Synthetic Communications

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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20

Naproxen derivatives: Synthesis, reactions, and

biological applications

Y. A. Ammar, M. A. Salem, Eman A. Fayed, M. H. Helal, M. S. A. El-Gaby & H.

Kh. Thabet

To cite this article: Y. A. Ammar, M. A. Salem, Eman A. Fayed, M. H. Helal, M. S. A. El-Gaby

& H. Kh. Thabet (2017) Naproxen derivatives: Synthesis, reactions, and biological applications,
Synthetic Communications, 47:15, 1341-1367, DOI: 10.1080/00397911.2017.1328066

To link to this article: http://dx.doi.org/10.1080/00397911.2017.1328066

Accepted author version posted online: 10

May 2017.
Published online: 10 May 2017.

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SYNTHETIC COMMUNICATIONS®
2017, VOL. 47, NO. 15, 1341–1367
https://doi.org/10.1080/00397911.2017.1328066

SYNTHETIC COMMUNICATIONS REVIEWS none defined

Naproxen derivatives: Synthesis, reactions, and biological

applications
Y. A. Ammara, M. A. Salema,b, Eman A. Fayedc, M. H. Helala,d, M. S. A. El-Gabye, and
H. Kh. Thabeta,d
a
Department of Chemistry, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt; bDepartment of
Chemistry, Faculty of Arts and Science, King Khalid University, Mohail Assir, KSA; cDepartment of Organic
Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt; dDepartment of Chemistry,
Faculty of Arts and Science, Northern Border University, Rafha, KSA; eDepartment of Chemistry,
Faculty of Science, Al-Azhar University at Assiut, Assiut, Egypt

ABSTRACT ARTICLE HISTORY

This review describes the synthesis and reactions of naproxen Received 25 April 2017
derivatives and highlights the effects of compounds containing the
KEYWORDS
naproxen moiety in important biological applications. Amidation; anti-
inflammatory; antioxidant;
GRAPHICAL ABSTRACT antitumor; antiviral;
esterification; naproxen

Introduction
Naproxen, 2-(6-methoxynaphthalen-2-yl)propionic acid (1), is one of the most regularly
used propionic acid derivatives for the treatment of pain, joint swelling, and symptoms
of arthritis, it is believed to work by blocking the action of cyclooxygenase (COX) involved
in the production of prostaglandins that are produced in response to injury or certain
diseases and cause pain, swelling, and inflammation. However, its use is associated with
some gastrointestinal side effects possibly caused by the free acidic group present.
Masking of this free acidic group therefore was thought to be a possible solution to this
problem.[1]

CONTACT M. A. Salem m_eltayyeb@hotmail.com Department of Chemistry, Faculty of Science, Al-Azhar University,

Nasr City, Cairo 11284, Egypt; Department of Chemistry, Faculty of Arts and Science, King Khalid University,
Mohail Assir, KSA.
Color versions of one or more of the figures in this article can be found online at www.tandfonline.com/lsyc.
© 2017 Taylor & Francis
1342 Y. A. AMMAR ET AL.

Synthesis of naproxen
Synthesis of naproxen from substituted naphthalene
The first large-scale synthesis of naproxen 1 produced 500 kg of material in 1970. Friedel–
Crafts acylation of 2-methoxynaphthalene (nerolin) 2 afforded 2-acetyl-6-
methoxynaphthalene (3), which was converted to a naphthaylacetic acid 4 by the
Willgerodt reaction. α -methylation yields the d,l-acid 5, which can be efficiently resolved
using cinchonidine[2,3] (Scheme 1).
Another process was addressed as the first naproxen manufacturing process. In which
β-naphthol was brominated in methylene chloride to produce 1,6-dibromonaphthol. The
labile bromine at 1-position was removed with bisulfate. Then the resulting product 8
was methylated with methyl chloride in water-2-propanol. BMN was converted to
Grignard reagent, then zinc chloride and ethyl bromopropionate and base to afford 1[2]
(Scheme 2).

Synthesis of naproxen from 1-(6-methoxy-2-naphthyl) ethanol

Acylation of 1-(6-methoxy-2-naphthyl)ethanol (10) with acetic anhydride afforded the
corresponding acetate derivative 11 which was treated with trimethylsilalyl cyanide or
diethylaluminum cyanide as cyanating agent to give the nitrile derivative 12, this
compound was converted to naproxen 1. While, when the acetate derivative 11 was treated
with diethyl(phenylethenyl)-aluminum, the acetylene derivative 13 was isolated which on
hydrogenation, followed by oxidation and esterification with diazomethane yielded
naproxen methyl ester 14[4] (Scheme 3).
Biological activity of the 2-arylpropionic acids is largely, if not entirely, stereo specific
with the (S)-enantiomer being more active in the inhibition of prostaglandin biosynthesis

Scheme 1.
 SYNTHETIC COMMUNICATIONS® 1343

Scheme 2.

