Synthesis of novel N-(naphthalen-1-yl)propanamide derivatives and evaluation their antimicrobial activity

Article abstract of DOI:10.1080/10426507.2019.1657428

New N-(naphthalen-1-yl)propanamide was synthesized and studied for their antimicrobial activity. The final compounds were procured by reacting N-(naphthalen-1-yl)propanamide with some 2-mercapto aryl or dithiocarbamate salt derivatives. Their structures w

Full text of DOI:10.1080/10426507.2019.1657428

Phosphorus, Sulfur, and Silicon and the Related Elements
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Synthesis of novel N-(naphthalen-1-
yl)propanamide derivatives and evaluation their
antimicrobial activity
Asaf E. Evren, Leyla Yurttas & Meral Yılmaz-Cankilic
To cite this article: Asaf E. Evren, Leyla Yurttas & Meral Yılmaz-Cankilic (2019): Synthesis of
novel N-(naphthalen-1-yl)propanamide derivatives and evaluation their antimicrobial activity,
Phosphorus, Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2019.1657428
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2019.1657428
Synthesis of novel N-(naphthalen-1-yl)propanamide derivatives and evaluation
their antimicrobial activity
Asaf E. Evrena,b , Leyla Yurttasa , and Meral Yılmaz-Cankilicc
b
aDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskisehir, Turkey; Vocational School of Health Services,
c
Bilecik S¸eyh Edebali University, Bilecik, Turkey; Department of Biology, Faculty of Sciences, Eskis¸ehir Technical University, Eskisehir, Turkey
ABSTRACT
ARTICLE HISTORY
Received 13 June 2018
Accepted 15 August 2019
New N-(naphthalen-1-yl)propanamide was synthesized and studied for their antimicrobial activity.
The final compounds were procured by reacting N-(naphthalen-1-yl)propanamide with some 2-mer-
capto aryl or dithiocarbamate salt derivatives. Their structures were determined by 1H-NMR and 13C-
NMR spectroscopy and LC-MS/MS spectral data. The synthesized compounds were investigated for
their antimicrobial activities against 10 bacteria and 10 fungi species. All compounds showed notable
activity. Especially, compounds 2-[(5-methyl-1,3,4-thiadiazol-2-yl)thio]-N-(naphthalen-1-yl)propana-
mide (2a), 2-(benzothiazol-2-ylthio)-N-(naphthalen-1-yl)propenamide (2b), 2-[(1-methyl-1H-imidazol-
2-yl)thio]-N-(naphthalen-1-yl)propanamide (2c), and N-(naphthalen-1-yl)-2-[(5-nitro-1H-benzimidazol-
2-yl)thio]propanamide (2e) exhibited antifungal activity against at least one fungus at the half
potency of ketoconazole. Also, 2-[(1-methyl-1H-imidazol-2-yl)thio]-N-(naphthalen-1-yl)propanamide
(2c), N-(naphthalen-1-yl)-2-[(5-nitro-1H-benzimidazol-2-yl)thio]propanamide (2e) and 2-[(4-methyl-
4H-1,2,4-triazol-3-yl)thio]-N-(naphthalen-1-yl)propanamide (2f) showed anti-gram-positive bacterial
activity at the half potency of chloramphenicol. Only one compound, 2-(benzothiazol-2-ylthio)-N-
(naphthalen-1-yl)propanamide (2b) displayed anti-gram-negative bacterial activity against Yersinia
enterocolitica (Y53).
KEYWORDS
Naphthalene; propanamide;
antimicrobial activity
GRAPHICAL ABSTRACT
Introduction
In recent years, global mortality and morbidity rates have
extensively increased due to the emergence of antimicrobial
resistance developed by certain bacteria and fungi.[6,7] The
World Health Organization (WHO) released a list of 12 bac-
teria and bacterial families that are often implicated in
MDR. One of the most concerning microorganisms in this
list is Staphylococcus aureus, since this bacterium is known
to be potentially life-threatening, particularly by causing
acquired infections in hospitals. Outside of medical centers,
these pathogenic microorganisms also pose risks not only to
patients, but also to healthy individuals in society.[8,9]
Likewise, Candida species, especially Candida albicans have
been reported to develop resistance to chemotherapeutic
agents, as presented in several reports.[10–13] To combat
these health risks, one area of focus is the synthesis of new
antimicrobial agents to increase therapeutic alternatives in
cases of MDR.[14,15]
In nature, multicellular organisms live harmoniously with
microorganisms. If this harmony gets disrupted, an inflam-
matory response can occur depending on the pathogenic
microorganisms present. These inflammatory responses
remove harmful stimuli for the purposes of protection.
