Synthesis and antimicrobial evaluation of novel N-substituted 4-ethylsulfanyl-2-pyridones and triazolopyridines

Article abstract of DOI:10.1007/s00044-018-2264-z

The design and development of new methods for the synthesis of antimicrobial drugs is an important goal currently for medicinal chemistry. Sixteen novel N-substituted-amino-, N-arylsulfonylamino-, and N-aryl-4-ethylsulfanyl-2-pyridones were synthesized. A

Full text of DOI:10.1007/s00044-018-2264-z

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-018-2264-z
ORIGINAL RESEARCH
Synthesis and antimicrobial evaluation of novel N-substituted 4-
ethylsulfanyl-2-pyridones and triazolopyridines
Rasha A. Azzam1 Galal H. Elgemeie1
●
Received: 24 May 2018 / Accepted: 15 November 2018
©
Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
The design and development of new methods for the synthesis of antimicrobial drugs is an important goal currently for
medicinal chemistry. Sixteen novel N-substituted-amino-, N-arylsulfonylamino-, and N-aryl-4-ethylsulfanyl-2-pyridones
were synthesized. Antimicrobial activities of the compounds were evaluated against four fungal and eight bacterial strains.
Antimicrobial results showed that compound 14b had excellent activities as compared to all other newly synthesized
compounds and a variety of standard ones against a variety of bacterial and fungal strains. Triazolo[1,5-a]pyridines 10c and
1
0e showed as well marked activities toward three of the tested Gram-negative bacteria.
●
●
●
Keywords 2-Pyridones N-cyanoacetohydrazide Cyanoaceto-N-phenylsulfonylhydrazide Antimicrobial activity
Introduction
Elgemeie et al. 2002), which have come into interest and
application of NIH, NIAID and others as new forms of
chemotherapeutic agents (https://pubchem.ncbi.nlm.nih.
gov/compound/391346). The promising interest have led
our research laboratory to continue this research to explore
the new molecular mechanisms of these synthetic com-
pounds and to use them as a promising chemotherapeutics.
We have recently identified and reported different synthetic
methods for preparing azoloazines using cyanoketene
dithioacetals (Elgemeie et al. 2001, 2002, 2003, Elgemeie
and Jones 2004). Derivatives of these ring systems are
important as antimetabolic agents in biochemical reactions
(Elgemeie et al. 2004, 2006). The present research deals
with a novel synthesis of N-amino-, N-substituted-amino-,
N-arylsulfonylamino-, and N-aryl-4-ethylsulfanyl-2-pyr-
idones 6, 12, 14, and [1,2,4]triazolo[1,5-a]pyridines 10 by
the reaction of cyanoketene dithioacetal 2 with substituted
cyanohydrazides and the determination of their anti-
microbial potency.
The resistance of the majority of microorganisms to anti-
microbial drugs is a major problem affecting the health of
people all around the world. According to WHO report on
antimicrobial resistance, it is estimated that more than ten
million people will suffer from multi-drug resistance
infections with the number of human mortality is expected
to rise as antimicrobial drug resistance increases (Li et al.
2
000). Innovation, therefore, must be strengthened in this
area of research activities related to the development of new
and effective antimicrobial and antifungal drugs (Fassihi
et al. 2009). N-Substituted 2-pyridones are important het-
erocycles that possess antimicrobial and antifungal activities
making them ideal for a wide range of pharmaceutical
applications (Desai et al. 2013, Maruza et al. 1992). As part
of our program directed toward the preparation of potential
antimetabolic agents (Elgemeie 2003; Elgemeie et al. 2017,
2
018; Abu-Zaied et al. 2011), we have recently conducted
numerous researches to develop different innovative syn-
thetic methods for the preparation of N-sulfonylamino- and
N-substituted-2-pyridones (Elgemeie and Jones 2002, 2016;
Materials and methods
Chemistry
*
Galal H. Elgemeie
elgemeie@yahoo.com
All melting points were uncorrected on a Gallenkamp
melting point apparatus. IR spectra (KBr discs) were
recorded on a FTIR plus 460 or Pye unicam SP-1000
1
Chemistry Department, Faculty of Science, Helwan University,
Helwan, Cairo 11795, Egypt
1
13
spectrophotometer. H NMR and C NMR spectra were

Medicinal Chemistry Research
1
3
recorded on a Mercury-300BB (300 and 75 MHz, respec-
C NMR (75 MHz, DMSO-d ): δ = 15.4 (CH ), 29.5
6
3
tively), at Cairo University, in DMSO-d as solvent using
(CH ), 116.9, 118.0 (CN), 83.3, 88.4, 128.5, 129.5, 130.3,
6
2
TMS [Si(CH ) ] as internal standard and chemical shifts are
133.6, 149.2, 154.1, 156.0, 161.4 (ArC). Anal. calcd. for.
