Synthesis and antimicrobial evaluation of some novel dithiolane, thiophene, coumarin, and 2-pyridone derivatives

Article abstract of DOI:10.1080/00397911.2017.1336776

Novel 2-cyano-N-[1-(naphtha-2-yl)ethylidene] acetohydrazide 1 was utilized as key intermediate for the synthesis of some new dithiolane, thiophene, coumarin, 2-pyridone, and other related products containing a hydrazide moiety. Newly synthesized compounds

Full text of DOI:10.1080/00397911.2017.1336776

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis and Antimicrobial Evaluation of Some
Novel Dithiolane, Thiophene, Coumarin and 2-
pyridone Derivatives
Mahmoud R. Mahmoud, Fatma S.M. Abu El-Azm, Amira T. Ali & Yasmeen M.
Ali
To cite this article: Mahmoud R. Mahmoud, Fatma S.M. Abu El-Azm, Amira T. Ali & Yasmeen M.
Ali (2017): Synthesis and Antimicrobial Evaluation of Some Novel Dithiolane, Thiophene, Coumarin
and 2-pyridone Derivatives, Synthetic Communications, DOI: 10.1080/00397911.2017.1336776
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Date: 14 June 2017, At: 02:20

Synthesis and Antimicrobial Evaluation of some Novel Dithiolane, Thiophene,
Coumarin and 2-Pyridone Derivatives
1
1,*
1
1
Mahmoud R. Mahmoud , Fatma S. M. Abu El-Azm , Amira T. Ali , Yasmeen M. Ali
1
Chemistry Department, Faculty of Science, Ain Shams University, Abbassia , Cairo,
Egypt
Corresponding to author: Fatma S.M. Abu El-Azm Chemistry Department, Faculty of
Science, Ain Shams University, Abbassia, Cairo, Egypt. E-mail: ftmsaber@yahoo.com
Abstract
Novel 2-cyano-N-[1-(naphtha-2-yl)ethylidene] acetohydrazide 1 was utilized as key
intermediate for the synthesis of some new dithiolane, thiophene, coumarin, 2-pyridone,
and other related products containing a hydrazide moiety. Newly synthesized compounds
1
13
were characterized by elemental analyses and spectral data (IR, H NMR, C NMR and
mass spectra). The antimicrobial activity of the synthesized compounds was evaluated.
Graphical Abstract
1

KEYWORDS: Hydrazide-hydrazone, Cyanoacetohydrazide, dithiolane derivatives,
thiophene derivatives
INTRODUCTION
The bicyclic naphthalene skeleton constitutes a large number of clinical drugs, such as
[
1]
[2]
[3]
propranolol , naphazoline (a cardiovascular agent) , naproxen , nabumetone (an anti-
[
4]
[5]
inflammatory agent) and methallenestril (a non-steroid oestrogen) . It is well known
that naphthalene derivatives (e.g., 2-(3-(3,4-dimethylphenyl)-5-(naphthalen-2-yl)-4,5-
dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one, etc.) display anti-tumor, anti-arrhythmia,
[
6]
and antioxidant activities . A number of hydrazide–hydrazone derivatives have been
[
7,8]
claimed to have exciting bioactivity such as antimicrobial, antitubercular,
[
9]
[10]
[11]
[12]
anticonvulsant, analgesic, anti-inflammatory, antiplatelet aggregation,
[
13,14]
[15]
[16]
[17]
[18]
anticancer,
antifungal, antiviral, antibacterial, and antimalarial activities.
Furthermore, coumarin derivatives have attracted considerable attention because of a
large number of natural and synthetic products containing coumarin nucleus. Also, they
[
19]
[20,21]
[22]
have been reported to exert notable antimicrobial, antifungal,
and cytotoxic
[
23]
activities. In addition, some 2-pyridones are also reported to possess antitumor,
[
24]
[25,26]
antibacterial and other biological activities
. In view of the previously mentioned
facts and in continuation of our interest to identify new candidates that may be valuable
[
27–31]
in designing new, potent, selective, and less toxic antimicrobial agents
, we report
herein the synthesis of a series of hydrazide–hydrazone derivatives together with their use
in a series of heterocyclic transformations and evaluation as antimicrobial agents.
2