Some pathogenic infections are also related to contagious
diseases. These diseases can be transmitted through environ-
mental factors, such as water, food, and air.[1–3] Therefore,
researchers focus on preventing the spread of disease, con-
trolling disease transmission, or killing the pathogenic
microbes responsible for infection.[4] Recently, one major
threat to human health surrounding pathogenic microorgan-
isms is the development of multidrug resistance (MDR),
commonly known as drug-resistance (XDR) and pan-drug
resistance (PDR).[5]
CONTACT Asaf E. Evren
asafevrimevren@anadolu.edu.tr
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskisehir,
26470 Turkey.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2019.1657428.
ß 2019 Taylor & Francis Group, LLC

2
A. E. EVREN ET AL.
According to the literature, the naphthalene ring system 10.09–11.09 ppm indicated the N-H proton of propanamide.
has been demonstrated to harbor various therapeutic prop- The appearance of singlets, doublets, triplets, and/or multi-
erties, such as antimycobacterial,[16] antibacterial,[17] antifun- plet peaks at d 6.71–8.68 ppm was due to the aromatic pro-
tons. The 13C-NMR spectra of compounds showed signals at
d 110.10–168.27 ppm for aromatic carbon. Carbonyl (C ¼ O)
carbon was seen at d 170.18–171.15 ppm and thiocarbonyl
(C ¼ S) carbon was seen at d 190.81–194.68 ppm. M þ 1
peaks in LC-MS/MS spectra were compatible with the calcu-
lated molecular weight of the target compounds (2a–2k).
gal,[18–20] anticonvulsant,[21] anticancer,[22,23] tyrosine kinase
inhibition,[24] DNA protective functions,[25] inhibition of
tyrosyl-tRNA synthetase,[26] anti-inflammatory,[27,28] herbici-
[30]
dal,[29] and anti-HIV
activities. In particular, various N-
(naphthalen-1/2-yl)amide derivatives show remarkable anti-
microbial activity.[31–34] Tolnaftate and naftifine are two
examples of antimicrobial agents in this group that contain
the naphthalene ring as shown in Figure S1.[35–38]
Prediction of ADME parameters
In addition to compounds containing the naphthalene
ring, (benz)azole derivatives like imidazole, triazole, thiadia-
zole benzimidazole, and benzothiazole have been reported to
exhibit strong antibacterial and antifungal activities.[39–44]
Furthermore, (benz)azole derivatives containing a naphtha-
lene group have also been tested for their antimicrobial
activity.[45–48] Specifically, N-methylimidazole derivatives
have been of particular interest because they have been
shown to exhibit strong antibacterial activity specifically
against S. aureus and drug-resistant S. aureus.[49,50]
ADME (Absorption, Distribution, Metabolism, and
Excretion) properties of the synthesized compounds (2a–2k)
and reference drugs (chloramphenicol and ketoconazole)
were calculated using Molinspiration software and Molsoft
software.[51,52] The Log P values were found between 2.70 and
5.42 for the synthesized compounds. For all molecules, num-
ber of hydrogen bond donor (HBD) was stated as 1, except
compounds 2d and 2e. Also, hydrogen bond acceptor (HBA)
for all compounds was determined between 2 and 5. The
number of stereo centers was stated as 1 for the synthesized
compounds. The results are in the congruent range according
to Lipinski’s rule of 5. Even if there is no exact finding in prac-
tice, these scores are in harmony with the activity potential of
the compounds. Drug-likeness model scores (DLMS) were
found between ꢀ0.65 and 1.47. All findings were shown in
Table S1 (Supplemental Materials). According to these results,
all compounds have a good pharmacokinetic profile. These
findings predict that these synthesized compounds may be
considered as oral antimicrobial agents.
Based on these preliminary findings, this research was
directed towards the synthesis and development of novel N-
(naphthalen-1-yl)propanamide derivatives and investigation
of their antifungal and antibacterial activities.
Results and discussion
Chemistry
In this work, we synthesized 11 compounds that included N-
(naphthalen-1-yl)propanamide in the core structure. The syn-
thesis reaction was carried out via two steps. In the first step,
naphthalen-1-amine was acylated with 2-chloropropionyl
chloride. Then the obtained product (1) was reacted with 2-
mercapto aryl derivatives to gain the final compounds 2a–2g.
And compound (1) was also reacted with dithiocarbamate salt
derivatives to obtain final compounds 2h–2k as shown in
Scheme 1. All the synthesized compounds were fully charac-
terized by their analytical and spectral data.
Antimicrobial activity
The antimicrobial activity of the compounds 2a–2k was
determined by finding MIC values shown in Table S2
(Supplemental Materials). And their antimicrobial activity
was evaluated versus the standard drugs, chloramphenicol
and ketoconazole.
All compounds exhibited antifungal activity. Particularly,
compounds 2a, 2b, and 2e (MIC: 187.5 mg/ml) were found
more effective than the synthesized compounds against C.
albicans (ATCC 90028), and their anticandidal activity was
determined as half the potency of ketoconazole (MIC:
93.75 mg/ml). Also, compound 2c displayed notable antican-
didal activity against Candida krusei (ATCC 6258) at half
the potency of ketoconazole. Compounds 2a, 2b, 2g, 2h,
and 2i exhibited anticandidal activity at same concentration
(MIC: 187.5 mg/ml) against Candida glabrata (ATCC 90030).
