Synthesis and characterization of new types of 2-(6-methoxy-2-naphthyl) propionamide derivatives as potential antibacterial and antifungal agents

Article abstract of DOI:10.1007/s00044-013-0524-5

A series of novel 2-(6-methoxy-2-naphthyl)propionamide derivatives have been efficiently synthesized in excellent yields via the reaction of naproxenoyl chloride with different amino compounds. Most of the synthesized compounds were screened in vitro for

Full text of DOI:10.1007/s00044-013-0524-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0524-5
ORIGINAL RESEARCH
Synthesis and characterization of new types of 2-(6-methoxy-2-
naphthyl)propionamide derivatives as potential antibacterial
and antifungal agents
•
Mohamed H. Helal Samir Y. Abbas
•
•
•
Mohamed A. Salem Awatef A. Farag
Yousry A. Ammar
Received: 21 December 2012 / Accepted: 31 January 2013
Ó Springer Science+Business Media New York 2013
Abstract A series of novel 2-(6-methoxy-2-naphthyl)pro-
pionamide derivatives have been efficiently synthesized in
excellent yields via the reaction of naproxenoyl chloride with
different amino compounds. Most of the synthesized com-
pounds were screened in vitro for their antibacterial and
antifungal activities. Most of the compounds showed signifi-
cant antibacterial and antifungal activities, reaching, in certain
cases, the same level of antimicrobial activity as the standard
antibacterial agent Ampicilline and antifungal agent Fluca-
nazole. N-(4-(N-arylsulfamoyl)phenyl)-2-(6-methoxynaphth-
alen-2-yl)propanamide (4a–c), 4-(4-fluorobenzylidene)-2-(1-
(6-methoxynaphthalen-2-yl)ethyl)oxazol-5(4H)-one (10b),
2-(6-methoxynaphthalen-2-yl)-N-((5-thioxo-4,5-dihydro-1H-
1,2,4-triazol-3-yl)methyl)propanamide (12), and N-((4-
amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)-2-
(6-methoxynaphthalen-2-yl)propanamide (13) were found to
be the most potent compounds against most of the tested
strains. The antimicrobial activity was further supported by
using MIC technique. Structure activity relationship studies
revealed several matching pairs.
Keywords Propionamides ꢀ Naproxen ꢀ Carboxamides ꢀ
Chiral carbon ꢀ Antibacterial ꢀ Antifungal activity
Introduction
Despite many significant progresses in antimicrobial therapy,
infectious diseases caused by bacteria and fungi remain a major
worldwide health problem due to rapid development of resis-
tance to the existing antimicrobial drugs (antibacterial and
antifungal drugs). In other words, the increasing use and misuse
of the existing antimicrobial drugs have resulted in the devel-
opment of resistant pathogens (Berber et al., 2003; Appelbaum,
2006). So, the medical community faces a serious problem
against infections caused by the pathogen bacteria and needs an
effective therapy and search for novel antimicrobial agents.
Staphylococcus aureus, as example, has been recognized
as an important pathogen of humans. Infections caused by
this bacteria species can lead to serious consequences,
especially in hospitalized patients. The appearance of
methicillin-resistant strains of S. aureus (MRSA) has been a
concern all over the world. This situation becomes worse and
more threatening regarding the ease of transmission of the
pathogen among individuals, resulting in the dissemination
of MRSA (Gomes et al., 2006). The resistance to a great
number of antibiotics presented by MRSA makes it difficult
to control in hospital environments (Hiramatsu et al., 2002).
M. H. Helal
Department of Chemistry, Faculty of Science,
Northem Border University, Rafha, Saudi Arabia
M. H. Helal ꢀ M. A. Salem ꢀ Y. A. Ammar (&)
Department of Chemistry, Faculty of Science,
Al-Azhar University, Cairo, Egypt
e-mail: yossry@yahoo.com
S. Y. Abbas (&)
Organometallic and Organometalloid Chemistry Department,
National Research Centre, Cairo, Egypt
e-mail: samiryoussef98@yahoo.com
M. A. Salem ꢀ Y. A. Ammar
Department of Chemistry, Faculty of Science,
King Khaled University, Abha, Saudi Arabia
A. A. Farag
Department of Chemistry, Faculty of Science,
Al-Azhar University (Girls), Cairo, Egypt
A. A. Farag
Department of Chemistry, Faculty of Education,
Taif University, Taif, Saudi Arabia
123

Med Chem Res
Considering the antimicrobial agents more recently
approved for clinical use, a series of carboxamides, showed
excellent in vitro and in vivo antibacterial activity present
activity against Gram ?ve organisms, including MRSA
(Strigacova et al., 2000; Zanatta et al., 2007; Zhuravel et al.,
2005). Carboxamides which contain -CONH- bridge con-
nect the benzene or heterocyclic rings with antimycobacte-
rial activity. This moiety can form centrosymmetric dimer
pairs with the peptidic carboxamido group of some peptides,
needed for binding to the receptor site, possibly by forming
being the pharmacophore responsible for the broad spectrum
of biological activities shown by these moieties.
Results and discussion
Chemistry
The synthesis of the target compounds is depicted in
Schemes 1, 2, and 3. The starting material, naproxenoyl
chloride (2), was prepared through treatment of naproxen
(1) with thionyl chloride (Al-Sehemi et al., 2006). This
compound was proven to be a good synthons for different
highly biologically active compounds. Thus, propionamide
derivatives 3a–d were prepared via interaction of com-
pound 2 with some aromatic amines. The structure of the
products was characterized from their spectroscopic as well
as elemental analytical data. For example, the IR spectrum
of compound 3d revealed the absorption bands at: 3,386,
3,301, 1,651 cm-1 corresponding to two 2NH and C=O
ˇ
hydrogen bond (Matsuoka et al., 1999; Dolezal et al., 2006).
In view of the scenario presented above, the search for new
and effective antimicrobial agents, resistant to the mechanisms
of defense of these bacteria, is of paramount importance.
As a part of our extensive research program to rapidly
assemble novel bioactive heterocycles under mild conditions
(Khalifa et al., 2013; Farag et al., 2012; Ismail et al., 2010;
Ammar et al., 2006; Aly et al., 2010), we have employed
naproxenoyl chloride (2) to prepare various new propiona-
mide derivatives incorporating chiral carbon atom and also
methoxy as lipophilic group to evaluate antimicrobial
activity, hopefully, the new analogs with enhanced potency
or of finding new applications. Various functional groups
were introduced into the target compounds in order to
investigate their preliminary structure activity relationships.
