphthalene with
different aromatic aldehydes followedby cyclisation with hydrazine hydrate and with different primary or
secondary amines (Mannichs reaction), respectively. The structures of new compounds were confirmed
by 1H-NMR and IR spectral data. Anti-inflammatory and ulcerogenic activities invivo were evaluated
and compared with the standard drugs 19.
N N.CO.CH2

NH R

Fig.-23: 1-acetyl-5-substitutedaryl-3-(-aminonaphthyl)-2-pyrazolines
NH
CO NHR

Fig.-24: -(substituted aminoethyl) amidonaphthalenes

Strom et al., 20 have reviewed the important structural features affecting the antimicrobial activity of 15-
residue derivatives of lactoferricins. His investigations were based on an alanine-scan of a 15 residue
bovine lactoferricin derivative that revealed the absolute necessity of two tryptophan residues for
antimicrobial activity. They prepared a synthetic 15-residue derivative of bovine lactoferricin (LFB).
containing naphthalene derivative and concluded that 2-naphthalene peptide more active than 1-
naphthalene isomers; 2, the naphthalene moiety in 2-Nal is pointing more away from the b-carbon atom
than in 1-Nal, giving 2-Nal a more elongated shape; 2-Nal thereby has a longer side chain than 1-Nal, and
was able to penetrate deeper into the cell membrane of bacteria, thus offering an explanation as to why
the 2-Nal peptides display a higher antimicrobial activity than the 1-Nal peptides 18.
Oliveira et. al. 21 synthesizd 3-Hydrazino-naphthoquinones as analogs of lapachol. Several 1, 4-
naphthoquinone derivatives having a hydrazino side chain were synthesized from 3-diazo-naphthalene-
1,2,4-trione and tested as potential antimicrobial agents. These naphthoquinone derivatives 2-[N-(1-
acetyl-2-oxo-propylidene) -hydrazino] -3-hydroxy [1,4] naphthoquinone, ethyl2-[(3-hydroxy-1,4-dioxo-
1,4-dihydro-naphthalen-2-yl)-hydrazono]-3-oxo-butyrate, t-butyl2-[(3-hydroxy -1,4-dioxo-1,4-dihydro-
naphthalen-2-yl)-hydrazono]-3-oxobutyrate, 3-hydroxy-2-[(di -O-isopropylidene-malonate)-hydrazino]-1,
4 naphtho-quinone, and diethyl 2- [(3-hydroxy -1,4- dioxo-1,4- dihydro naphthalene -2-yl)-hydrazono]-
malonate showed greater antibacterial activity at the level of the preliminary susceptibility testing in disk
21
.
O
OH
O
N 2
NH R
O 1
O R
Fig.-25: Naphthoquinone derivatives

Ambrogi et al., 22 prepared new halogenated 1, 4-naphthoquinones together with other known 1, 4-
naphthoquinones and screened these derivatives for their antibacterial activity by turbidimetric method
and for antifungal activity by diffusion method on agar medium.

NAPHTHALENE DERIVATIVES 978 Y.B. Rokade and R.Z. Sayyed

 Vol.2, No.4 (2009), 972-980

O
4 1
R R

3 2
R R
O
Fig.-26: 1, 4-naphthoquinones

Husain et al., 23 showed the hypoglycemic activity of some thiosemicarcarbazides and

naptholoxyaceticacid derivatives 23.
N N
O NH
S

Fig.-27: 2-(arylamino-5-(2-napthyloxymethyl)-1, 3, 4-thidiazoles

N N
O NH
O

Fig.-28:2-arylamino-5-(2-napthyloxymethyl)-1, 3, 4-oxadiazoles

Marketed drugs containing naphthalene and azetidin-2-one1

O COOH
O
N

NH
S

OC 2 H 5
Fig.-29:Naficilin

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(Received: 5 December 2009 Accepted: 11 December 2009 RJC-499)

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