Except compound 2e, all compounds showed antifungal
activity at the quarter potency of ketoconazole against
Fusarium solani (obtained from our laboratory).
Compounds 2a, 2c, 2d, 2f, 2g, 2i, 2j, and 2k displayed anti-
fungal activity against Fusarium moniliforme (NRRL 2374)
at the quarter potency of ketoconazole.
1
The H-NMR spectra of synthesized compounds (2a–2k)
showed doublet or multiplet signals at d 1.55–1.81 ppm for
methyl (CH3) proton of propanamide. The quartets or
multiplet peaks seen at d 4.41–5.18 ppm for methylene (CH)
proton of propanamide. The broad single peak seen at d
Compounds 2a, 2c, and 2i (MIC: 375 mg/ml) were stated
more effective than the other synthesized compounds
against Penicillium chrysogenum (ATCC 10106). Compounds
Scheme 1. The synthesis diagram of the compounds. Reactions & conditions: (a)
TEA, THF, ClCOCH2Cl, 0–5 ꢁC, then r.t 3 h; (b) Acetone, Potassium carbonate, rt;
(c) Acetone, rt.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
2a, 2b, 2c, 2d, 2i, and 2j (MIC: 375 mg/ml) were found more Chemicals (Merck KGaA, Darmstadt, Germany). All melting
active than the other compounds against Penicillium citri- points (m.p.) were determined by MP90 digital melting
num (ATCC 9849). All compounds (2a–2k) exhibited anti-
fungal activity at the same concentration (MIC: 375 mg/ml)
against Penicillium expansum (ATCC 24692). Compounds
2a–2i displayed anticandidal activity at the same concentra-
tion (MIC: 375 mg/ml) against Candida parapsilosis (ATCC
22019). Compounds 2a, 2b, and 2c (MIC: 375 mg/ml) were
stated more active than the other compounds against
Aspergillus niger (ATCC 9807). But the activity results
described in this paragraph, unfortunately, are not meaning-
ful enough to explain the activity-structure relationship.
According to the antifungal activity results, the sulfur
bridged derivatives (2a–2g) were more active than dithiocar-
bamate bridged derivatives (2h–2k). The synthesized com-
pounds showed slightly better activity against C. albicans
(ATCC 90028) than the other fungi. Especially, 2-methyl-
thiadiazol-2-yl (2a) and N-methyl-imidazol-2-yl (2c) substi-
tutions at the second position on propanamide increased the
activity. Their log P values, molecular weights and molecular
volumes correlate with the properties of ketoconazole.
However, benzothiazole-2-yl (2b) and N-(naphthalen-1-yl)-
point apparatus (Mettler Toledo, Ohio, USA) and were
uncorrected. All reactions were monitored by thin-layer
chromatography (TLC) using Silica Gel 60 F254 TLC plates
(Merck KGaA, Darmstadt, Germany). Spectroscopic data
were recorded with the following instruments: IR Shimadzu
8400S spectrophotometer (Shimadzu, Tokyo, Japan), 1H
NMR (nuclear magnetic resonance) Bruker DPX 300 FT-
NMR spectrometer, 13C NMR, Bruker DPX 75 MHz spec-
trometer (Bruker Bioscience, Billerica, MA, USA) M þ 1
peaks were determined by Shimadzu 8040 LC/MS/MS sys-
tem (Shimadzu, Tokyo, Japan).
Materials and methods
General procedure for the synthesis of 2-chloro-N-(naph-
thalen-1-yl)propanamide derivatives (1)
Naphthalen-1-amine (0.05 mol, 7.16 g) and triethylamine
(0.05 mol, 8.47 mL) were dissolved in THF (150 mL) with a
constant stirring at 0–5 ꢁC, then 2-chloropropyl chloride
(0.05 mol, 5.82 mL) was added dropwise gradually to this
solution. The reaction mixture thus obtained was further
stirred for 2 h at 0–5 ꢁC. The reaction was monitored by
TLC. After the solvent was vaporized to dryness, the solid
was filtered and washed with water. Finally, the raw product
was recrystallized from ethanol.
2-[(5-nitro-1H-benzimidazol-2-yl)thio]propanamide
(2e)
substitutions at same position may also increase antifungal
activity. Also, the findings proved that the electron with-
drawing group (2c) has positively increased antibacterial
activity in comparison with electron donating group (2d).
All compounds showed antibacterial activity. Especially,
compounds 2c, 2e, and 2f displayed antibacterial activity
against S. aureus (ATCC 6538) at half potency of chloram-
phenicol (MIC: 93.75 mg/ml). Also, compound 2b (MIC:
187.5 mg/ml) was determined as the most active compound
against Yersinia enterocolitica (Y53), but no more than
chloramphenicol (MIC: 93.75 mg/ml). Additionally, com-
pound 2c demonstrated good anti-gram-positive bacterial
activity in comparison with the other synthesized com-
pounds against Bacillus cereus (ATCC 10876) and Bacillus
subtilis (NRRL NRS-744). But, all compounds presented the
lowest activity against Enterococcus faecalis (ATCC 51299),
Klebsiella pneumoniae (ATCC 700603), and Micrococcus
luteus (NRRL B-4375). On the other hand, compounds 2a,
2b, 2e, 2g, 2h, and 2j displayed the lower activity than
chloramphenicol against Listeria monocytogenes (ATCC
19111). Also, compounds 2c and 2e increased the antibac-
terial activity against Escherichia coli (ATCC 25922).