Scheme 3.

through nonselective inhibition of both cyclooxygenase (COX-1 and COX-2) enzymes. The
enzymatic bioinversion of (R)-(-)-ibuprofen and other chiral 2-arylpropionic acids to the
biologically active (S)-enantiomer has been proven to be a unidirectional process produc-
ing compounds with the desired analgesic effects.[5,6] (S)-naproxen is about 28 times more
active than its (R)-isomer.[7–10] This awareness led to great synthetic efforts to obtain
optically pure compounds of this class. (S)-naproxen was prepared using kinetic resolution
of benzylic alcohols. Secondary alcohols 10 (readily prepared by Friedel–Crafts acylation,
followed by NaBH4 reduction of the corresponding aromatic ketones) were used as the
starting materials, palladium catalyzed of these (�)-alcohol 10 using (-) sparteine as a
chiral ligand in toluene at 80 °C afforded the corresponding (S)(-)-alcohols 15 in excellent
optical purity (up to 98%). Chiral (S)(-)-alcohol was then treated with PBr3 in presence of
pyridine to afford the bromo compound (R)-16 with complete inversion of configuration.
Bromo compound was then treated with NaCN in dimethyl-formamide (DMF) as solvent
to yield the corresponding (S)-cyano compound 12, again with complete inversion of
1344 Y. A. AMMAR ET AL.

Scheme 4.

configuration at benzylic carbon atom. The cyano compound was finally hydrolyzed using
4N HCl to afford the corresponding (S)-naproxen 1 in good yield and excellent optical
purity (up to 92%)[8] (Scheme 4).

Hydroformylation of styrenes
Naproxen was found to be synthesized by catalytic asymmetric hydroformylation of
2-methoxy-6-vinylnaphthalene 17 using a rhodium catalyst with BINAPHOS ligand which
can produce an optically active aldehyde 19 which on oxidation yields (S)-naproxen 1[2]
(Scheme 5).

Hydrogenation of 2-arylpropenoic acids

Optically active saturated acids, such as naproxen 1, are accessible from unsaturated acids
20 by catalytic asymmetric hydrogenation. Using a ruthenium (S)-BINAP in 98% yield.
This method was done under reduced pressure (30 atm)[2] (Scheme 6).

Scheme 5.
 SYNTHETIC COMMUNICATIONS® 1345

Scheme 6.

Reactions of naproxen
The reported literatures confirm that gastrointestinal side effects of naproxen and other
aroylpropanoic acids are due to the presence of free carboxylic group in the parent drug.[11]
Therefore, the temporarily masking or manipulation of the acidic group in nonsteroidal
anti-inflammatory drugs (NSAID’s) are promising means to reduce or to abolish the GI
toxicity due to the local action mechanism.[12–14]

1-Esterification
In 1999, Mahfouz et al.[15] reported that N-hydroxymethyl-succinimide (HMSI) and
N-hydroxymethylisatin (HMIS) were used as esterificating agents for naproxen 1 in
presence of ethyl chloroformate and triethylamine to afford the corresponding derivatives
22 (Scheme 7).
In the next year, Rautio et al.[16] found that various novel morpholinyl 24a,b and
methylpiperazinylacyloxyalkyl 24c,f esters of 2-(6-methoxy-2-naphthyl)propionic acid
were synthesized and evaluated in vitro for topical drug delivery as potential prodrugs
of naproxen 1. Compounds 24a–f were prepared by coupling the corresponding naproxen
hydroxyalkyl ester 23 with the morpholinyl or (4-methyl-1-piperzinyl)acyl acid in the
presence of dicyclohexylcarbodiimide and DMAP in dry dichloromethane (DCM) as
follows (Scheme 8).
Moreover, in 2006, Ranatunge et al.[17] reported that esterification of naproxen 1 with
tert-butylbromoacetate in the presence of NaHCO3 in DMF at room temperature furnished
the tert-butyl ester derivative 25 (Scheme 9).
In the next year, Metwally et al.[18] found that naproxen 1 was esterified with different
alcohols in presence of sulfuric acid to afford the corresponding esters 26 (Scheme 10).
Additionally, in 2010, Kumar et al.[19] reported that naproxen 1 was reacted with
2-phenylethanol 27 and its derivatives, in presence of oxalyl chloride, in DCM to yield
the corresponding ester derivatives 28 (Scheme 11).

Scheme 7.
1346 Y. A. AMMAR ET AL.

Scheme 8.

Scheme 9.

Scheme 10.