The preceding functional groups have been suggested as
1
functions, respectively. H NMR spectrum of 3c showed
signals at: 1.47, 3.45 corresponding to CH3 and CH2 pro-
tons and showed a quartet signal at: 3.97 due to the CH
proton and two D2O exchangeable signals at 10.08 and
11.34 corresponding to NH and COOH protons. The sul-
fonamide functional group has a long and rich history in
CH3
H
N
ArNH2
Ar
O
H3CO
CH3
3a
3c
, Ar=C6H4CH2COOH-4
, Ar=C6H4CH3-4
b, Ar=C6H4COOH-3 d, Ar=C6H4NHC6H5
COOH
H3CO
CH3
H
CH3
1
N
SO2NHR
Cl
Sulfa
SOCl2
O
O
H3CO
H3CO
4a
, R=COCH3
2
b
, R=5-methylisooxazol-3-yl
c,
R=2-pyrimidinyl
H2NXNH2
2
CH3
CH3
O
CH3
O
CH3
H
H
H
N
N
COOH
N
N
X
HN
R
O
H3CO
OCH3
H3CO
H3CO
7
6a,
b
6c
, X=(CH2CH2)2NH
d,
X=C6H4-p
X=0
, X=CH2CH2
5a
b
, R=H; , R=CH3
Scheme 1 Synthesis of propionamide, sulfonamide, acyl aminoacid, bispropionamide and benzoimidazole derivatives
CH3
CH3
H
H
N
N
CH3COCl
O
3d
O
H3CO
N
H
H3CO
N
8
COCH3
CH3
H
N
S
I2/ S
O
9
H3CO
N
H
Scheme 2 Synthesis of N-phenylacetamido and phenothiazine derivatives
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Med Chem Res
CH3
H
N
COOH
O
H3CO
CH3
O
CH3
O
5a
H
N
N
Ar'NH2
ArCHO
Ar
Ar
Ac2O/AcONa
O
H3CO
H3CO
NHAr'
O
11, Ar = C6H4Cl-4 Ar' = C6H4CH3-4
10a, Ar=C6H4Cl-4 c, Ar=C6H4CH3-4
b, Ar=C6H4F-4 d, Ar=C6H4OCH3-4
CH3
N
NH
H
N
H2NNHCSNH2
N
S
H
O
H3CO
12
H2NNHCSNHNH2
N
NH
CH3
H
N
N
S
O
13
NH2
H3CO
Scheme 3 Synthesis of oxazolone, acrylamide and 1,2,4-triazole derivatives
organic chemistry and drug discovery. Beginning with the
discovery of the ‘sulfa’ antibiotics in the 1930s that revolu-
tionized the treatment of bacterial infections, and continuing
into the present day with the development of potent anti-
retrovirals used to treat patients infected with HIV, sulfon-
amides remain a particularly important class of compounds
for the treatment of infectious diseases. Thus, condensation
of the acid chloride 2 with some derivatives of sulfa drugs
afforded the corresponding carboxamide derivatives 4a–c,
Scheme 1. The analytical and spectral data were in agree-
ment with the proposed structure. Thus, the 1H NMR spec-
trum of 4a showed a singlet at: d = 1.88 for the CH3 of acetyl
group and two singlets at: 9.85 and 10.56 singlet for two NH
groups. Owing to the higher biological activity of amino
acids, the authors planned to couple some of the amino acids
with naproxene in one structure through an amide linkage.
Hence, reaction of the naproxenoyl chloride with amino
acids in the presence of pyridine furnished the amide
derivatives 5a,b, Scheme 1. The structure of the isolated
products was evidenced by its spectroscopic and elemental
analysis data. Thus, IR spectrum of 5a exhibited absorption
bands at: 3,380, 3,200–2,700, 1,740, 1,675 corresponding to
desired molecular ion peaks with the appropriate isotopic
distributions where applicable. Thus, the mass spectrum of
compound 6d showed m/z at: 532 (M?) which is the base
peak. Structures of the prepared compounds were further
elucidated by the use of NMR and IR techniques. Thus, IR
spectrum of product 6a revealed absorption bands at:
3,178 cm-1 due to NH group, a band near 1,651 cm-1 that
1
was attributed to the carbonyl group. H NMR spectrum of
compound 6b revealed, besides an aromatic multiplet in the
region of d = 7.12–7.80 ppm, two singlet signals at: d = 3.1,
8.1 attributed to CH2 and NH, respectively. The authors
planned to couple naproxene moiety with biologically active
heterocyclic compounds such as benzimidazole moiety. Thus,
heating the acid chloride 2 with o-phenylenediamine in DMF
under reflux affected cyclization to afford benzimidazole
derivative 7. Structure 7 was suggested for this product based
on analytical and spectral data. Thus, the IR spectrum
revealed absorption bands at 3,225 and 1,608 due to (NH) and
(C=N), respectively, and the absence of a band in the region
1
of C=O group absorption. The H NMR spectrum revealed
D2O exchangeable proton at 10.80 due to NH besides the ten
aromatic protons in the region signals at: d = 7.20–7.89; the
mass spectrum of this product showed the molecular ion peak
at m/z 302 (M?, 85.0) and base peak at 151 (100).
1
NH, COOH, and two C=O groups. Moreover, its H NMR
spectrum revealed signals corresponding to CH2 protons at:
3.72 and two D2O-exchangeable signals at: 8.25 and 12.55
corresponding to one NH and COOH. Further, the molecular
ion peak recorded in the mass spectrum is also in agreement
with the molecular weight of the compound.
Now, we have extended our synthetic program to the
synthesis of otherwise inaccessible ring system utilizing
compound 3d as the key starting material. A mixture of 3d
and acetyl chloride were reacted in dioxane under reflux
condition in the presence of catalytic amounts of pyridine to
yield a product which may be formulated as the acetyl
derivative 8. The structure of acetyl derivative 8 was estab-
Bis-compounds were reported to possess a wide range of
biological activities. Thus, bis-naproxamide derivatives 6a–
d weresynthesizedthroughinteractionoftwomolesoftheacid
chloride derivative 2 with hydrazine hydrate, ethylenediamine,
diethylenetriamine, and p-phenylenediamine, Scheme 1.
Their structural assignment was secured via spectroscopic and
microanalytical methods. Thus, the microanalyses were in
satisfactory agreement with the calculated values (C, H, N
fvalues were within 0.4 %). The mass spectra produced the
1
lished from their IR, H NMR, and mass spectra. Its IR
spectrum showed the presence of peaks at 3,280 due to NH
group, in addition, for two bands in the region of 1,680, 1,670
1
corresponding to two carbonyl groups. H NMR spectrum
showed two singlet signals at: 1.95, 10.2 due to CH3 acetyl
and NH, and a multiplet signal in the region of 6.8–7.94 due
123

Med Chem Res
to 15 aromatic protons. Mass spectrum showed molecular
ion peak at: m/z 438 (M?) (29.13 %) with a base peak m/
z 184. Also, upon treatment of compound 3d with sulfur and
iodine in dichlorobenzene, the corresponding phenothiazine
derivative 9 was obtained. Structure 9 was suggested for this
product based on analytical and spectral data. The IR spec-
trum revealed absorption bands at: 3,312, 3,224 cm-1
Gram -ve bacteria, S. aureus RCMB 010027 and Bacillus
subtilis RCMB 010063; and Gram-negative bacteria,
Escherichia coli RCMB 000103 and Pseudomonas aeru-
ginosa RCMB 010043. The results are summarized in
Table 1. Antimicrobial tests were carried out by the agar
well diffusion method (Scott, 1989) using 100 ll of tested
compound solution prepared by dissolving 1 mg of the
chemical compound in 1 ml of dimethyl sulfoxide
(DMSO). The inoculated plates were then incubated for
1
(2NH), 1,650 cm-1 (C=O). H NMR spectrum revealed
signals at: d = 7.18–7.85 and 10.12, 12.13 ppm due to the
aromatic and 2NH protons, respectively. (Scheme 2).