2-(Substituted thio)-N-(naphthalen-1-yl)propanamide
derivatives (2a–2g)
A mixture of N-(naphthalen-1-yl)propanamide (1.50 mmol,
0.35 g) and mercapto derivatives (1.50 mmol) were dissolved
in acetone (15 ml). For catalytic purposes, potassium carbon-
ate (1.50 mmol, 0.21 g) was added to the round bottom flask.
After 2 h, the reaction was monitored by TLC. Ultimately
the solvent was vanished to dryness, the solid was filtered
and washed with water. The final products were recrystal-
lized from ethanol.
1-(Naphthalen-1-ylamino)-1-oxopropan-2-yl substituted-1-
carbodithioate derivatives (2h–2k)
A mixture of N-(naphthalen-1-yl)propanamide (1.50 mmol,
0.35 g) and dithiocarbamate derivatives (1.50 mmol) were
dissolved in acetone (15 mL). After 4 h, the reaction was
monitored by TLC. Ultimately the solvent was vanished to
dryness, the solid was filtered and washed with water. The
In the antibacterial activity investigation, the sulfur
bridged derivatives (2a–2g) were more active than dithiocar-
bamate bridged derivatives (2h–2k). In particularly, N-
methyl-imidazol-2-yl (2c) substitution exhibited positively final products were recrystallized from ethanol.
effect on antibacterial activity. In general, the activity against
gram-positive bacteria was found greater than the activity
against gram-negative bacteria.
2-[(5-Methyl-1,3,4-thiadiazol-2-yl)thio]-N-(naphthalen-1-
yl)propanamide (2a)
1
m. p. 63–66 ꢁC, yield 73%, H-NMR (300 MHz, DMSO-d6,
Experimental
ppm) d 1.73 (d, J ¼ 6.96 Hz, 3H, CH3), 2.71 (s, 3H, thiadia-
zole-CH3), 4.90–4.97 (q, J1 ¼ 6.88 Hz, J2 ¼ 14.62 Hz, H,
Chemistry
CH), 7.48–7.58 (m, 3H, Ar-H), 7.70 (d, J ¼ 7.17 Hz, H, Ar-
All chemicals were purchased from Sigma-Aldrich Chemical H), 7.79 (d, J ¼ 8.1 Hz, H, Ar-H), 7.93–7.96 (m, H, Ar-H),
Co (Sigma-Aldrich Corp., St. Louis, MO, USA) and Merck 8.08 (d, J ¼ 7.74 Hz, H, Ar-H), 10.41 (brs, H, NH). 13C-

4
A. E. EVREN ET AL.
NMR (75 MHz, DMSO-d6, ppm) 15.73 (CH3), 19.18 (CH3), J ¼ 7.07 Hz, 3H, CH3), 5.02–5.09 (q, J1 ¼ 7.05 Hz, J2
¼
47.63 (CH), 122.30, 123.03, 126.01, 126.21, 126.49, 126.60,
133.38, 134.16, 163.31, 167.07, 170.18 (C ¼ O). For
C16H15N3OS2 calculated: HRMS (m/z): [M þ 1]þ calculated
330.0729; found 330.0724.
14.16 Hz, H, CH), 7.49–7.74 (m, 5H, Ar-H), 7.91 (d,
J ¼ 7.80 Hz, 2H, Ar-H), 8.00–8.04 (dd, J1 ¼ 2.17 Hz, J2
¼
8.85 Hz, H, Ar-H), 8.25–8.27 (m, H, Ar-H), 8.37 (s, H, Ar-
H), 11.09 (brs, H, NH), 12.45 (brs, H, NH). 13C-NMR
(75 MHz, DMSO-d6, ppm) 18.53 (CH3), 44.62 (CH), 110.79,
113.94, 117.06, 120.60, 122.78, 125.38, 126.13, 126.31,
126.52, 127.47, 128.67, 133.92, 134.12, 141.58, 141.99,
147.12, 159.18, 171.15 (C ¼ O). For C20H16N4O3S calculated:
HRMS (m/z): [M þ 1]þ calculated 393.1016; found 393.1020.