C H N OS (321.36): C, 59.80; H, 3.45; N, 21.79. Found:
C, 59.77; H, 3.43; N, 21.67
3
4
expressed as δ ppm. Elemental analyses were obtained from
the Microanalytical Data Center at Cairo University, Egypt
and were performed on Vario El III Elemental CHNS
analyzer. Progress of the reactions was monitored by TLC
using aluminum sheets coated with silica gel 60 F254
1
6
11
5
2-(4-Chlorophenyl)-7-(ethylthio)-5-oxo-3,5-dihydro-[1,2,4]
triazolo[1,5-a]-pyridine-6,8-dicarbonitrile (10b)
(
Merck). Viewing under a short-wavelength UV lamp
effected detection.
Beige; yield 85%; mp 317 °C; IR (KBr) ν
3495, 3418,
max
-
1 1
2216, 1628 cm ; H NMR (300 MHz, DMSO-d ): δ = 1.24
6
Synthesis of 1,6-diamino-4-(ethylthio)-2-oxo-1,2-
dihydropyridine-3,5-dicarbonitrile (6)
(3H, t, J = 7.2 Hz, CH ), 3.18 (2H, q, J = 7.2 Hz, CH ),
3
2
7.57 (2H, d, J = 9 Hz, C H ), 8.15 (2H, d, J = 9 Hz, C H );
6
4
6
4
1
3
C NMR (75 MHz, DMSO-d ): δ = 15.1 (CH ), 29.7
6
3
To a solution of compound 1 (0.01 mol) in ethanol (30 mL),
(CH ), 116.7, 118.2 (CN), 83.1, 88.0, 129.0, 129.4, 129.8,
2
2
equivalents of ethyl iodide were added (0.02 mol). The
135.2, 148.8, 153.9, 156.2, 161.6 (ArC). Anal. calcd. for.
C H ClN OS (355.80): C, 54.01; H, 2.83; N, 19.68.
Found: C, 53.76; H, 2.80; N, 18.98.
reaction mixture was refluxed for 3 h and then the solvent
was evaporated under vacuum. The residue was dissolved
in dioxane and added to a solution of cyanoacetohyrdazide
1
6
10
5
3
(0.01 mol) in dioxane (10 ml) containing (0.01 mol) of
7-(Ethylthio)-2-(4-methoxyphenyl)-5-oxo-3,5-dihydro-[1,2,4]
KOH. After stirring at room temperature for 24 h, the solid
product formed was filtered, washed with absolute ethanol,
dried and recrystallized from ethanol.
triazolo[1,5-a]-pyridine-6,8-dicarbonitrile (10c)
Pale yellow; yield 73%; mp 214 °C; IR (KBr) ν
3397,
max
−
1 1
Yellow; yield 70%; mp 209 °C; IR (KBr) ν
208, 2211, 1619 cm ; H NMR (300 MHz, DMSO-d ): δ
3490,
3297, 2210, 1645 cm ; H NMR (300 MHz, DMSO-d ): δ
max
6
−
1 1
3
= 1.27 (3H, t, J = 7.2 Hz, CH ), 3.26 (2H, q, J = 7.2 Hz,
6
3
13
=
1.25 (3H, t, J = 7.2 Hz, CH ), 3.24 (2H, q, J = 7.2 Hz,
CH ), 3.87 (3H, s, °CH ), 7.00-7.96 (4H, m, C H );
C
3
2
3
6
4
13
CH ), 5.54 (2H, s, NH ), 8.40 (2H, br, NH ); C NMR (75
NMR (75 MHz, DMSO-d ): δ = 15.2 (CH ), 29.3 (CH ),
2
2
2
6 3 2
MHz, DMSO-d ): δ = 15.1 (CH ), 29.2 (CH ), 115.5, 116.3
55.7 (OCH ), 114.7, 116.5 (CN), 78.2, 83.4, 115.5, 129.0,
6
3
2
3
(
CN), 77.7, 90.2, 156.2, 156.7, 159.2 (ArC). Anal. calcd.