The authors planned to cover the coupling of naproxen
moiety with different biologically active heterocyclic com-
pounds such as oxazolone and triazole moieties.
24 h at 37 °C. The solution of Ampicilline (25 lg ml-1
)
was prepared in sterilized water and used as standards for
comparison of antibacterial activity. After incubation time,
antimicrobial activity was evaluated by measuring the
inhibition zone diameters against the test organisms and
compared with standard zone size ranges that determine
susceptibility, intermediate susceptibility, or resistance to
the screened compounds. Visual bacterial growth is
observed only in areas in which the drug concentrations are
below those required for growth inhibition. The experiment
was carried out in triplicate, and the average zone of
inhibition was calculated.
Compound5a wasalsousedasa precursorforthe synthesis
of heterocyclic compounds. Thus, treatment of 5a with aro-
matic aldehydes in acetic anhydride containing catalytic
amounts of sodium acetate under reflux afforded the oxazo-
lone derivatives 10a–d, (Scheme 3). The structure of the
obtained products was confirmed by their IR, NMR, and mass
spectrum. The IR spectrum of compound 10a confirmed the
formation of the lactone function through the presence of the
carbonylgroupat:1,730.1HNMRspectrum ofcompound10c
showed the presenceoftwo singletsignals at: 2.32, 3.80due to
CH3 and OCH3, also the presence of doublet and quartet
signals at: 1.48 and 3.9 corresponding to CH3 and CH besides
multiplet signals at: d = 7.13–7.88 ppm due to 11 aromatic
protons. Mass spectrum of 10a exhibited a molecular ion peak
at m/z 391 (M?: 8.4 %) with a base peak at: 197. The lactone
function in the oxazolone ring was opened upon treatment of
compound10a with p-toluidine in ethanol under reflux, where
the acrylic acid amide derivative 11 was obtained from
Scheme 3. The IR spectrum showed absorption bands at
To obtain a clear picture about the structure activity
relationship for the synthesized compounds, the target
compounds were represented in general formula in
Table 1. The mean values of inhibition zone diameters
show that all tested compounds in the antibacterial assay
possess significant activity against the growth of most test
organisms.
The tabulated antimicrobial screening results of the
tested compounds revealed that: Structure 3, Ar was aryl
moiety (3a; 4-methylphenyl, 3b; 4-carboxyphenyl, 3c;
4-carboxymethylphenyl, 3d; 4-phenylaminophenyl): the
presence of 4-carboxyphenyl moiety showed the maximum
potent activities against the most tested organisms, 4-car-
boxyphenyl moiety showed result near to the reference
drug against the two gram-negative bacteria: E. coli and P.
aeruginosa. Other moieties showed moderate activity
against the most tested organisms. Structure 4 has sulfon-
amide side chain ending with alkyl or aryl moieties; these
moieties were acetyl; 4a, 5-methylisoxazol-3-yl; 4b, and
2-pyrimidinyl; 4c. The presence of pyrimidinyl moiety in
4c exhibited the highest antibacterial activity against most
of the test organisms; pyrimidinyl moiety showed results
equipotent to the reference drug against the most tested
organisms. Also, 4a,b showed good activity against the
most tested compounds. 4a,b showed strong activity
against E. coli near to reference drug. Structure 5, Ar was
CHRCOOH moiety (5a; R=H), 5b; R=CH3): all derivatives
showed moderate activity against Staphylococcus aureus
and B. subtilis, E. coli and no activities toward P. aeru-
ginosa. Biscompounds 6a, b with two naphthyl and two
amide moieties showed moderate activity against Staphy-
lococcus aureus, B. subtilis and no activities toward P.
1
3,300 cm-1 (NH) and 1,675 cm-1 (C=O amide); HNMR
showed two D2O exchangeable protons at: d = 8.87 and
11.40duetoNHprotonsandasingletsignalat2.23duetoCH3
group. In addition, compound 5a was allowed to react with
either thiosemicarbazide or thio-carbohydrazide, where the
triazole derivatives 12, 13 were obtained, respectively.
Structure 13 was proved by its IR spectrum which revealed
stretching frequencies of NH2 and NH at 3,400, 3,300 cm-1
,
and1,221(C=S).The1HNMRforcompound13 showedthree
D2O exchangeable at: 5.56, 8.51, and 13.5 due to NH2, NH
amide, and NH triazole, respectively, besides multiplet bands
at d = 7.13–7.82 ppm due to six aromatic protons.
Biological activity
Antibacterial activity
The synthesized compounds 3a–d, 4a–c, 5a, b, 6a, b, 8, 9,
10a, b, 11–13 (18 compounds) were tested in vitro for
antibacterial activity against the following bacterial strains:
123

Med Chem Res
Table 1 Antimicrobial activity of the synthesized compounds against the pathological organisms expressed as inhibition diameter zones in
millimeters (mm) based on well diffusion assay
CH3
N
Ar
O
H3CO
O
10
CH3
H
N
Ar
O
H3CO
3-9, 11-13
Compd. no. Ar
Gram ?ve
Gram -ve
Fungi
S. aureus
B. subtilis
E. coli
P. aeruginosa Aspergill
Candida
3a
16.1 0.1 17.2 0.3 15.6 0.6
NA
14.7 0.1 12.8 0.6
C
CH3
3b
21.6 0.5 23.7 0.2 20.3 0.8 15.9 0.6
19.4 0.3 15.6 0.6
13.9 0.5 12.2 0.4
C
COOH
3c
17.3 0.6 18.4 0.4 16.6 0.3
NA
NA
C
CH2COOH
3d
13.9 0.2 15.4 0.6
NA
17.6 0.2
NA
C
NHPh
4a
23.3 0.4 23.4 0.6 21.3 0.5 14.5 0.4
20.6 0.6 21.7 0.6 19.9 0.3 13.0 0.3
25.3 0.2 28.7 0.2 21.6 0.4 16.8 0.3
18.6 0.3 17.8 0.3
17.3 0.4 16.5 0.4
C
SO2NHCOCH3
O
N
S N
4b
H
O
C
O
CH3
O
H
4c
11.7 0.2
NA
N
N
C
S N
O
5a
5b
CH2COOH
14.2 0.3 16.4 0.6 13.4 0.6
15.1 0.4 15.8 0.7 14.3 0.4
NA
NA
20.9 0.3 20.6 0.2
12.7 0.4 10.6 0.6
CH(CH3)COOH
CH3
6a
17.9 0.5 19.4 0.5 17.1 0.7
NA
16.0 0.3 13.5 0.4
NH
O
H3CO
CH3
6b
8
13.1 0.5 14.5 0.3
NA
NA
NA
12.6 0.4
12.4 0.7
NA
NHCH2CH2
O
H3CO
16.2 0.3 17.1 0.2 14.6 0.6
9.3 0.2
COCH3
C
C
N
S
9
21.4 0.6 24.6 0.4 20.2 0.2 13.6 0.7
17.6 0.7 16.9 0.4
N
H
10a
13.9 0.3 15.0 0.3
NA
NA
14.5 0.3
NA
C
Cl
123

Med Chem Res
Table 1 continued
Compd. no.