2-Amidation of naproxen
In 2002, Levit et al.[20] reported that naproxen amino acid amide derivatives 30 were
prepared upon reaction of the acid chloride of naproxen 29 (prepared through treatment
of naproxen with thionyl chloride) with some amino acid esters (Scheme 12).

Scheme 11.
 SYNTHETIC COMMUNICATIONS® 1347

Scheme 12.

Khalifa et al.[21,22] found that naproxenoyl chloride 29 was proven to be a good synthons
for different highly biologically active compounds. Thus, propionamide derivatives 31 were
prepared through interaction of naproxenoyl chloride with some amino benzoic acids and
sulfa drug (Scheme 13).
Additionally, in 2014, Fernandes et al.[23] found that a series of novel substituted
2-(6-methoxynaphthalen-2-yl)-N-phenylpropanamides (33) have been synthesized upon
refluxing 2-(6-methoxynaphthalen-2-yl)propanoic acid (1) with different substituted
anilines 32 in the presence of pyridine and silicon tetrachloride as coupling reagent
(Scheme 14).
Recently, Ammar et al.[24] and Fayed et al.[25] were found that the reaction of the acid
chloride of naproxen 29 with 2-aminopyridine derivatives in refluxing dioxane containing
a catalytic amount of triethylamine furnish 2-(6-methoxynaphthalen-2-yl)-N-(pyridine-yl)
propan-amide 34. Also, treatment of the acid chloride 29 with each of 2-or 3-aminopyri-
dine in refluxing dioxane containing a catalytic amount of triethylamine afforded the
respective pyridinecarboxamides 35a,b (Scheme 15).

Scheme 13.

Scheme 14.
1348 Y. A. AMMAR ET AL.

Scheme 15.

Hydrazinolysis of naproxen
In 2007, Amir et al.[26] found that 2-(6-methoxy-2-naphthyl)propanoic acid hydrazide 36
was prepared in two consequence steps by esterification of naproxen 1 with boiling ethanol
containing a catalytic amount of concentrated H2SO4 followed by treatment of the
resulting ester 26b with hydrazine hydrate in refluxing absolute ethanol (Scheme 16).
Furthermore, in 2015, Mohamed et al.[27] reported that 2-hydroxy-N′-[2-(6-
methoxynaphthalen-2-yl)propanoyl]benzohydrazide 38 was prepared when a mixture of
equimolar quantities of naproxenoyl chloride 29 and salicylic acid hydrazide 37 was
refluxed for 2 h in THF. Also, they found that 2-(4-isobutylphenyl)propionicacid-N′-[2-
(6-methoxy-naphthalen-2-yl)propionyl]hydrazide (40) was prepared by the reaction of
the acid chloride 29 and ibuprofen acid hydrazide 39 was refluxed in THF (Scheme 17).

Scheme 16.

Scheme 17.
 SYNTHETIC COMMUNICATIONS® 1349

Scheme 18.

Scheme 19.

Additionally they reported that the interaction of the hydrazide derivative 36 with ben-
zene-1,3-dicarbonyl dichloride 41 in THF produced the corresponding N′1,N′3-bis{(2-[2-
(6-methoxynaphthalen-2-yl)propanoyl]hydra-zinecarbonyl}-benzene (42)[27] (Scheme 18).
Furthermore, in 2015, Tok et al.[28] reported that naproxen-based acylhyrazone deriva-
tives 36 were synthesized using both conventional and microwave-assisted method 50, 100,
200, and 300 W for 2 min starting with the hydrazide derivative 43 (Scheme 19).

4-Naproxen derivatives in heterocyclic synthesis

In 2002, Ammar et al.[29] reported naproxen as starting material in the synthesis of triazole
and fused triazole. Thus, fusion of naproxen 1 with thiocarbohydrazide afforded the
corresponding 4-amino-5-[1-(6-methoxyna-phthalen-2-yl]-2,4-dihydro[1,2,4]triazole-3-
thione (44), which was subjected to react with ethyl chloroacetate, bromomalononitrile,
and dichloronaphthoquinone and produced triazolothiadiazine derivatives 45–47, respect-
ively (Scheme 20).
Also, they[29] reported that the cyclocondensation of the aminotriazole 44 derivative
with formic acid, carbon disulfide, and [bis(methylsulfanyl)methylidene]-malononitrile
gave the corresponding thiadiazolo triazole derivatives 49–51 (Scheme 21).
Khalifa et al.[21] were found that reaction of naproxen acid chloride 29 with thiosemi-
carbzide afforded thiourea derivative 52. Cyclocondensation of 52 was achieved through
heating under reflux with phosphorous oxychloride to give 5-(1-(6-methoxynaphthalen-
2-yl)ethyl)-1,3,4-thiadiazol-2-amine 53. Reaction of 29 with sodium azide in DMF
produced the azido derivative 54. When the azido derivative 54 was refluxed with different
sulfonamides and aminopyridines,[24] the urea derivatives were obtained through the Cur-
tius rearrangement, where the amino group of sulfonamides reacts with the intermediate
(isocyanates) to form the urea derivatives 55a–f. Moreover, the reaction of acid chloride
1350 Y. A. AMMAR ET AL.