RESULTS AND DISCUSSION
In the present work, Condensation of 2-cyanoethanoic hydrazide with 2-acetyl
naphthalene in refluxing dioxane afforded the corresponding condensation product 2-
cyano-N-[1-(naphtha-2-yl) ethylidene] acetohydrazide 1. (Scheme 1) The assignment of
structure 1 was supported by elemental analysis and spectral data. The observation of δ
4
.3 ppm integrated for 2H attributable for the cyano methylene protons and singlet
1
integrated for one proton disappeared with D O at δ 11.09 ppm (NH) in the H-NMR
2
spectrum which completely in accord with the assigned structure 1. Moreover, the IR
-1
-1
spectrum displayed υNH at 3256 cm , υ at 2266 cm representing the saturated nitrile
C≡N
group.
Coumarin derivatives are widely used for production of highly effective fluorescent dyes
[
32]
for synthetic fibers and day-light fluorescent pigments. It was reported that the
reaction of cyanoacetamido compounds with salicylaldehyde yielded the coumarin
derivatives. Herein cyclocondensation of 1 with salicylaldehyde in dioxane containing
triethylamine or ammonium acetate furnished smoothly the 2-imino coumarin derivative
2
. (Scheme 2) The presence of sharp stretching absorption bonds at 3311, 1674 and 1643
-1
cm characteristic for NH, CO and C=N group frequencies and the absence of carbonyl
1
band for δ-lactone confirm the imino coumarin structure. Moreover, H-NMR spectrum
of the product revealed the presence of signals for five types of protons and the highest
recorded peak in the mass spectrum at m/z = 355 (9.8%) representing the molecular ion
peak for molecular formula C H N O .
2
2
17
3
2
3

The reaction of cyanoacetohydrazide derivative 1 with 4-methoxybenzylidene
malononitrile in boiling dioxane in the presence of a catalytic amount of piperidine
afforded on hot a crystalline product with molecular formula C H N O . (Scheme 2)
1
4
11
5
2
1
The H-NMR spectrum of this product revealed the absence of naphthalene, methyl
protons and the presence of two NH protons which ruled out the expected structure 3
2
and confirm the structure 4. Moreover, the IR spectrum of this product displayed the
-1
-1
coupling bands for υNH2 at 3455, 3395, 3320, 3269 cm , υ
(sharp band) at 2216 cm
C≡N
-1
and υC=O at 1641 cm (the low frequency of the carbonyl band may be due to the H-
bonding with the adjacent amino group). Also the highest recorded peak in the mass
spectrum at m/z = 281 attributable for the correct molecular ion peak and the base peak
for molecular formula C H N O . Furthermore, the strong clue for the structure 4 is
1
4
11
5
2
forthcoming by authentic sample prepared from the reaction of cyanoethanoic acid
hydrazide with 4-methoxy benzylidene malononitrile in boiling dioxane in the presence
of catalytic amount of piperidine (TLC, m.p and IR comparison). (Scheme 2) Probably
the reaction mechanism is assumed to proceed via initial attack of the carbanion derived
from the active methylene of the acetamido group to the β-carbon of the activated nitrile
to give the Michael adduct followed by intramolecular cyclization then hydrolysis of the
imino group with elimination of 2-acetyl naphthalene. (Scheme 3)
Hydrazinolysis of cyanoacetohydrazide derivative 1 using hydrazine hydrate
(80%) in refluxing dioxane yielded a crystalline product with molecular formula
C H N [M.Wt= 336] which by spectral data identified as the azine of 2-acetyl
24
20
2
4