Ar
Gram ?ve
Gram -ve
Fungi
S. aureus
B. subtilis
E. coli
P. aeruginosa
Aspergill
Candida
10b
11
20.3 0.4
19.9 0.4
20.6 0.4
19.3 0.2
14.3 0.3
15.3 0.4
18.3 0.4
14.8 0.3
19.9 0.6
C
C
F
O
19.6 0.4
23.9 0.4
NA
13.6 0.6
18.8 0.4
N
H
CH3
C6H4Cl-4
N
NH
12
21.9 0.3
20.9 0.6
16.8 0.4
20.2 0.3
H2C
H2C
S
S
N
H
N
NH
13
21.6 0.1
28.9 0.1
23.7 0.2
34.6 0.4
20.3 0.7
21.4 0.3
15.9 0.6
17.3 0.1
19.4 0.3
21.9 0.1
20.6 0.6
26.4 0.2
Standard
N
NH2
aeruginosa. Structure 8 showed moderate activity against
two Gram ?ve bacteria, one Gram -ve bacteria (E coli)
and showed no activity toward P. aeruginosa. Compound 9
with phenothiazine moiety showed strong activities against
all of tested organisms. The activity was equipotent to the
reference drug against the two Gram -ve bacteria. Structure
10 has oxazole side chain ending with chlorophenyl and
fluorophenyl moieties. The presence of fluorophenyl moi-
ety in case of 10b showed activity more than chlorophenyl
moiety in case of 10a. Fluorophenyl moiety showed strong
results against the most tested organisms. Compounds 12,
13, the aryl group have triazole moiety, showed good
results against most of the test organisms. Compounds 12,
13 showed activity equipotent to the reference drug against
E. coli and P. aeruginosa. The comparison between the
antibacterial activities of our potent synthesized com-
pounds and ciprofloxacin as standard antibacterial
reference drug against the used Gram ?ve and Gram-
negative bacteria was represented graphically in Fig. 1.
Antifungal activity
The search for newer antifungal agents continues due to the
rapid development of the resistance among fungi to the
existing antifungal agents. Even though novel broad
spectrum antifungal agents were reported in recent years,
the emergence of resistance has become an obstacle. Thus,
more effective classes of such agents are desired. As such,
propionamide derivatives may comprise a new class of
antifungal agents. We chose Aspergillus ochraceus
(RCMB 02593) and Candida albicans (RCMB 05035) in
the antifungal susceptibility tests. Antifungal agents are
evaluated against isolates of standard strains of fungi by the
agar well diffusion method (Scott, 1989). The compounds
Fig. 1 The comparison
between the antibacterial
40
35
30
25
20
15
10
5
activities of our potent
synthesized compounds and
standard drug against the used
Gram positive and Gram
negative bacteria
S. aureus
B. subtilis
E. coli
P. aeruginosa
0
Compound number
123

Med Chem Res
were tested at a concentration of 1 mg ml-1 in DMSO
solution. The solution of Flucanazole (25 lg ml-1) was
prepared in sterilized water and used as standards for
comparison of antifungal activity. The inoculated plates
were then incubated for 72 h at 25 °C. After incubation
time, antifungal activity was evaluated by measuring the
inhibition zone against the test organisms and compared
with that of the standard. Antifungal activities were
expressed as inhibition zone diameter in millimeters (mm).
The experiment was carried out in triplicate, and the
average zone of inhibition was calculated. The results are
tabulated in Table 1.
comparison between the antifungal activities of our potent
synthesized compounds and Flucanazole as standard anti-
fungal drug against the used fungi is represented graphi-
cally in Fig. 2.
Minimum inhibitory concentrations against various
tested strains
The minimum inhibitory concentration (MIC) is a standard
technique used to measure the lowest concentration of a
compound required to inhibit visible growth of a micro-
organism being investigated after approximately 24 h of
incubation in the appropriate growth medium. MIC tech-
nique is a reliable means to determine the susceptibilities
of microorganisms to drugs and also to monitor the activity
of new ones. This technique provides a quantitative
assessment of in vitro antimicrobial activity. Hence, further
to the preceding tests of the potential antimicrobial and
antifungal activities of synthesized compounds, we con-
ducted a more quantitative assessment of the antimicrobial
and antifungal activity of a narrow selection of potential
leads by evaluating their minimum inhibitory. MIC values
of the highest eight active synthesized compounds were
measured by the procedure outlined in the Manual of
Clinical Microbiology (Jones et al., 1984) against the same
strains used earlier, and the results were reported in
Table 2. As shown in Table 2, all compounds tested
showed inhibitory effect, ranging from as low as
0.24 lg ml-1 to as high as 62.5 lg ml-1. In certain cases,
such values are low enough to render such agents as
potential candidates for further studies. Most of the tested
compounds revealed MIC values lower than the standard
against P. aeruginosa,, whereas compound 4c was con-
sistently the most effective against all bacterial strains,
producing the lowest MIC against test organisms. In rela-
tion to structure activity trends, the effect of the aryl moiety
In general, some compounds were very effective anti-
fungal agents and in several cases achieved similar or
greater levels of activity as the standard antifungal agent
Flucanazole (22 and 26 mm). It is noted, though, that some
fluctuation in antibacterial activity for individual tested
compounds was observed across the two strains of tested
fungi. As anticipated, a clear difference in antifungal
activity is noted between compounds within and between
each series, pointing to the reinforcing and opposing effects
of the Ar groups. The presence of 4-carboxyphenyl moiety
in structure 3 showed the maximum potent activities
against the test organism, 4-carboxyphenyl moiety showed
result near to the reference drug against A. ochraceus.
Other moieties showed moderate activity against the test
organisms. For instance, compound 5a (Ar=CH2COOH)
showed good activities against A. ochraceus (21 mm) and
C. albicans (21 mm) related to the standard antifungal
agent (21 and 26 mm). 10b, which has oxazole side chain
ending with fluorophenyl moieties, showed good activity
against the test fungi. Compounds 12, 13, the aryl group
have triazole moiety and showed strong results near to the
reference drug against A. ochraceus. Thus, these com-
pounds comprise a promising new class of promising and
potential broad spectrum antifungal agents. The
Fig. 2 The comparison
30
between the antifungal activities
of our potent synthesized
compounds and standard drug
25
20
15
10
5
Aspergillus
Candida
0
Compound number
123

Med Chem Res
Ar–H). 13C NMR: 18.24 (CH3), 45.21(CH), 55.32 (OCH3),
105.59 (C-5), 119.01 (C-7), 126.12 (C-4), 126.26 (C-8a),
127.21, 128.91, 129.31, 133.79, 135.16, 157.68, 179.27.
Table 2 Minimum inhibitory concentration (lg ml-1) of the most
potent synthesized compounds against the pathological organisms
Compd. Gram ?ve
No.