Scheme 20.

Scheme 21.

29 with ammonium thiocyanate in acetone under reflux gave naproxenoyl isothiocyanate

56, which subjected for the reaction with 2-or 3-aminopyridine to furnish in each case
only a sole product that was identified as N1-naproxenoyl-N2-pyridyl thiourea derivative
(57a,b)[24] (Scheme 22).
Moreover, in 2013, Raghavendra et al.[30] reported that a series of substituted
2-(6-methoxynapthalen-2-yl)propanoic acid amides 58 containing different heterocyclic
moieties were synthesized through the reaction of the acid chloride of naproxen 29 with
some heterocyclic compounds (Scheme 23).
On the other hand, Helal et al.[22] reported that the oxazolone derivative 60 was
synthesized through the reaction of the acid chloride 29 with glycine to afford the acid
derivative 59 followed by its treatment with aromatic aldehydes in acetic anhydride
containing catalytic amount of sodium acetate. Also, heating the acid chloride 29 with
o-phenylenediamine in DMF under reflux affected cyclization to afford benzimidazole
derivative 61 (Scheme 24).
 SYNTHETIC COMMUNICATIONS® 1351

Scheme 22.

Scheme 23.

Accordingly, acid chloride 29 was allowed to react with 4-aminoethyl-benzoate to

produce ester derivative 62. Hydrazinolysis of the produced ester 62 using ethanolic
hydrazine hydrate afforded the hydrazide derivative 63, which was allowed to react with
cyclohexyl isothiocyanate to yield the corresponding thiosemicarbazide derivative 64. Both

Scheme 24.
1352 Y. A. AMMAR ET AL.

Scheme 25.

1,3,4-oxadiazol-2-amine 65 and 1,2,4-tria-zole-3-thione 66 were obtained by oxidative

cyclization to give 64 by elimination of H2S using iodine and potassium iodide in ethanolic
sodium hydroxide or smooth cyclization through dehydration with 4N NaOH in ethanol to
give 66, respectively[21] (Scheme 25).
Furthermore, El-sehemi et al.[31] were found that the reaction of the acid chloride 29
with p-aminoacetophenone afforded N-(4-acetylphenyl)-2-(6-methoxynaphthalen-2-yl)
propanamide (67). The presence of acetyl group in 67 makes it versatile precursor for
the synthesis of pyrazoline derivatives. Thus, the Claisen–Schmidt condensation of 67 with
aromatic aldehydes in ethanolic potassium hydroxide furnished the chalcone derivatives
68. Cyclocondensation of chalcones 68 with hydrazine hydrate in boiling ethanol furnished
the respective pyrazolines 69 (Scheme 26).
Thabet et al.[32] were reported the reaction of N-(4-acetylphenyl)-2-(6-methoxynaphtha-
len-2-yl)propanamide (67) with Br2 in glacial acetic acid to produce N-(4-(2-bromoacetyl)
phenyl)-2-(6-methoxynaphthalen-2-yl)propanamide (70) in good yield. The ω-bromoace-
tyl derivative 70 was used as starting material for construction of thiazole scaffold. Thus,
cyclocondensation of compound 70 with thiocarbamide derivatives, namely (thiourea, phe-
nylthiourea), in boiling ethanol containing a catalytic amount of fused sodium acetate
afforded thiazole derivatives 71a,b. Treatment of ω-bromoacetyl derivative 70 with thiose-
micarbazide, the 2-hydrazinylthiazole derivative 72 was obtained. Condensation of 72 with
4-methoxybenzaldehyde gave the corresponding hydrazone derivative 73. Structure of 73
was firmly established by the reaction of 2-bromoacetyl derivative 70 with 4-methoxyben-
zylidenethiosemicarbazone (74) which gave thiazolidine derivative identical in all respects
(m.p., mixed m.p. and spectral data) with the hydrazone derivative 73. Furthermore, the
reaction of 2-bromoacetyl derivative 70 with a mixture of active methylene (malononitrile
and/or ethyl acetoacetate) and phenyl isothiocyanate in dry dimethylformamide at room
 SYNTHETIC COMMUNICATIONS® 1353

Scheme 26.

temperature in the presence of potassium hydroxide afforded the corresponding thiophene

derivatives 76 and 77 in high yield (85%) through the nonisolable intermediate 75
(Scheme 27).
Also, 2-(thiazol-2-yl)acetonitrile derivative 78 was obtained through the reaction of
2-bromoacetyl derivative 70 with cyanothioacetamide in refluxing dioxane. The reactivity
of 2-(thiazol-2-yl)acetonitrile derivative 78 toward some electrophilic reagents was
investigated. Thus, 2-iminochromene 79 and 2-iminobenzo[f]chromene derivatives 80
were obtained through the cyclocondensation of compound 78 with salicylaldehyde and

Scheme 27.
1354 Y. A. AMMAR ET AL.