2-(Benzothiazol-2-ylthio)-N-(naphthalen-1-yl)propana-
mide (2b)
m. p. 126–128 ꢁC, yield 70%, IR (KBr) Vmax (cmꢀ1): 3334
(N-H), 1674 (C ¼ O), 1541–1427 (C ¼ C and C ¼ N). 1H-
NMR (300 MHz, DMSO-d6, ppm) d 1.81 (d, J ¼ 6.99 Hz, 3H,
CH3), 5.11–5.18 (m, H, CH), 7.41 (t, J ¼ 7.58 Hz, H, Ar-H),
7.49–7.53 (m, 4H, Ar-H), 7.71 (d, J ¼ 7.38 Hz, H, Ar-H),
2-[(4-Methyl-4H-1,2,4-triazol-3-yl)thio]-N-(naphthalen-1-
7.80 (d, J ¼ 8.1 Hz, H, Ar-H), 7.96 (d, J ¼ 7.56 Hz, 2H, Ar- yl)propanamide (2f)
1
m. p. 93–96 ꢁC, yield 76%, H-NMR (300 MHz, DMSO-d6,
ppm) d 1.64 (d, J ¼ 6.78 Hz, 3H, CH3), 3.62 (s, 3H, triazole-
CH3), 4.64 (q, J1 ¼ 6.62 Hz, J2 ¼ 13.46 Hz, H, CH),
7.53–7.56 (m, 3H, Ar-H), 7.71 (d, J ¼ 7.2 Hz, H, Ar-H), 7.78
(d, J ¼ 8.31, H, CH3), 7.92–7.95 (m, H, Ar-H), 8.03–8.11 (m,
H, Ar-H), 8.68 (s, H, Ar-H), 10.38 (brs, H, NH). 13C-NMR
(75 MHz, DMSO-d6, ppm) 18.95 (CH3), 31.56 (triazole-
CH3), 46.71 (CH3), 122.07, 123.03, 126.01, 126.09, 126.46,
126.58, 128.61, 133.46, 134.15, 143.11, 147.02, 148.22, 170.62
(C ¼ O). For C16H16N4OS calculated: HRMS (m/z):
[M þ 1]þ calculated 313.1118; found 313.1120.
H), 8.06 (d, J ¼ 7.95 Hz, H, Ar-H), 8.12 (d, J ¼ 7.41 Hz, H,
Ar-H), 10.47 (brs, H, NH). 13C-NMR (75 MHz, DMSO-d6,
ppm) 19.33 (CH3), 47.41 (CH), 121.65, 122.33, 122.43,
123.02, 125.23, 126.02, 126.21, 126.44, 126.58, 128.31,
128.63, 133.43, 134.15, 135.36, 153.08, 165.61, 170.27
(C ¼ O). For C20H16N2OS2 calculated: HRMS (m/z):
[M þ 1]þ calculated 365.0777; found 365.0777.
2-[(1-Methyl-1H-imidazol-2-yl)thio]-N-(naphthalen-1-yl)pro-
panamide (2c)
1
m. p. 68–72 ꢁC, yield 82%, H-NMR (300 MHz, DMSO-d6,
ppm) d 1.55 (d, J ¼ 6.96 Hz, 3H, CH3), 3.68 (s, 3H, imid-
azole-CH3), 4.51–4.58 (q, J1 ¼ 6.74 Hz, J2 ¼ 13.71 Hz, H,
CH), 7.25 (s, H, Ar-H), 7.46–7.56 (m, 4H, Ar-H), 7.71–7.78
(m, 2H, Ar-H), 7.92–7.95 (m, H, Ar-H), 8.05 (d, J ¼ 7.05 Hz,
H, Ar-H), 10.58 (brs, H, NH). 13C-NMR (75 MHz, DMSO-
d6, ppm) 18.44 (CH3), 34.17 (CH3), 46.90 (CH), 121.73,
123.07, 124.94, 125.87, 126.01, 126.40, 126.54, 127.84,
128.01, 128.59, 133.63, 134.15, 138.73, 170.85 (C ¼ O). For
C17H17N3OS calculated: HRMS (m/z): [M þ 1]þ calculated
312.1165; found 312.1165.
N-(naphthalen-1-yl)-2-(phenyl thio)propanamide (2g)
1
m. p. 91–93 ꢁC, yield 73%, H-NMR (300 MHz, DMSO-d6,
ppm) d 1.55 (d, J ¼ 6.93 Hz, 3H, CH3), 4.41 (q, J1 ¼ 6.88 Hz,
J2 ¼ 14.12 Hz, H, CH), 7.32–7.42 (m, 3H, Ar-H), 7.49–7.62
(m, 6H, Ar-H), 7.78 (d, J ¼ 8.13 Hz, H, Ar-H), 7.84–7.86 (m,
H, Ar-H), 7.91–7.94 (m, H, Ar-H), 10.10 (brs, H, NH). 13C-
NMR (75 MHz, DMSO-d6, ppm) 18.35 (CH3), 46.25 (CH),
122.42, 123.06, 125.99, 126.04, 126.32, 126.52, 127.92,
128.56, 129.57, 132.23, 133.58, 134.14, 171.25 (C ¼ O). For
C19H17NOS calculated: HRMS (m/z): [M þ 1]þ calculated
308.1104; found 308.1102.