Gram -ve
Fungi
S.
aureus
B.
subtilis
E. coli P.
Aspergillus Candida
Synthesis of propionamides 3a–d
aeruginosa
3b
4a
4b
4c
9
0.24
0.97
31.25
0.24
3.9
3.9
0.97
62.5
7.81
0.97
3.9
1.95
3.9
15.63
125
7.81
15.63
7.81
62.5
31.25
250
Equimolar amounts of naproxenoyl chloride (2) (0.01 mol)
and the requisite amine (namely p-toluidine, 4-aminoben-
zoic acid, 2-(4-aminophenyl)acetic acid, and N1-phenyl-
benzene-1,4-diamine) (0.01 mol) in dioxane (20 ml) were
treated with pyridine (0.5 ml). The reaction mixture was
heated under reflux for 3 h. The solution was concentrated
under vacuum, left to cool. The resulting solid was filtered
off and recrystallized from ethanol.
3.9
1.95
3.9
3.9
3.9
NA
7.81
15.63
7.81
7.81
1.95
7.81
15.63
15.63
7.81
31.25
125
10b
12
10
7.81
3.9
62.5
0.97
0.97
0.007
31.25
62.5
31.25
62.50
0.24
3.9
15.63
1.95
Standard 0.06
31.25
is much more discernible and dominant as clearly reflected
in the significant disparity of MIC values obtained against a
given strain for compound with a different aryl moiety.
2-(6-Methoxynaphthalen-2-yl)-N-(4-methylphenyl)-
propionamide (3a)
Yield 70 %; mp 130–131 °C; IR: t/cm-1 = 3,250 (NH),
3,039(CH–Ar), 2,979–2,932 (CH-sp3), 1,653(C=O); 1H
NMR: d/ppm = 1.56 (d, 3H, CH3), 2.34 (s, 3H, CH3), 3.84
(s, 3H, OCH3), 3.90 (q, 1H, CH), 7.25–8.89 (m, 10H, Ar–
H), 10.0 (s, 1H, NH); 13C NMR; 18.24 (CH3), 20.25 (CH3),
45.31(CH), 55.38 (OCH3), 105.76 (C-5), 119.21 (C-7),
120.42, 120.43, 126.25 (C-4), 126.27 (C-8a), 127.23,
128.94, 129.32, 129.53, 129.54, 133.24, 133.82, 135.16,
138.2, 157.67, 179.65; Anal. Calc. for C21H21NO2
(319.40): C, 78.97; H, 6.63; N, 4.39. Found: C, 78.80; H,
6.40; N, 4.20.
Conclusion
In conclusion, sulfonamide and triazoles containing (6-
methoxy-naphthalen-2-yl)-propionamide which were eas-
ily prepared revealed promising antibacterial and anti-
fungal activities. Thus, these compounds could be used as
lead structure in pharmaceutical chemistry.
Experimental section
4-(2-(6-Methoxynaphthalen-2-yl)propanamido)benzoic
acid (3b)
Melting points were determined on a digital Gallen-Kamp
MFB-595 instrument and are uncorrected. IR spectra (KBr)
1
Yield 73 %; mp 235–236 °C; IR: t/cm-1 = 3,278 (NH),
3,230–2,750 (broad COOH), 3,073(CH–Ar), 2,985–2,919
were measured on a Shimadzu 440 spectrometer. HNMR
and 13C spectra were recorded in deuterated dimethyl-
sulfoxide (DMSO-d6) on a Varian Gemini 300 (500 MHz)
spectrometer using TMS as an internal standard; chemical
shifts are reported as d units. Mass spectra were performed
on a Shimadzu GSMS-QP 1000 Ex mass spectrometer at
70 eV. The elemental analyses were carried out at the
Microanalytical Center, Cairo University, Cairo (Egypt).
1
(CH-sp3), 1,700, 1,658(2C=O); H NMR: d/ppm = 1.53
(d, 3H, CH3), 3.80 (s, 3H, OCH3), 3.86 (q, 1H, CH),
7.13–7.88 (m, 10H, Ar–H), 9.54, 11.25 (2s, 2H, NH ?
COOH); 13C-NMR: 18.35 (CH3), 45.23(CH), 55.38
(OCH3), 105.63 (C-5), 119.22 (C-7), 121.23, 121.25,
126.23 (C-4), 126.28 (C-8a), 126.89, 127.27, 128.87,
129.39, 130.12, 130.14, 133.87, 135.34, 137.23, 157.65,
173.32, 179.46; Anal. Calc. for C21H19NO4 (349.38): C,
72.19; H, 5.48; N, 4.01. Found: C, 72.30; H, 5.20; N, 4.20.
Synthesis of naproxenoyl chloride (2)
Naproxenoyl chloride was synthesized according to our
reported procedure (Al-Sehemi et al., 2006) as follows: To
a solution of naproxen (1) (0.01 mol) in m-xylene (30 ml),
POCl3 (5 ml) was added. The reaction mixture was heated
under reflux for 3 h, left to cool, the resulting precipitate
was filtered off, washed with ether, and dried to give 2 as
2-(4-(2-(6-Methoxynaphthalen-2-yl)propanamido)-
phenyl)acetic acid (3c)
Yield 68 %; mp 245–246 °C; IR: t/cm-1 = 3,330, (NH),
3,250–2,750 (broad COOH), 3,070(CH–Ar), 2,970 (CH-
1
1
colorless crystals; mp 80–82 °C; Yield 75 %; H NMR:
d/ppm = 1.62 (d, 3H, J = 6.5 Hz, CH3), 3.84 (q, 1H,
J = 6.5 Mz, CH), 3.94 (s, 3H, OCH3), 7.13–7.73 (m, 6H,
sp3), 1,720, 1,660 (2C=O); H NMR: d/ppm = 1.47 (d,
3H, CH3), 3.45 (s, 2H, CH2), 3.84 (s, 3H, OCH3), 3.97
(q,1H, CH), 7.10–7.80 (m, 10H, Ar–H), 10.08, 11.34 (2s,
123

Med Chem Res
2H, NH ? COOH); 13C-NMR: 18.26 (CH3), 41.43 (CH2),
45.28(CH), 55.38 (OCH3), 105.46 (C-5), 119.21 (C-7),
120.86, 120.89, 126.23 (C-4), 126.36 (C-8a), 127.25,
128.87, 129.45, 130.12, 130.14, 131.34, 133.65, 135.34,
138.21, 157.76, 177.23, 179.34; Anal. Calc. for C22H21NO4
(363.41): C, 72.71; H, 5.82; N, 3.85. Found: C, 72.60; H,
5.50; N, 3.60.
2-(6-Methoxynaphthalen-2-yl)-N-(4-(N-pyrimidin-2-
ylsulfamoyl)phenyl)propanamide (4c)
Yield 74 %; mp 175–176 °C; IR: t/cm-1 = 3,350, 3,234
(2NH), 3,085(CH–Ar), 2,970 (CH-sp3), 1,680(C=O); H
1
NMR: d/ppm = 1.48(d, 3H, CH3), 3.87 (s, 3H, OCH3),
3.91 (q, 1H, CH), 7.23–8.32 (m, 13H, Ar–H), 9.32, 10.21
(2s, 2H, 2NH); Anal. Calc. for C24H22N4O4S (462.52): C,
62.32; H, 4.79; N, 12.11. Found: C, 62.40; H, 4.50; N,
12.20.