naphthalene 5 as a clear cut product in good yield without affording the expected
pyrazole structure of type 6. (Scheme 2) The IR spectrum of this product lacked the
absorption bands for CN and NH groups and only one absorption band observed at 1596
2
-1
1
cm which may be attributable for C=N group. H-NMR spectrum of the product
consistent with the azine structure 5 and revealed signals characteristic for aromatic
protons as multiplet at 8.22-6.88 ppm integrated for 14H. The methyl protons observed
up field at δ2.36 ppm. A further support for the structure of the azine 5 is forthcoming
from the identity with an authentic sample prepared from the condensation of 2-acetyl
naphthalene with excess hydrazine hydrate in refluxing ethanol.
The active methylene group in the cyanoacetohydrazide derivative 1 readily adds
to one carbon donor such as carbon disulphide in DMF containing potassium hydroxide
at room temperature to give the dipotassium dithiocarbazate salt 7 which separated in
pure crystalline form then underwent heterocyclization upon treatment with dihalide and
α-halocarbonyl compounds such as 1,2-dibromoethane, chloroacetyl chloride and ω-
bromo-4-nitroacetophenone to afford the corresponding 1,3-dithiolane, 1,3- dithiolone
and thiophene derivatives 8-10, respectively. (Scheme 4) The assignment of the
structures 8-10 were based on elemental analysis and spectral data. The element test in
general showed the presence of sulfur element. All data for compound 8 were consistent
1
with the proposed structure. Thus, the absence of the δ- H CH cited for the acetamido
2
methylene protons observed with 1 at δ 4.3 ppm and the appearance of a multiplet
integrated for 4H at δ 3.3-3.25 ppm attributable for -CH -CH - protons of 1,3-dithiolane
2
2
ring. Furthermore, the mass spectrum of 8 show the correct molecular ion peak at m/z =
5

3
53 (36.4%) together with the base peak at m/z = 170 which confirm the structure 8. The
structures 9 and 10 were deduced from the study of spectral data. The observed carbonyl
-1
stretching absorption band at 1717 cm attributable for five-membered ringed ketone in
the IR spectrum and the correct molecular ion peak at m/z = 367 (22.9%) in the mass
spectrum of compound 9 in consistent with the assigned structure. Moreover, the
-1
presence of coupling bands at 3423, 3340 cm characteristic for NH group and the
2
absence of nitrile group in the IR spectrum of 10 together with the recorded peak at m/z =
1
4
90 (81%) representing the molecular ion peak and finally, the H-NMR spectrum
revealed all the signals which completely in accord with the proposed structure 10.
Treatment of the dipotassium dithiocarbazate salt 7 with ethyl chloroacetate in refluxing
dioxane gave the uncyclized S-alkylation product 11 and no evidence was recorded for
the cyclized products 9 or 12. (Scheme 5) The appearance of strong absorption band for
-1
-1
the nitrile group 2178 cm and the carbonyl ester group at 1729 cm with the absence of
vibrational coupling bands for NH group in the IR spectrum of the product, completely
2
in agreement with the structure 11 and ruled out the cyclized products 9 or 12. Moreover,
1
H-NMR spectrum of the product revealed the existence of triplet at δ 1.23 ppm and
quartet at δ 4.14 ppm with equal coupling constants characteristic for ethyl protons and
no recorded signals for the NH protons.
2
The ketene S,S-dithioacetal 13 was prepared by alkylation of the dipotassium
dithiocarbazate salt 7 with methyl iodide. (Scheme 5) The structure of 13 was elucidated
on the basis of the elemental analysis and spectral data. The IR spectrum showed the
6