132.3, 144.7, 153.2, 155.0, 156.1, 161.3 Anal. calcd. for.
for. C H N O S (375.43): C, 45.95; H, 3.86; N, 29.77.
C H N O S (351.38): C, 58.11; H, 3.73; N, 19.93. Found:
1
5
13
5
3
2
17 13
5
2
Found: C, 44.87; H, 3.88; N, 28.44.
C, 58.42; H, 3.77; N, 19.40.
General procedure for the synthesis of 7-(Ethylthio)-
7-(Ethylthio)-5-oxo-2-p-tolyl-3,5-dihydro-[1,2,4]triazolo[1,5-
a]pyridine-6,8-dicarbonitrile (10d)
5-oxo-3,5-dihydro-[1,2,4]triazolo[1,5-a]pyridines
(10a–f)
Buff; yield 70%; mp 268 °C; IR (KBr) ν
2212, 1632 cm ; H NMR (300 MHz, DMSO-d ): δ =
3423, 3215,
max
−
1
1
To a solution of compound 1 (0.01 mol) in ethanol (30 mL),
equivalents of ethyl iodide were added (0.02 mol). The
6
2
1.23 (3H, t, J = 7.5 Hz, ethyl CH ), 2.31 (3H, s, CH ), 3.14
3
3
reaction mixture was refluxed for 3 h and then the solvent
was evaporated under vaccum. The residue was dissolved in
dioxane and added to a solution of 1-cyanoacetyl-4-
arylidenesemicarbazide 7a–f (0.01 mol) in dioxane contan-
ing (0.01 mol) of KOH. After stirring at room temperature
for 24 h, the solid product formed was filtered, washed with
absolute ethanol, dried and recrystallized from ethanol.
(2H, q, J = 7.5 Hz, CH ), 7.06 (2H, d, J = 9 Hz, C H ), 8.08
2 6 4
1
3
(2H, d, J = 9 Hz, C H ). C NMR (75 MHz, DMSO-d ): δ
6
4
6
= 15.1 (ethyl CH , 21.4 (CH ), 29.1 (CH ), 116.1, 117.0
3
3
2
(CN), 76.8, 91.0, 126.5, 128.5, 139.4, 145.1, 153.2, 158.5,
159.0 (ArC); Anal. calcd. for. C H N OS (335.38): C,
1
7
13
5
60.88; H, 3.91; N, 20.88. Found: C, 60.46; H, 3.89; N,
20.79.
7
-(Ethylthio)-5-oxo-2-phenyl-3,5-dihydro-[1,2,4]triazolo[1,5-
7-(Ethylthio)-2-(4-fluorophenyl)-5-oxo-3,5-dihydro-[1,2,4]
triazolo[1,5-a]pyridine-6,8-dicarbonitrile (10e)
a]pyridine-6,8-dicarbonitrile (10a)
White; yield 70%; mp 222 °C; IR (KBr) ν
3413, 3205,
Beige; yield 82%; mp 287 °C; IR (KBr) ν
2223, 1632 cm ; H NMR (300 MHz, DMSO-d ): δ =
3545, 3447,
max
max
−
1
1
−1
1
2
1
212, 1635 cm ; H NMR (300 MHz, DMSO-d ): δ =
6
6
.25 (3H, t, J = 7.5 Hz, CH ), 3.16 (2H, q, J = 7.5 Hz,
1.24 (3H, t, J = 7.5 Hz, CH ), 3.18 (2H, q, J = 7.5 Hz,
3
3
CH ), 7.04–7.07 (2H, m, C H ), 8.06–8.10 (3H, m, C H ).