2-(6-Methoxynaphthalen-2-yl)-N-(4-(phenylamino)-
phenyl)propanamide (3d)
Yield 70 %; mp 135–137 °C; IR: t/cm-1 = 3,386, 3,301
(2NH), 3,062 (CH–Ar), 2,936 (CH-sp3), 1,651(C=O); H
Synthesis of acyl aminoacid derivatives 5a, b
1
NMR: d/ppm = 1.45 (d, 3H, CH3), 3.85 (s, 3H, OCH3),
3.95 (q, 1H, CH), 7.13–7.87 (m, 15H, Ar–H), 9.65, 10.45
(2s, 2H, 2NH); Anal. Calc. for C26H24N2O2 (396.48): C,
78.76; H, 6.10; N, 7.07. Found: C, 78.60; H, 6.30; N, 7.20.
Equimolar amounts of naproxenoyl chloride (2) (0.01 mol)
and the requisite aminoacids (namely glycine and alanine)
(0.01 mol) in dioxane (20 ml) were treated with pyridine
(0.5 ml). The reaction mixture was heated under reflux for
3 h. The solution was concentrated under vacuum, left to
cool. The resulting solid was filtered off and recrystallized
from ethanol.
Synthesis of sulfonamide derivatives 4a–c
A mixture of 2 (0.01 mol) and the appropriate sulfa drugs
(namely sulfacetanilide, Sulfamethoxazole, and sulfadia-
zine) (0.01 mol) in dioxane (30 ml) was treated with pyr-
idine (0.5 ml). The reaction mixture was heated under
reflux for 3 h. The solution was concentrated under vac-
uum, left to cool. The resulting solid was filtered off and
recrystallized from a mixture of ethanol/diaxone.
2-(2-(6-Methoxynaphthalen-2-yl)propanamido)-
acetic acid (5a)
Yield 80 %; mp 125–126 °C; IR: t/cm-1 = 3,380 (NH),
3,200–2,700 (COOH), 3,075(CH–Ar), 2,945 (CH-sp3),
1,740, 1,675(2C=O); 1H NMR: d/ppm = 1.41 (d, 3H,
CH3), 3.80 (s, 3H, OCH3), 3.86 (q, 1H, CH), 3.95 (d, 2H,
CH2), 7.09–7.74 (m, 6H, Ar–H), 8.25 (s, 1H, NH), 12.5
(hump, 1H, NH); 13C NMR: 18.35 (CH3), 45.28(CH),
48.21 (CH2), 55.43 (OCH3), 105.63 (C-5), 119.28 (C-7),
126.39 (C-4), 126.48 (C-8a), 127.34, 128.89, 129.87,
133.84, 135.68, 157.69, 176.34, 179.64; MS, m/z (%): 287
(M?; 1.2), 257 (4.77), 243 (3.82), 213 (4.98), 199 (3.78),
185 (100), 154 (13.43), and 126 (7.76); Anal. Calc. for
C16H17NO4 (287.31): C, 66.89; H, 5.96; N, 4.88. Found: C,
66.60; H, 5.70; N, 4.70.
N-(4-(N-acetylsulfamoyl)phenyl)-2-(6-methoxynaphthalen-
2-yl)propanamide (4a)
Yield 75 %; mp 230–231 °C; IR: t/cm-1 = 3,325, 3,116
(2NH), 3,052(CH–Ar), 2,977 (CH-sp3), 1,710, 1,681(2C=O);
1H NMR: d/ppm = 1.50 (d, 3H, CH3), 1.88 (s, 3H, COCH3),
3.87 (s, 3H, OCH3), 4.01(q, 1H, CH), 7.14–7.85(m, 10H, Ar–
H), 9.85, 10.56 (2s, 2H, 2NH); 13C NMR: 16.56 (CH3), 18.34
(CH3), 45.43(CH), 55.42 (OCH3), 105.23(C-5), 119.25(C-7),
120.87, 120.88, 125.34, 125.35, 126.34 (C-4), 126.65 (C-8a),
127.35, 128.87, 129.24, 133.67, 135.12, 135.24, 142.54,
157.62, 174.54, 179.45; Anal. Calc. for C22H22N2O5S
(426.49): C, 61.96; H, 5.20; N, 6.57. Found: C, 61.60; H, 5.30;
N, 6.20.
2-(2-(6-Methoxynaphthalen-2-yl)propanamido)
propanoic acid (5b)
Yield 65 %; mp 108–109 °C; IR: t/cm-1 = 3,312 (NH),
3,200–2,750 (COOH), 3,076(CH–Ar), 2,954 (CH-sp3),
1,732, 1,665(2C=O); 1H NMR: d/ppm = 1.42, 1.49 (2d, 6H,
2CH3), 3.87 (s, 3H, OCH3), 3.91, 4.23 (2q, 2H, 2CH),
7.13–7.67 (m, 6H, Ar–H), 8.92, 11.87 (2s, 2H, NH,COOH);
13C-NMR: 16.32 (CH3), 18.25 (CH3), 45.28(CH), 52.21
(CH), 55.43 (OCH3), 105.64 (C-5), 119.23 (C-7), 126.34 (C-
4), 126.45 (C-8a), 127.24, 128.87, 129.54, 133.76, 135.61,
157.67, 176.34, 179.42; Anal. Calc. for C17H19NO4
(301.34): C, 67.76; H, 6.36; N, 4.65. Found: C, 66.80; H,
6.60; N, 4.70.
2-(6-Methoxynaphthalen-2-yl)-N-(4-(N-(5-methylisoxazol-
3-yl)sulfamoyl)phenyl)propanamide (4b)
Yield 80 %; mp 130–131 °C; IR: t/cm-1 = 3,365, 3,254
(2NH), 3,087(CH–Ar), 2,937 (CH-sp3), 1,664 (C=O); H
1
NMR: d/ppm = 1.49(d, 3H, CH3), 2.43 (s, 3H, CH3), 3.86
(s, 3H, OCH3), 3.94 (q, 1H, CH), 4.87 (s, 1H, CH-isox-
azole), 7.15–7.77(m, 10H, Ar–H), 9.45, 10.32 (2s, 2H,
2NH); Anal. Calc. for C24H23N3O5S (465.52): C, 61.92; H,
4.98; N, 9.03. Found: C, 61.60; H, 4.70; N, 9.20.
123

Med Chem Res
Synthesis of bispropionamide derivatives 6a–d
2H, 2CH), 7.13–7.83 (m, 16H, Ar–H), 10.06 (s, 2H, 2NH);
MS, m/z (%): 532 (M?; 100), 347 (35.2), 333 (14.35), 199
(27.22), 182 (1.48),171 (13.71); Anal. Calcd for
C34H32N2O4 (532.63): C, 76.67; H, 6.06; N, 5.26. Found:
C, 77.50; H, 6.20; N, 5.40.
To a solution of the acid chloride 2 (0.01 mol) in dioxane
(20 ml), hydrazine hydrate (0.012 mol) was added. In case
of ethylenediamine, diethylenetriamine, or p-phenylenedi-
amine (0.01 mol), pyridine (0.5 ml) was added. The reac-
tion mixture was heated under reflux for 2 h. The solution
was left to cool. The resulting solid was filtered off and
recrystallized from dioxane.