-1
appearance of absorption bands at 3178, 2198, 1652 cm for NH, C N and C=O groups,
1
respectively. It's H-NMR spectrum (CDCl ) showed singlet signal at δ 2.73 ppm for 6
3
protons of two similar S-methyl protons, signal for the CH protons at δ 2.41 ppm and
3
signal for NH proton at δ 9.22 ppm disappeared with D O.
2
PHARMACOLOGY
Antimicrobial evaluation. All the newly synthesized compounds were evaluated for in
vitro antibacterial activity against Gram-positive bacteria (Staphylococcus aureus) and
Gram-negative bacteria (Escherichia coli) and fungi (Candida albicans) using a
[
33]
conventional broth dilution method. Ampicillin and amphotericin B were used as
reference drugs. The results were recorded for each tested compound as the average
diameter of inhibition zones of bacterial or fungal growth around the disks in mm. The
minimal inhibitory concentrations (MICs) for compounds that showed significant growth
[
34]
inhibition zones (>10mm) were determined using a twofold serial dilution method.
The inhibition zone diameters and MIC (μmol/ml) values are recorded in Tables 1 and 2.
The results revealed that the synthesized compounds showed varying degrees of
inhibition against the tested microbes. In general, the best activity was displayed by
compounds 8, 9, 11, and 13 (Tables 1 and 2), because they showed potential antibacterial
activity against almost all bacterial pathogens tested. Compounds 11 and 13 exhibited the
highest affectivity against all tested microorganisms with inhibition zones range from 11
to 17 mm (% activity index from 57.8 to 100) with minimum inhibitory concentrations
(MIC) range from 50.4 to 205 μg/ml. On the other hand, compounds 11 and 13 were
7

equipotent to ampicillin in inhibiting the growth of E. Coli. All compounds exhibited
activity ranges from very weak activity to strong activity against C. albicans as compared
with standard amphotericin B.
Structure–activity relationship. The structure–antimicrobial activity relationship of the
synthesized compounds against the pathological strains of bacteria and fungi revealed
that compounds 8, 9, 10, 11, and 13 have higher antimicrobial activities than other
compounds. The increased antimicrobial activity of these compounds is thought to be due
[
35]
to the larger size of the sulfur atom. Sulfur atoms might block enzymatic activity in
[
36]
microorganisms and in doing so prevent bacterial division and growth.
EXPERIMENTAL
All melting points were taken on a Griffin and Geory melting-point apparatus and are
uncorrected. IR spectra were recorded on Pye Unicam SP1200 spectrophotometer using
1
13
the KBr wafer technique. H NMR and C NMR spectra were determined on a Varian
Gemini 300MHz using tetramethylsilane (TMS) as internal standard (chemical shifts in
scale). EI-MS were measured on a Schimadzu-GC-MS operating at 70 eV. Elemental
analyses were carried out at the Microanalytical Unit, Faculty of Science, Ain Shams
University, using a Perkin-Elmer 2400 CHN elemental analyzer, and satisfactory
analytical data ( 0.4) were obtained for all compounds. The homogeneity of the
synthesized compounds was controlled by thin layer chromatography (TLC) using
aluminum sheet silica gel F254 (Merck).
8

/
Synthesis Of (Z)-2-Cyano-N -(1-(Naphthalene-2-Yl) Ethylidene)Acetohydrazide 1
A mixture of 2-acetyl naphthalene (2g, 11mmol) and 2-cyanoacetohydrazide (1.15 g, 11
mmol) in dioxane (30 mL) was refluxed for 2hrs. The deposited solid on hot was filtered
о
off, dried and recrystallized from dioxane to give 1 as white crystals; mp: 220-222 C,
yield: 51%. Anal. Calc. for C H N O (251.28): C, 71.70; H, 5.21; N, 16.72. Found: C,
1
5
13
3
-1
7
1.59; H, 5.11; N, 16.58. IR (υ/cm ): 3256 (NH), 2266 (C≡N), 1710 (C=O), 1685 (C=N).
+
.
MS m/z (%): 251 (M ; 65.2), 250 (100), 211 (14.6), 183 (40.8), 153 (41.7), 127 (46.7).
1
H-NMR (DMSO-d ) δ (ppm): 11.09 (s, 1H, NH, exchangeable with D O), 8.27-7.52 (m,
6
2
1
3
7
1
1
Harom), 4.3 (s, 2H, CH ), 2.38 (s, 3H, CH ). C-NMR (DMSO-d ) (ppm) δ: 13.63, 24.95,
2 3 6
23.50, 126.28, 126.42, 126.55, 126.82, 127.44, 127.68, 128.47, 132.68, 133.24, 133.33,
35.06, 148.91, 165.83.
SUPPORTING INFORMATION
Full experimental details and spectroscopic data (IR spectra, 1H-NMR and MS) for
compounds 2, 4, 5, 7-11, 13 can be found via the Supplementary Content section of this
article’s Web page.
ANTIMICROBIAL EVALUATION
The disks of a Whatman filter paper were prepared with standard size (5.0-mm diameter)
and kept into 1.0-oz screw-capped wide-mouthed containers for sterilization. These
bottles are kept into a hot air oven at a temperature of 150°C. Then, the standard
sterilized filter paper disks impregnated with a solution of the test compound in DMSO (1
mg/mL) were placed on nutrient agar plate seeded with appropriate test organism in
9