CH ), 7.30–7.36 (2H, m, C H ), 8.16–8.21 (2H, m, C H );
2
6
5
6
5
2
6
4
6
4

Medicinal Chemistry Research
1
3
7.58 (2H, d, J = 8.1, C H ), 7.82 (1H, br, NH); 13C NMR
6 4
C NMR (75 MHz, DMSO-d ): δ = 15.1 (CH ), 29.1
6
3
(
CH ), 116.1, 117.0 (CN), 83.2, 87.9, 126.4, 128.0, 129.9,
(75 MHz, DMSO-d ): δ = 15.2 (ethyl CH ), 21.6 (CH ),
2
6 3 3
1
35.2, 147.9, 153.2, 158.5, 159.0 (ArC); Anal. calcd. for.
30.0 (CH ), 116.6, 118.0 (CN), 75.9, 91.2, 118.7, 127.7,
2
C H FN OS (339.35): C, 56.63; H, 2.97; N, 20.64.
Found: C, 55.99; H, 2.86; N, 20.44.
132.4, 150.0, 153.9, 156.8, 160.5 (ArC); Anal. calcd. for.
C H N O S (389.45): C, 49.34; H, 3.88; N, 17.98.
1
6
10
5
1
6
15
5
3 2
Found: C, 48.98; H, 3.69; N, 16.97.
7
-(Ethylthio)-2-(3-nitrophenyl)-5-oxo-3,5-dihydro-[1,2,4]
triazolo[1,5-a]pyridine-6,8-dicarbonitrile (10f)
General procedure for the synthesis of N-aryl-2-
pyridones (14a–f)
Yellowish brown; yield 82%; mp 223 °C; IR (KBr) ν
max
−
1
1
3
437, 3199, 2214, 1628 cm ; H NMR (300 MHz,
To a solution of compound 1 (0.01 mol) in ethanol (30 mL),
2 equivalents of ethyliodide were added (0.02 mol). The
reaction mixture was refluxed for 3 h and then the solvent
was evaporated under vacuum. The residue was dissolved
in dioxane and added to a solution of arylcyanoacetamide
13a–f (0.01 mol) in dioxane containing (0.01 mol) of KOH.
After stirring at room temperature for 3 h, the solid product
thus formed was filtered, washed with absolute ethanol,
dried, and recrystallized from ethanol.
DMSO-d ): δ = 1.24 (3H, t, J = 7.2 Hz, CH ), 3.19 (2H, q,
6
3
13
J = 7.2 Hz, CH ), 7.80–8.87 (4H, m, C H ); C NMR (75
2
6
4
MHz, DMSO-d ): δ = 15.4 (CH ), 28.8 (CH ), 116.3, 117.0
6
3
2
(
1
CN), 83.5, 87.9, 118.2, 124.0, 128.2, 129.0, 133.2, 147.4,
48.2, 153.6, 158.9, 161.2 (ArC); Anal. calcd. for.
C H N O S (366.35): C, 52.46; H, 2.75; N, 22.94. Found:
1
6
10
6
3
C, 52.40; H, 2.74; N, 22.74.
General procedure for the synthesis of N-
arylsulfonylamino-2-pyridones (12a, b)
6-Amino-4-(ethylthio)-2-oxo-1-phenyl-1,2-dihydropyridine-
3,5-dicarbonitrile (14a)
To a solution of compound 1 (0.01 mol) in ethanol (30 mL),
2
equivalents of ethyl iodide were added (0.02 mol). The
White; yield 88%; mp 281 °C; IR (KBr) ν
2205, 1608 cm ; H NMR (300 MHz, DMSO-d ): δ =
3409, 3296,
max
−
1
1
reaction mixture was refluxed for 3 h and then the solvent
was evaporated under vacuum. The residue was dissolved
in dioxane and added to a solution of N-cyanoacetoar-
ylsulfonylhydrazides 11a, b (0.01 mol) in dioxane con-
taining (0.01 mol) of KOH. After stirring at room
temperature for 24 h, the solid product formed was filtered,
washed with absolute ethanol, dried, and recrystallized from
ethanol.
6
1.33 (3H, t, J = 7.5 Hz, CH ), 3.31 (2H, q, J = 7.5 Hz,
3
13
CH ), 7.32–7.59 (5H, m, C H ), 7.69 (2H, br, NH ).