Synthesis of 2-(1-(6-methoxynaphthalen-2-yl)ethyl)-
1H-benzo[d]imidazole (7)
A mixture of 2 (0.01 mol) and o-phenylenediamine
(0.01 mol) in DMF (20 ml) was heated under reflux for
4 h. The solution was poured into ice-contained HCl, the
obtained product was filtered and crystallized from ethanol:
yield 67 %; mp 211-212 °C; IR: t/cm-1 = 3,225 (NH),
3,065 (CH–Ar), 2,950 (CH-sp3), 1,608 (C=N); 1H NMR: d/
ppm = 1.56 (d, 3H, CH3), 3.77 (s, 3H, OCH3), 4.8 (q, 1H,
CH), 7.20–7.89 (m, 10H, Ar–H), 10.80 (s, 1H, NH); MS,
m/z (%): 302 (M?; 85), 256 (25), 227 (65), 184(71), 151
(100), 133 (78), 94 (82); Anal. Calcd for C20H18N2O
(302.37): C, 79.44; H, 6.00; N, 9.26. Found: C, 79.50; H,
6.30; N, 9.40.
2-(6-Methoxynaphthalen-2-yl)-N0-(2-(6-
methoxynaphthalen-2-yl)propanoyl)propanehydrazide (6a)
Yield 72 %; mp 230–232 °C; IR: t/cm-1 = 3,178 (NH),
3,066 (CH–Ar), 2,943 (CH-sp3), 1,654(C=O); H NMR:
1
d/ppm = 1.45 (d, 6H, 2CH3), 3.75 (s, 6H, 2OCH3), 3.88
(q, 2H, 2CH), 6.98–7.81 (m, 12H, Ar–H), 8.2 (s, 2H, 2NH);
MS, m/z (%): 456 (M?; 2.32), 242 (0.32), 228 (1.12), 212
(100), 184 (13.75), 170 (22.8),128 (2.2); Anal. Calcd for
C28H28N2O4 (456.53): C, 73.66; H, 6.18; N, 6.14. Found:
C, 73.80; H, 6.30; N, 6.20.
N,N0-(ethane-1,2-diyl)bis(2-(6-methoxynaphthalen-2-
yl)propanamide) (6b)
Synthesis of 2-(6-methoxynaphthalen-2-yl)-N-(4-(N-
phenylacetamido)phenyl)propanamide (8)
Yield 76 %; mp 200–202 °C; IR: t/cm-1 = 3,294 (NH),
3,076 (CH–Ar), 2,939 (CH-sp3), 1,651(C=O); 1H NMR: d/
ppm = 1.37 (d, 6H, 2CH3), 3.1 (m, 4H, 2CH2), 3.67 (s, 6H,
2OCH3), 3.87 (q, 2H, 2CH), 7.12–7.80 (m, 12H, Ar–H),
8.1 (s, 2H, 2NH); MS, m/z (%): 484 (M?; 6.41), 300
(10.71), 255 (14.53), 242 (2.52), 228 (33.97), 212 (94.95),
184 (13.3), 171 (100), 100 (3.21); Anal. Calcd for
C30H32N2O4 (484.59): C, 74.36; H, 6.66; N, 5.78. Found:
C, 74.60; H, 6.40; N, 5.80.
A mixture of 3d (0.01 mol), acetyl chloride (0.02 mol),
and pyridine (0.5 ml) in dioxane (20 ml) was heated under
reflux for 4 h. The obtained product was filtered and
crystallized from ethanol: yield 75 %; mp 180–182 °C; IR:
t/cm-1 = 3,280 (NH), 3,085 (CH–Ar), 2,950 (CH-sp3),
1,680, 1,670 (2C=O); 1H NMR: d/ppm=1.59 (d, 3H, CH3),
1.95 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 4.00 (q, 1H, CH),
6.80–7.94 (m, 15H, Ar–H), 10.20 (s, 1H, NH); MS, m/
z (%): 438 (M?; 29.13), 396 (51.46), 227 (61.49), 214
(61.34), 185(97.09), 184 (100), 154 (17.6),128 (7.12);
Anal. Calcd for C28H26N2O3 (438.52): C, 76.69; H, 5.98;
N, 6.39. Found: C, 76.50; H, 5.70; N, 6.40.
N,N0-(2,20-azanediylbis(ethane-2,1-diyl))bis(2-(6-
methoxynaphthalen-2-yl)propanamide) (6c)
Yield 68 %; mp 220–222 °C; IR: t/cm-1 = 3,317 (NH),
3,075 (CH–Ar), 2,939 (CH-sp3), 1,651(C=O); H NMR:
1
Synthesis of 2-(6-methoxynaphthalen-2-yl)-N-(4aH-
phenothiazin-7-yl)propanamide (9)
d/ppm = 1.29 (d, 6H, 2CH3), 3.0–3.14 (m, 8H, 4CH2),
3.76 (s, 6H, 2OCH3), 3.87 (q, 2H, 2CH), 7.12–7.81(m,
12H, Ar–H), 8.14, 9.18 (2 br, 3H, 3NH); Anal. Calcd for
C32H37N3O4 (527.65): C, 72.84; H, 7.07; N, 7.96. Found:
C, 72.50; H, 7.20; N, 7.80.
A mixture of 3d (0.01 mol), sulfur metal and iodine
(0.01 mol) in dichlorobenzene (20 ml) was heated under
reflux for 6 h. The obtained product was filtered and
crystallized from ethanol: yield 65 %; mp 305–306 °C; IR:
t/cm-1 = 3,312, 3,224 (2NH), 3,079 (CH–Ar), 2,940 (CH-
N,N0-(1,4-phenylene)bis(2-(6-methoxynaphthalen-2-
yl)propanamide) (6d)
1
sp3), 1,650 (C=O); H NMR: d/ppm = 1.48 (d, 3H, CH3),
3.84 (s, 3H, OCH3), 3.92 (q, 1H, CH), 7.18–7.85 (m, 13H,
Ar–H), 10.12, 12.13 (2s, 2H, 2NH); Anal. Calcd for
C26H22N2O2S (426.53): C, 73.21; H, 5.20; N, 6.57. Found:
C, 73.44; H, 5.45; N, 6.80.
Yield 74 %; mp 260–262 °C; IR: t/cm-1 = 3,302 (NH),
3,065 (CH–Ar), 2,943 (CH-sp3), 1,666(C=O); H NMR:
1
d/ppm = 1.48 (d, 6H, 2CH3), 3.87 (s, 6H, 2OCH3), 3.96 (q,
123

Med Chem Res
Synthesis of oxazolone derivatives 10a–d
heated under reflux for 2 h. The obtained product was fil-
tered and crystallized from ethanol: yield 64 %; mp
140–142 °C; IR: t/cm-1 = 3,300 (NH), 3,069 (CH-Ar),
2,970 (CH-sp3), 1,675 (C=O); 1H NMR: d/ppm = 1.49 (d,
3H, CH3), 2.23 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 3.93 (q,
1H, CH), 7.18–7.89 (m, 15H, Ar–H ? CH=), 8.87 (s, 1H,
1NH); 11.4 (s, 1H, 1NH); Anal. Calcd for C30H27ClN2O3
(499.0): C, 72.21; H, 5.45; N, 5.61. Found: C, 72.40; H,
5.60; N, 5.70.