2-[(5-Methoxy-1H-benzimidazol-2-yl)thio]-N-(naphthalen-1-
yl)propanamide (2d)
1
m. p. 124–126 ꢁC, yield 85%, H-NMR (300 MHz, DMSO-d6,
ppm) d 1.70–1.73 (m, 3H, CH3), 3.74 and 3.79 (2 s, 3H, O-
CH3), 4.94–5.02 (m, H, CH), 6.71–6.75 (m, H, Ar-H),
6.83–6.87 (m, H, Ar-H), 7.05–7.08 (m, H, Ar-H), 7.49–7.60
(m, 3H, Ar-H), 7.67–7.96 (m, 3H, Ar-H), 8.07–8.18 (m, H,
Ar-H), 10.73 (brs, H, NH), 12.42 (brs, H, NH). 13C-NMR
(75 MHz, DMSO-d6, ppm) 18.68 (CH3), 45.25 (CH), 55.07
(OCH3), 110.17, 110.45, 111.61, 121.08, 122.60, 122.80,
123.01, 125.63, 126.53, 128.65, 133.57, 133.72, 134.12,
148.64, 156.14, 168.27, 170.90 (C ¼ O). For C21H19N3O2S
calculated: HRMS (m/z): [M þ 1]þ calculated 378.1271;
found 378.1274.
1-(Naphthalen-1-ylamino)-1-oxopropan-2-yl piperidine-1-
carbodithioate (2h)
1
m. p. 102–104 ꢁC, yield 75%, H-NMR (300 MHz, DMSO-d6,
ppm) d 1.61 (brs, 6H, piperidine-CH2), 1.70 (d, J ¼ 7.11 Hz,
3H, CH3), 3.91 (s, 2H, piperidine-CH2), 4.23 (s, 2H, piperi-
dine-CH2), 5.00 (q, J ¼ 7.15 Hz, H, CH), 7.48–7.57 (m, 3H,
Ar-H), 7.7 (d, J ¼ 7.29 Hz, H, Ar-H), 7.79 (d, J ¼ 8.13 Hz, H,
Ar-H), 7.93–7.96 (m, H, Ar-H), 8.14 (d, J ¼ 8.19 Hz, H, Ar-
H), 10.25 (brs, H, NH). 13C-NMR (75 MHz, DMSO-d6,
ppm) 18.75 (CH3), 23.96 (piperidine-CH2), 25.71 (piperi-
dine-CH2), 26.32 (piperidine-CH2), 50.92 (CH), 51.68
(piperidine-CH2), 52.64 (piperidine-CH2), 122.28, 123.16,
126.01, 126.37, 126.53, 128.40, 128.61, 133.73, 134.18, 170.81
(C ¼ O), 190.81 (C ¼ S). For C19H22N2OS2 calculated:
N-(naphthalen-1-yl)-2-[(5-nitro-1H-benzimidazol-2-yl)thio]-
propanamide (2e)
m. p. 88–90 ꢁC, yield 80%, IR (KBr) Vmax (cmꢀ1): 3205 (N-
H), 1670 (C ¼ O), 1558–1404 (C ¼ C and C ¼ N), 1550–1340
HRMS
(m/z):
[M þ Na]þ
calculated
381.1066;
(NO2). 1H-NMR (300 MHz, DMSO-d6, ppm) d 1.72 (d, found 381.1075.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
1-(Naphthalen-1-ylamino)-1-oxopropan-2-yl morpholine-4- of 3 to 7 d growing at 30 ꢁC on a PD agar substrate were
carbodithioate (2i)
used for the preparation of fungal spore suspensions. Sterile
0.1% Tween 80 was used for the rinsing of the spores and
their further dilution to about 106 CFU/mL was performed
in accordance with the procedural recommendations
of CLSI.[53]
Minimum inhibitory concentration (MIC) of the substan-
ces was determined by a serial dilution technique using 96-
well microtiter plates. A stock solution of 60 mg of each of
1
m. p. 185–188 ꢁC, yield 79%, H-NMR (300 MHz, DMSO-d6,
ppm) d 1.68–1.71 (m, 3H, CH3), 3.69 (t, J ¼ 4.43 Hz, 4H,
morpholine-CH2), 3.98 (s, 2H, piperidine-CH2), 4.23 (s, 2H,
morpholine-CH2), 4.95–5.05 (m, H, CH), 7.47–7.57 (m, 3H,
Ar-H), 7.62–7.64 (m, H, Ar-H), 7.79 (d, J ¼ 8.30 Hz, H, Ar-
H), 7.93–7.96 (m, H, Ar-H), 8.04–8.11 (m, H Ar-H), 10.29
(brs, H, NH). 13C-NMR (75 MHz, DMSO-d6, ppm) 18.56
(CH3), 50.89 (CH), 55.05 (morpholine N-CH2), 66.07 (mor- the substances in 6 mL DMSO (20%) was prepared, and sub-
pholine O-CH2), 122.42, 123.20, 126.00, 126.09, 126.40, sequently diluted ten times with twofold serial dilution
126.54, 128.58, 133.67, 134.16, 170.64 (C ¼ O), 194.68
[M þ Na]þ calculated 383.0858; found 383.0862.