Scheme 28.

2-hydroxyna-phthaldehyde in refluxing ethanol in the presence of a catalytic amount of

ammonium acetate. Also, reaction of 2-(thiazol-2-yl)acetonitrile derivative 78 with cinna-
monitrile derivatives 81a,b resulted in the formation of arylidene derivatives 83a,b. The
formation of compound 100 is believed to proceed through initial Michael addition of
the methine carbanion formed from 78 to the activated double bond of arylidene derivative
81 to form acyclic Michael adduct 82 followed by elimination of malononitrile molecule.
Further confirmation of 83 was achieved by reaction of acetonitrile derivative 78 with
the corresponding aromatic aldehydes[32] (Scheme 28).
Salem et al.[33] were reported that the reaction of N-(4-acetylphenyl)-2-(6-methoxy-
naphthalen-2-yl)propanamide (70) with dimethyl-formamide-dimethyl-acetal in refluxing
xylene afforded N-(4-(3(dimethylamino)-acryloyl)-phenyl)-2-(6-methoxynaphthalen-2-yl)
propanamide (84). Enaminone 84 are versatile precursors for the synthesis of several
heterocyclic compounds. Thus, treatment of enaminone 84 with hydrazine hydrate and/
or phenylhydrazine in ethanol/acetic acid medium at reflux temperature afforded pyrazole
derivatives 85a,b. Also, when enaminone 84 was condensed with 3-amino-1H-1,2,4-
triazole in ethanol/glacial acetic acid under reflux, the 1,2,4-triazolo[4,3-a]pyrimidine
derivative 87 was obtained through the formation of acyclic nonisolable intermediate 86,
which undergoes intramolecular cyclization by elimination of water molecule. Thiazolo
[3,2-a]pyrimidine derivative 88 was obtained through reaction of enaminone 84 with
2-aminothiazole. In addition, treatment of enaminone 84 with 2-aminopyridine in acetic
acid under reflux afforded the pyrido[1,2-a]pyrimidine derivative 89 (Scheme 29).
Furthermore, Salem et al.[33] were reported the condensation of N-(4-acetylphenyl)-2-
(6-methoxynaphthalen-2-yl)propan-amide (70) with hydrazines 90a–d (namely, hydra-
zine, phenyl hydrazine, thiosemicarbazide, and cyanoacetic acid hydrazide) to produce
the corresponding imino derivatives 91a–d as starting materials. Thus, cycloalkylation of
 SYNTHETIC COMMUNICATIONS® 1355

Scheme 29.

thiosemicarbazone derivative 91c with ethyl chloroacetate, ethyl-α -bromopropionate, and

chloroacetone in ethanol containing a catalytic amount of sodium acetate afforded the
corresponding 4-thiazolidinone derivative 92–94, respectively. On the other hand, reaction
of thiosemicarbazone derivative 91c with ethyl α -bromobutyrate gave 4-hydroxy-thiazole
derivative 96 rather than the compound 95 according to the elemental analyses and
spectral data[33] (Scheme 30).
In addition, they are found that[33] cyclocondensation of cyanoacetohydrazone deriva-
tive 91d with acetylacetone under fusion condition afforded pyridine derivative 97. Also,
2-inminochromene 98 and 2-iminobenzo[f]chromene 99 were obtained through

Scheme 30.
1356 Y. A. AMMAR ET AL.

Scheme 31.

condensation of cyanoacetohydrazone derivative 91d with salicylaldehyde and 2-hydroxy-