A solution of 5a (0.01 mol) in acetic anhydride (20 ml)
was treated with the requisite aldehyde (0.01 ml) and fused
sodium acetate (0.5 g). The reaction mixture was heated
under reflux for 2 h. The obtained product was filtered and
crystallized from ethanol:
4-(4-Chlorobenzylidene)-2-(1-(6-methoxynaphthalen-2-
yl)ethyl)oxazol-5(4H)-one (10a)
Synthesis of 1,2,4-triazoles 12 and 13
Yield 72 %; mp 240–242 °C; IR: t/cm-1 = 3,075 (CH–
Ar), 2,950 (CH-sp3), 1,730 (C=O); 1H NMR: d/
ppm = 1.47 (d, 3H, CH3), 3.81 (s, 3H, OCH3), 3.90 (q, 1H,
CH), 7.08–7.89 (m, 11H, Ar–H ? CH=); MS, m/z (%): 391
(M?; 8.40), 227 (5.76), 197 (100), 181 (5.4), 154 (4.92),
127 (13.57); Anal. Calcd for C23H18ClNO3 (391.85): C,
70.50; H, 4.63; N, 3.57. Found: C, 70.40; H, 4.60; N, 3.70.
A mixture of 5a (0.01 mol) and thiosemicarbazide or
thiocarbohydrazide (0.012 mol) was fused at 180 °C for
0.5 h. Left to cool, the solid product that remained was
triturated with ethanol (20 ml), then filtered and crystal-
lized from ethanol/dioxane.
2-(6-Methoxynaphthalen-2-yl)-N-((5-thioxo-4,5-dihydro-
1H-1,2,4-triazol-3-yl)methyl)propanamide (12)
4-(4-Fluorobenzylidene)-2-(1-(6-methoxynaphthalen-2-yl)
ethyl)oxazol-5(4H)-one (10b)
Yield 62 %; mp 235–236 °C; IR: t/cm-1 = 3,370, 3,300
(3NH), 3,071 (CH–Ar), 2,980 (CH-sp3), 1,650 (C=O),
1,223 C=S; Anal. Calcd for C17H18N4O2S (342.42): C,
59.63; H, 5.30; N, 16.36. Found: C, 59.40; H, 5.40; N,
16.50.
Yield 72 %; mp 190–192 °C; IR: t/cm-1 = 3,072 (CH–Ar),
2,954 (CH-sp3), 1,727 (C=O); 1H NMR: d/ppm = 1.46 (d,
3H, CH3), 3.84 (s, 3H, OCH3), 3.95 (q, 1H, CH), 7.1–7.84 (m,
11H, Ar–H ? CH=); Anal. Calcd for C23H18FNO3 (375.39):
C, 73.59; H, 4.83; N, 3.73. Found: C, 73.40; H, 4.60; N, 3.80.
N-((4-Amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-
yl)methyl)-2-(6-methoxynaphthalen-2-yl)propanamide (13)
2-(1-(6-Methoxynaphthalen-2-yl)ethyl)-4-(4-
methylbenzylidene)oxazol-5(4H)-one (10c)
Yield 63 %; mp 190–192 °C; IR: t/cm-1 = 3,400, 3,300
(NH2, NH), 3,069 (CH–Ar), 2,970 (CH-sp3), 1,656 (C=O),
1,221 C=S; 1H NMR: d/ppm = 1.45 (d, 3H, CH3), 3.80 (s,
3H, OCH3), 3.90 (q, 1H, CH), 4.29–4.36 (m, 2H, CH2),
5.56 (s, 2H, NH2), 7.13–7.82 (m, 6H, Ar–H), 8.51 (s, 1H,
NH), 13.5 (s, 2H, NH-triazole); 13C-NMR: 18.34 (CH3),
45.43 (CH), 46.21 (CH2), 55.54 (OCH3), 105.23 (C-5),
119.34 (C-7), 126.23 (C-4), 126.54 (C-8a), 127.234,
128.86, 129.45, 133.65, 135.23, 156.21, 158.20, 174.34,
187.23 (C=S); Anal. Calcd for C17H19N5O2S (357.43): C,
57.12; H, 5.36; N, 19.59. Found: C, 57.40; H, 5.60; N,
19.70.
Yield 63 %; mp 180–182 °C; IR: t/cm-1 = 3,071 (CH–Ar),
2,958 (CH-sp3), 1,732 (C=O); H NMR: d/ppm = 1.48 (d,
3H, CH3), 2,32 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 3.90 (q, 1H,
CH), 7.13–7.88 (m, 11H, Ar–H ? CH=); Anal. Calcd for
C24H21NO3 (371.43): C, 77.61; H, 5.70; N, 3.77. Found: C,
77.80; H, 5.50; N, 3.80.
1
4-(4-Methoxybenzylidene)-2-(1-(6-methoxynaphthalen-2-
yl)ethyl)oxazol-5(4H)-one (10d)
Yield 64 %; mp 175–176 °C; IR: t/cm-1 = 3,070 (CH–Ar),
1
2,958 (CH-sp3), 1,731 (C=O); H NMR: d/ppm = 1.47 (d,
3H, CH3), 3.79, 3.82 (s, 6H, 2OCH3), 3.98 (q, 1H, CH),
7.14–7.88 (m, 11H, Ar–H ? CH=); Anal. Calcd for C24H21
NO4 (387.43): C, 74.4; H, 5.46; N, 3.62. Found: C, 74.50; H,
5.50; N, 3.80.
Antimicrobial activity
Chemical compounds were individually tested against a
panel of Gram ?ve and gram-negative bacterial pathogens
and fungi. Antimicrobial tests were carried out by the agar
well diffusion method using 100 ll of suspension con-
taining 1 9 108 CFU/ml of pathological tested bacteria and
1 9 106 CFU/ml of yeast spread on nutrient agar (NA) and
Sabouraud dextrose agar (SDA) media, respectively. After
the media had cooled and solidified, wells (10 mm in
Synthesis of 3-(4-chlorophenyl)-2-(2-(6-methoxynaphtha-
len-2-yl)propanamido)-N-p-tolylacrylamide (11)
A solution of 10a (0.01 mol) in ethanol (30 ml) was treated
with p-toluidine (0.01 ml). The reaction mixture was
123

Med Chem Res
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diameter) were made in the solidified agar and loaded with
100 ll of tested compound solution prepared by dissolving
1 mg of the chemical compound in 1 ml of dimethyl
sulfoxide (DMSO). The inoculated plates were then incu-
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using DMSO employed for dissolving the tested com-
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microbial activities were expressed as inhibition diameter
zones in millimeters (mm). The experiment was carried out
in triplicate, and the average zone of inhibition was
calculated.
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ˇ
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then evaluated using the twofold serial dilution technique.
Twofold serial dilutions of the tested compounds solutions
were prepared using the proper nutrient broth. The final
concentration of the solutions were 100, 50, 25, 12.5, and
6.25 lg ml-1. The tubes were then inoculated with the test
organisms, grown in their suitable broth at 37 °C for 24 h
for tested microorganisms (1 9 108 CFU/ml for bacteria
and 1 9 106 CFU/ml of yeast), each 5 ml received 0.1 ml
of the above inoculum and incubated at 37 °C for 24 h.
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