method. Mueller-Hinton broth was utilized in the case of
bacterial cultures and SD broth was utilized in the case of
fungal cultures. A number of dilutions, the concentrations
of which varied between 6.0 mg/ml and 11.71 lg/mL from
(C ¼ S). For C18H20N2O2S2 calculated: HRMS (m/z):
bacterium, yeasts and fungal spore solutions and dilutions
1-(Naphthalen-1-ylamino)-1-oxopropan-2-yl 4-(pyrimidin-
were transferred into microtitration plates and incubated for
2-yl)piperazine-1-carbodithioate (2j)
24–48 h at 35–37 ꢁC for bacteria/yeasts and 25 ꢁC for fila-
m. p. 170–172 ꢁC, yield 80%, IR (KBr) Vmax (cmꢀ1): 3250
mentous fungi. One of the positive controls contained
(N-H), 1660 (C ¼ O), 1589–1417 (C ¼ C and C ¼ N). 1H-
100 lL of microorganism solution plus 20% DMSO solution
NMR (300 MHz, DMSO-d6, ppm) d 1.71 (d, J ¼ 7.17 Hz, 3H,
in a well and another one had 100 lL of microorganism
CH3), 3.90 (s, 4H, piperazine-CH2), 4.09 (s, 2H, piperidine-
CH2), 4.36 (s, 2H, piperazine-CH2), 4.94–5.04 (m, H, CH),
7.69 (t, J ¼ 4.67 Hz, H, Ar-H), 7.47–7.59 (m, 3H, Ar-H), 7.65
solution plus 100 lL Mueller-Hinton broth in a well. A third
control was chloramphenicol for bacterium and ketocon-
azole for fungi. Negative controls contained only dilute solu-
(d, J ¼ 7.24 Hz, H, Ar-H), 7.79 (d, J ¼ 8.39 Hz, H, Ar-H),
tions without microorganism. Positive and negative results
7.93–7.96 (m, H, Ar-H), 8.09–8.12 (m, H, Ar-H), 8.41 (d,
were evaluated according to turbidity occurred after 24–48 h
J ¼ 4.75 Hz, 2H, Ar-H), 10.28 (brs, H, NH). 13C-NMR
by comparing to the ones in the control wells. The lowest
(75 MHz, DMSO-d6, ppm) 18.86 (CH3), 42.98 (CH), 50.99
concentrations giving no visible growth for each micro-
(CH2), 55.06 (CH2), 111.10, 122.42, 123.20, 126.01, 126.09,
organism were defined as MIC. The determination of the
126.41, 126.55, 128.59, 133.68, 134.16, 158.47, 161.29, 170.67
minimal inhibitory concentration was performed using resa-
(C ¼ O), 194.44 (C ¼ S). For C22H23N5OS2 calculated:
zurin, which indicates oxidation-reduction and is employed
HRMS (m/z): [M þ 1]þ calculated 438.1417; found 438.1413.
for the assessment of microbial growth. Resazurin represents
a non-fluorescent dye of blue color which turns pink and
fluorescent in the case of reduction to resazurin with oxidor-
eductases inside viable cells. The minimal inhibitory concen-
tration (MIC) for the microorganism examined at the
determined concentration was described as the boundary
dilution with no altering color of resazurin.[54]
Antimicrobial activity was investigated for compounds
2a–2k. Their antimicrobial activities were tested against B.
cereus (ATCC 10876), B. subtilis (NRRL NRS-744), E. coli
(ATCC 25922), E. faecalis (ATCC 51299), K. pneumoniae
(ATCC 700603), L. monocytogenes (ATCC 19111), M. luteus
(NRRL B-4375), Salmonella typhimurium (ATCC 14028), S.
aureus (ATCC 6538), Y. enterocolitica (Y53), C. albicans
(ATCC 90028), C. glabrata (ATCC 90030), C. krusei (ATCC
6258), C. parapsilosis (ATCC 22019), P. chrysogenum
(ATCC 10106), P. citrinum (ATCC 9849), P. expansum
(ATCC 24692), F. solani (obtained from our laboratory), F.
moniliforme (NRRL 2374) and A. niger (ATCC 9807).
1-(Naphthalen-1-ylamino)-1-oxopropan-2-yl 4-phenylpiper-
azine-1-carbodithioate (2k)
1
m. p. 116–118 ꢁC, yield 75%, H-NMR (300 MHz, DMSO-d6,
ppm) d 1.70 (d, J ¼ 7.12, 3H, CH3), 2.45 (brs, 4 H, pipera-
zine-CH2), 3.93 (s, 2H, piperidine-CH2), 4.26 (s, 2H, piperi-
dine-CH2), 4.97–5.04 (m, H, CH), 7.25–7.34 (m, 5H, Ar-H),
7.47–7.56 (m, 3H, Ar-H), 7.68 (d, J ¼ 7.03 Hz, H, Ar-H),
7.77 (d, J ¼ 8.28 Hz, H, Ar-H), 7.92–7.95 (m, H, Ar-H),
8.11–8.14 (m, H, Ar-H), 10.28 (brs, H, NH). 13C-NMR
(75 MHz, DMSO-d6, ppm) 18.82 (CH3), 51.01 (CH2), 52.41
(CH), 55.08 (CH2), 122.33, 123.19, 126.02, 126.40, 126.54,
127.61, 128.73, 129.43, 133.72, 134.19, 137.95, 170.71
(C ¼ O), 194.11 (C ¼ S). For C24H25N3OS2 calculated:
HRMS (m/z): [M þ 1]þ calculated 436.1512; found 436.1515.