1-naphthaldehyde in refluxing ethanol containing a catalytic amount of ammonium acetate
(Scheme 31).
Fayed et al.[25] were reported the reaction of acid chloride 29 with cyanoacetohydrazide
to furnish N-(2-cyanoacetyl)-2-(6-methoxynaphthal-en-2-yl)propanehydrazide (100). This
compound was used as a starting material for the synthesis of many pyridine amide
derivatives. Thus, cyclocondensation of compound 100 with acetylacetone in the presence
of a catalytic amount of piperidine, the 2-pyridinone derivative 101 was smoothly afforded.
In addition, condensation of 100 with p-anisaldehyde furnished the corresponding
arylidene derivative 102. When compound 100 was reacted with 4-methoxy ethyl
cyanocinnamate 103 in ethanol containing catalytic amount of piperidine, the correspond-
ing hydroxyl pyridone derivatives 104 were obtained. Further confirmation of 104
was achieved by reaction of arylidene derivative 102 with ethyl cyanoacetace. Also,
3-cyanopyridone derivative 106 was produced through the reaction of 2-cyanoacetyl
derivative 100 with arylidene derivative 105 (Scheme 32).
Similarly, Ammar et al.[24] were reported the formation of N-[4-(cyanoacetamido)phe-
nyl-2-(6-methoxynaphthalen-yl)propanamide (108) from the reaction of acid chloride 29
with N-(4-aminophenyl)-2-acetamide (107). When the cyanoacetanilide 108 was reacted
with acetylacetone in the presence of a catalytic amount of piperidine, the 3-cyanopyridone
derivative 109 was smoothly obtained. Also, cyanoacetanilide derivative 108 was reacted
with aromatic aldehyde to afford the corresponding arylidene derivative 110. Micheal
addition of malononitrile with arylidene derivative 110 upon heating under reflux in the
presence of piperidine as catalyst furnished the 3-cyanopyridone derivative 111. On the
other hand, 3-cyanopyridone derivatives 111a–c were furnished through the reaction of
cyanoacetanilide 108 with arylidene malononitriles 105a–c. In addition, treatment of
108 with ethyl 4-methoxycyanocinnamate (103) in ethanol containing a catalytic amount
of piperidine afforded a single product for which two structures 112 and 113 seemed
possible. However, the 6-hydroxypyridone derivative 112 was assigned for the reaction
product on the basis of elemental analysis and spectral data (Scheme 33).
 SYNTHETIC COMMUNICATIONS® 1357

Scheme 32.

Scheme 33.
1358 Y. A. AMMAR ET AL.

Oxidative cyclization of hydrazide derivative 36[21] to 1,3,4 oxadiazole derivatives 115a

by elimination of H2S using iodine and potassium iodide in ethanolic sodium hydroxide.
However, N-cyclohexyl-5-(1-(6-methoxynaphthal-en-2-yl)ethyl)-1,3,4-thiadiazol-2-amine
(115b) was obtained by cyclization of 114 by treating with cold concentrated sulfuric
acid.[17–20] The addition reaction of the hydrazide 34 with the different sulfonyl/benzoyl
chlorides in the presence of pyridine as a base afforded a series hydrazides 116a–f.
Furthermore, in 2007,[18] it was reported that reaction of the acid hydrazide 36 with
aryl-S-methylisothiouronium iodides 117 in dry pyridine afforded 6-aryl-amino-4H-
1,2,4-triazoles (118) (Scheme 34).
In the same year,[26] a series of substituted 1,3,4-oxadiazole 119, 1,2,4-triazole 121,
and 1,3,4-thiadidzole 122 derivatives of naproxen have been synthesized by cyclization
of 2-(6-methoxy-2-naphthyl)propanoic acid hydrazide (36) and N1[2-(6-methoxy-2-
naphthyl)propanoyl]-N4-alkyl/aryl-thiosemicarbazides (120) under various reaction
conditions (Scheme 35).
In the same year, El-sehemi et al. reported that naproxenoyl hydrazine 36 was used as
versatile precursor for construction of pyrazole scaffold. Thus, condensation of the
hydrazide derivative 36 with each of 4-formylantipyrine and 1,3-diphenyl-4-
formylpyrazole in refluxing ethanol afforded the respective hydrazone derivatives 123
and 124, respectively.[34] In addition, cyclocondensation of the hydrazide 36 with
2-chloro-1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone in refluxing pyridine
gave the nonisolable hydrazone 125 which in situ underwent cyclization through
elimination of HCl molecule to give N-[1-(3-methyl-1-phenyl-1H-furo[2,3-c]pyrazol-4-
ylidene)-2-(6-methoxynaphthalen-2-yl)propionyl hydrazide (126)[31] (Scheme 36).
Also, they reported that refluxing of the hydrazide derivative 36 with acetylacetone in
glacial acetic acid afforded 3,5-dimethylpyrazole derivative 127 in good yield. Reaction
of hydrazide 34 with enaminones, namely, 3-dimethylamino-1-phenyl-propenone (128)

Scheme 34.
 SYNTHETIC COMMUNICATIONS® 1359

Scheme 35.

and 3-dimethylamino-1-thiophen-2-ylpro-penone (130) in boiling glacial acetic afforded

pyrazole derivatives 129 and 131.[31] Moreover, the reaction of hydrazide 36 with Mannich
base, namely, 3-dimethylamino-1-phenylpropan-1-one hydrochloride (132) in warming
ethanol containing a catalytic amount of acetic acid gave only a sole product that was

Scheme 36.
1360 Y. A. AMMAR ET AL.