triplicates. Standard conditions of 106 colony forming U/mL (CFU/mL) and 104
CFU/mL were used for antibacterial and antifungal assay, respectively. Pyrex glass Petri
dishes (9 cm in diameter) were used, and two disks of the filter paper were inoculated in
each plate. The utilized test organisms were S. aureus as examples of Gram-positive
bacteria and E. coli as examples of Gram-negative bacteria. They were also evaluated for
their in vitro antifungal potential against C. albicans fungal strain. Ampicillin and
amphotericin B were used as standard antibacterial and antifungal agents, respectively.
DMSO alone was used as control at the same previously mentioned concentration, and
because of this, there was no visible change in bacterial growth. The plates were
incubated at 36°C for 24 h for bacteria and for 48 h for fungi. Compounds that showed
significant growth inhibition zones (>10mm) using the twofold serial dilution technique
were further evaluated for their MICs.
MIC measurement. The microdilution susceptibility test in Müller-Hinton Broth
(Oxoid) and Sabouraud Liquid Medium (Oxoid) was used for the determination of
antibacterial and antifungal activity, respectively. Stock solutions of the tested
compounds, ampicillin and amphotericin B were prepared in DMSO at a concentration of
1
000 μg/mL. Each stock solution was diluted with standard method broth (Difco) to
prepare serial twofold dilution at concentrations of 500, 250 to 3.125 μg/mL); 10mL of
the broth containing about 106 CFU/mL of test bacteria was added to each well of a 96-
well microliter plate. The sealed microplates were incubated at 36°C for 24 h for
antibacterial activity and at 36°C for 48 h for antifungal activity in a humid chamber. At
the end of the incubation period, the MIC values were recorded as the lowest
1
0

concentrations of the substance that had no visible turbidity. Control experiments with
DMSO and uninoculated media were run parallel to the test compounds under the same
conditions.
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1
6

Table 1. Diameter of inhibition zone (mm) of the newly synthesized compounds
Compound no.
Diameter of inhibition zone (mm) of
bacteria
Fungi
Gram negative
Gram positive
bacteria
% activity
aureus index
bacteria
E.
% activity
S.
C.
% activity
coli
NA
NA
10
index
_
albicans
NA
index
_
1
2
8
NA
NA
16
_
_
_
13
68.4
_
83.3
88.8
NA
9
11
91.6
_
14
12
77.7
66.6
NA
NA
_
_
1
0
NA
1
1
1
3
12
12
100
100
15
13
83.3
72.2
11
17
57.8
89.4
Ampicillin
12
100
_
18
100
_
NA
19
_
Amphotericin B NA
NA
100
NA, no activity.
1
7

Table 2. Minimal inhibitory concentration (MIC, μmol/ml) of the newly synthesized
compounds
Compound no.
MIC, in μmol/ml
Gram negative Gram positive bacteria
bacteria
Fungi
E. coli
_
S. aureus
_
C. albicans
2
8
9
92.5
_
204
175
_
192
198
_
1
1
1
0
1
3
225
_
125
125
125
193
165
50.4
_
205
Ampicillin
187.5
Amphotericin B
_
_
9.8
1
8

Scheme 1.
1
9

Scheme 2.
2
0

Scheme 3.
2
1

Scheme 4.
2
2

Scheme 5.
2
3