Antimicrobial study
Mueller-Hinton agar plates were used to maintain bacterial
cultures. Potato dextrose (PD) agar and Sabouraud dextrose
(SD) agar were used for the maintenance of fungal cultures.
Test bacteria were acquired from bacterial cultures the incu-
bation of which was performed for 24 h at 37 ꢁC on
Mueller-Hinton agar substrate and the dilution of which
Conclusion
In this work, we synthesized novel 11 N-(naphthalen-1-
yl)propanamide derivatives and evaluated their antimicrobial
activity. Results showed that the 2-substituted-N-(naphtha-
was performed in accordance with the 0.5 McFarland stand- len-1-yl)propanamide moiety provides good antimicrobial
ard to about 108 CFU/mL. Fresh mature cultures at the age activity. Notedly, compounds 2a, 2b, and 2c exhibited

6
A. E. EVREN ET AL.
Tetrazol-2-yl]Propan-2-yl Acetate. Bioorg. Med. Chem. Lett.
2015, 25, 2657–2663. DOI: 10.1016/j.bmcl.2015.04.078.
antifungal activity against C. albicans (ATCC 90028), C. kru-
sei (ATCC 6258), and A. niger (ATCC 9807). Also, com-
pounds 2c, 2e, and 2f were the most active compounds
against S. aureus (ATCC 6538). In summary, considering
the inhibition activity shown against both microorganism
species, the most active compounds were determined to be
2b and 2c.
[13] Lukowska-Chojnacka, E.; Mierzejewska, J.; Milner-Krawczyk,
M.; Bondaryk, M.; Staniszewska, M. Synthesis of Novel
Tetrazole Derivatives and Evaluation of Their Antifungal
Activity. Bioorg. Med. Chem. 2016, 24, 6058–6065. DOI: 10.
1016/j.bmc.2016.09.066.
[14] Stana, A.; Vodnar, D. C.; Tamaian, R.; Pirnau, A.; Vlase, L.;
Ionut, I.; Oniga, O.; Tiperciuc, B. Design, Synthesis and
Antifungal Activity Evaluation of New Thiazolin-4-Ones as
Potential Lanosterol 14alpha-Demethylase Inhibitors. Int. J.
Mol. Sci. 2017, 18, 177. DOI: 10.3390/ijms18010177.
Disclosure statement
The author confirms that this article content has no conflict of interest.
[15] Bueso-Bordils, J. I.; Perez-Gracia, M. T.; Suay-Garcia, B.; Duart,
M. J.; Martin Algarra, R. V.; Lahuerta Zamora, L.; Anton-Fos,
G. M.; Aleman Lopez, P. A. Topological Pattern for the Search
of New Active Drugs against Methicillin Resistant
Staphylococcus aureus. Eur. J. Med. Chem. 2017, 138, 807–815.
DOI: 10.1016/j.ejmech.2017.07.010.
ORCID
Asaf E. Evren
Leyla Yurttas
http://orcid.org/0000-0002-8651-826X
http://orcid.org/0000-0002-0957-6044
[16] Upadhayaya, R. S.; Vandavasi, J. K.; Kardile, R. A.; Lahore,
S. V.; Dixit, S. S.; Deokar, H. S.; Shinde, P. D.; Sarmah, M. P.;
Chattopadhyaya, J. Novel Quinoline and Naphthalene
Derivatives as Potent Antimycobacterial Agents. Eur. J. Med.
Chem. 2010, 45, 1854–1867. DOI: 10.1016/j.ejmech.2010.01.024.
[17] Jha, K. K.; Samad, A.; Kumar, Y.; Shaharyar, M.; Khosa, R. L.;
Jain, J.; Kumar, V.; Singh, P. Design, Synthesis and Biological
Evaluation of 1,3,4-Oxadiazole Derivatives. Eur. J. Med. Chem.
2010, 45, 4963–4967. DOI: 10.1016/j.ejmech.2010.08.003.
[18] Yadav, P. P.; Gupta, P.; Chaturvedi, A. K.; Shukla, P. K.;
Maurya, R. Synthesis of 4-Hydroxy-1-Methylindole and
Benzo[b]Thiophen-4-ol Based Unnatural Flavonoids as New
Class of Antimicrobial Agents. Bioorg. Med. Chem. 2005, 13,
1497–1505. DOI: 10.1016/j.bmc.2004.12.032.
Meral Yılmaz-Cankilic
http://orcid.org/0000-0002-9758-7009
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