Scheme 37.

identified as 2-(6-methoxynaphthalen-2-yl)-1-(5-phenyl-2,3-dihydropyrazol-1-yl)propan-
1-one (133).[31] (Scheme 37).

Biological activity of naproxen and its derivatives

Naproxen and its derivatives have been the subject of chemical and biological studies on
account of their interesting pharmacological properties. They are associated with diverse
biological activities which could be summarized as follows.

Naproxen as anti-inflammatory agent

Anti-inflammatory effects of naproxen are generally thought to be related to its inhibition of
COX and consequent decrease in prostaglandin concentrations in various fluids and tissues.[35,36]
In 1999, Mahfouz et al.[15] reported the synthesis of ester prodrug 22a, 22b of naproxen
using HMSI and HMIS, respectively, as apromoieties to reduce GI toxicity and improve
bioavailability. The results suggested these esters to possess good potential as prodrugs with
an improved therapeutic index for oral delivery of NSAIDs.
 SYNTHETIC COMMUNICATIONS® 1361

Furthermore, in the same year, Mohammad et al.[37] reported the reaction of the precur-
sor hydrazide with carbon disulfide in alkaline medium to afford 2-mercapto-5-substituted
1,3,4-oxadiazole 134. Also precursor hydrazide by reaction with cyanogen bromide and
NaHCO3 to afford 2-amino-5-substituted 1,3,4 oxadiazole 135. Compounds 134 and
135 showed marked anti-inflammatory activity compared to naproxen.

In the next year, Rautio et al.[16] reported that various morpholinyl and methylpiperaziny-
lacyloxyalkyl ester of 2-(6-methoxy2-naphthyl)-propionic acid (24) were synthesized and
evaluated in vitro for topical drug delivery as potential prodrug of naproxen. The resulting
structures showed improved topical delivery of naproxen.

In 2001, Berk et al.[38] reported combined 6-methoxy-α -methyl-2-naphthalene acetic acid

with 1,2,4-triazole and thiazole[3,2-b]-1,2,4-triazole-5-(6)-one rings. These structure 136a,
b,f,g,i,m showed significant anti-inflammatory activity with no ulcerogenic activity com-
pared to naproxen.

Moreover, in 2002, Levit et al.[20] reported the synthesis of naproxen amide compounds
30a,b with methyl esters of amino acid derivatives which exhibit reliable anti-inflammatory
activity, while possessing less pronounced anti-inflammatory properties exhibit a some-
what lower acute toxicity.
1362 Y. A. AMMAR ET AL.

In 2006,[17] naproxen glycol amide nitrate 137 were synthesized and possessed an oral
anti-inflammatory activity equivalent to that of the conventional NSAIDS, naproxen with
a significantly less gastric damage.

Also in the next year, Metwaly et al.[18] reported the synthesis of compounds 138 and 139
by replacement of carboxyl function of naproxen by 1,2,4-triazoles 138 and 1,2,4-triazolo
[3,4-b]-1,3,4-thiadiazoles 139. All these compounds displayed more potent anti-
inflammatory activity with no or minimal ulcerogenic effects.

In 2013, Raghavendra et al.[30] found that compounds 2-(1-2(2(2-methoxynaphthalen-6-yl)

propanoyl)-1H-indol-2-yl)acetic acid (58f) and (m-aminobenzoic acid analog of naproxen)
58g were the most active compounds as anti-inflammatory agents and having less
ulcerogenic effects.

Moreover, in the next year, Fernandes et al.[23] reported that the amide prodrug of
naproxen compounds 33a–d showed significant anti-inflammatory activity compared to
standard drug naproxen.
 SYNTHETIC COMMUNICATIONS® 1363

Furthermore, Redasani et al.[39] reported that the glyceride ester derivatives 140a and 140b
demonstrate better anti-inflammatory activity with percentage inhibition of 58 and 55% in
comparison to 51% for naproxen when studied up to 6 h.

Naproxen as antimicrobial agent

In 2013, Helal et al.[22] reported that propane-amide derivatives of naproxen 31 showed
good antibacterial activity against Gram-positive bacteria as Staphylococcus aureus and
Bacillus subtilis and Gram-negative bacteria as Escherichia coli and Pseudomonas aerugi-
nosa comparable to standard drugs Ampicillin and Ciprofloxacin for Gram-positive &
Gram-negative bacteria, respectively.

Also, they found that sulfonamide derivatives of naproxen 31f–h possess significant
antibacterial activity against Gram-positive bacteria as S. aureus with (MIC ¼ 0.97,
31.25, 0.24 µg/ml) for compounds 31f–h, respectively, and B. subtilis (MIC ¼ 0.97, 62.5,
7.81 µg/ml) for compounds 31f–h, respectively, compared to standard drug Ampicillin
(MIC ¼ 0.06, 0.007) for S. aureus and B. subtilis, respectively.[22]

Furthermore, they reported that phenothiazine derivatives of naproxen 141 exhibit

very good antibacterial activity against Gram-positive bacteria as S. aureus with
(MIC ¼ 3.9 µg/ml) and B. subtilis (MIC ¼ 0.97 µg/ml) compared to standard drug
Ampicillin (MIC ¼ 0.06, 0.007 µg/ml) for S. aureus and B. subtilis, respectively.[22]
1364 Y. A. AMMAR ET AL.

Moreover, in the same paper, they found oxazole derivatives of naproxen 60 have good
activity against Gram-positive bacteria as B. subtilis with (MIC ¼ 3.9 µg/ml) compared to
standard drug Ampicillin (MIC ¼ 0.007 µg/ml) and Gram-negative bacteria as E. coli with
(MIC ¼ 15.63 µg/ml) compared to standard drug Ciprofloxacin (MIC ¼ 1.95 µg/ml).[22]

Additionally, they reported that triazole derivative of naproxen 65 was found to have
good activity against Gram-positive bacteria as B. subtilis with (MIC ¼ 0.97 µg/ml)
compared to standard drug Ampicillin (MIC ¼ 0.007 µg/ml) and Gram-negative bacteria
as P. aeruginosa with (MIC ¼ 31.25 µg/ml) equipotent to standard drug Ciprofloxacin
(MIC ¼ 31.25 µg/ml). Concerning the fungicidal evaluation, it showed significant activity
against Aspergillus ochraceus and Candida albicans with (MIC ¼ 7.81, 31.25 µg/ml),
respectively, compared to reference drug Flucanazole with (MIC ¼ 1.95, 0.24 µg/ml).[22]

In 2014, Fernandes et al.[23] reported that carboxamide derivatives of naproxen showed good
antibacterial activity compared to the parent drug naproxen. Compounds 33a–d
were screened for their antibacterial activity against B. subtilis, S. aureus, E. coli, and
P. aeruginosa showing good antibacterial activity compared to standard drug Ciprofloxacin.

Naproxen as antitumor agent

In 2003, Piffar et al.[40] reported that the tumor-bearing rats treated with naproxen 1 (PG
inhibitor) have tumor growth rate reduced by 58%.
 SYNTHETIC COMMUNICATIONS® 1365

Moreover, in 2006, Xia et al.[41] reported that the four commercial drugs, naproxen, 4-
biphenylacetic acid, brufen, and 5-fluorouracil, were tested in vitro for their inhibition on
four kinds of human cancer cells, KB, A-549, MDA, and Bell-7402. The data showed that
the inhibition rate of 4-biphenylacetic acid and naproxen on Bel-7402 cell was equivalent
with 5-fluorouracil, while their inhibition on KB cell was higher than that of 5-fluorouracil
due to their intercalating effect on DNA. In the same year, Tian et al.[42] reported the syn-
thesis of a series of six novel 5-fluorouracil derivative 142 in which naproxen was attached
to 5-FU, this compound was found to inhibit liver tumor growth in vivo.

Furthermore, in 2008, Chen et al.[43] found that hydroxamic acid derivative of naproxen
143 have a potent HDAC (histone deacetylase) inhibitor.

Additionally, in 2012, Khalifa et al.[21] reported that urea derivatives of naproxen 31 and
propanamide derivative 65 were found to have promising inhibitory activity against colon
cancer cell line HCT-116.

Naproxen as antiviral agent

In 2013, Lejal et al.[44] reported that naproxen 1 is a promising lead compound for novel
antiviral against influenza A virus that targets nucleoprotein in its RNA-binding groove.
1366 Y. A. AMMAR ET AL.

Naproxen as antioxidant agent

In 2009, Spadro et al.[45] developed a new naproxen prodrug with beneficial antioxidant
activity by synthesizing naproxen ester containing tocopherol 144. They focused on
γ- tocopherol, for its potent antioxidant properties and anti-inflammatory activity.

Naproxen as analgesic agent

Naproxen ester 145 showed analgesic effects when exposed to the writhing test with mice.
Naproxencacalol (1a) ester as well as acetylsalicylic acid inhibited the frequency of writhes
as compared with vehicle in 77.1, 36.4, and 39.2%, respectively.[46]

Conclusion
The data considered in this review clearly demonstrate the high synthetic potential of
naproxen. Many biologically active heterocyclic compounds have been obtained based
on these reagents. This suggests that naproxen can be particularly promising synthon in
combinatorial synthesis of functionalized heterocyclic compounds used in the design of
novel highly effective pharmaceuticals with a broad spectrum of bioresponses.

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