C
2
6
5
2
NMR (75 MHz, DMSO-d ): δ = 14.8 (CH ), 28.7 (CH ),
6
3
2
115.4, 116.0 (CN), 78.1, 90.5, 128.5, 129.8, 130.2, 133.8,
156.6, 157.7, 158.9 (ArC); Anal. calcd. for. C H N OS
(296.35): C, 60.79; H, 4.08; N, 18.91. Found: C, 60.11; H,
4.10; N, 18.34.
1
5
12
4
N-(6-Amino-3,5-dicyano-4-(ethylthio)-2-oxopyridin-1(2H)-yl)
benzene-sulfonamide (12a)
6-Amino-1-(4-chlorophenyl)-4-(ethylthio)-2-oxo-1,2-
dihydropyridine-3,5-dicarbonitrile (14b)
White; yield 77%; mp 273 °C; IR (KBr) ν
3429, 3396,
Beige; yield 87%; mp 296 °C; IR (KBr) ν
2209, 1608 cm ; H NMR (300 MHz, DMSO-d ): δ =
3405, 3301,
max
max
−
1
1
−1
1
2
214, 1628 cm ; H NMR (300 MHz, DMSO-d ): δ =
6
6
1
.24 (3H, t, J = 7.5 Hz, CH ), 3.16 (2H, q, J = 7.5 Hz,
1.32 (3H, t, J = 7.5 Hz, CH ), 3.30 (2H, q, J = 7.5 Hz,
3
3
1
3
CH ), 7.34–7.71 (5H, m, C H ), 7.72 (1H, br, NH);
NMR (75 MHz, DMSO-d ): δ = 15.1 (CH ), 29.7 (CH ),
C
CH ), 7.40 (2H, d, J = 9 Hz, C H ), 7.61 (2H, d, J = 9 Hz,
2
6
5
2
6
4
1
3
C H ), 7.86 (2H, br, NH ); C NMR (75 MHz, DMSO-d6):
6 4 2
6
3
2
1
1
16.7, 118.2 (CN), 75.8, 91.0, 116.1, 127.4, 129.7, 148.7,
53.8, 156.3, 161.8 (ArC); Anal. calcd. for. C H N O S
3 2
14.8 (CH ), 28.7 (CH ), 115.2, 116.0 (CN), 78.0, 90.7,
3 2
130.3, 130.6, 132.7, 134.7, 156.6, 158.0, 158.8 (ArC);
Anal. calcd. for. C H ClN OS (330.79): C, 54.46; H,
15
13
5
(
3
375.43): C, 47.99; H, 3.49; N, 18.65. Found: C, 47.86; H,
.40; N, 18.62.
1
5
11
4
3.35; N, 16.94. Found: C, 54.28; H, 3.31; N, 16.94.
N-(6-Amino-3,5-dicyano-4-(ethylthio)-2-oxopyridin-1(2H)-
yl)-4-methylbenzene-sulfonamide (12b)
6-Amino-4-(ethylthio)-1-(4-methoxyphenyl)-2-oxo-1,2-
dihydropyridine-3,5-dicarbonitrile (14c)
Beige; yield 83%; mp 292 °C; IR (KBr) ν
3409, 3283,
White; yield 85%; mp 262-263 °C; IR (KBr) ν
3307, 2206, 1648 cm ; H NMR (300 MHz, DMSO-d ): δ
3402,
max
max
−
1
1
−1 1
2
1
214, 1609 cm ; H NMR (300 MHz, DMSO-d ): δ =
6
6
.24 (3H, t, J = 7.2 Hz, ethyl CH ), 2.32 (3H, s, CH ), 3.17
= 1.33 (3H, t, J = 7.2 Hz, CH ), 3.30 (2H, q, J = 7.2 Hz,
3
3
3
(
2H, q, J = 7.2 Hz, CH ), 7.15 (2H, d, J = 8.1 Hz, C H ),
CH ), 3.82 (3H, s, °CH ), 7.09 (2H, d, J = 8.1 Hz, C H ),
2
6
4
2
3
6
4

Medicinal Chemistry Research
Table 1 Antibacterial activities
gram positive bacteria) of the
synthesized compounds
Sample
Gram positive bacteria
(
S. pneumoniae
S. aureus
B. subtilis
E. faecalis
1
1
1
1
1
1
1
1
1
1
1
1
1
0a
0b
0c
0d
0e
2a
2b
4a
4b
4c
4d
4e
4f
21.2 ± 1.5
10.6 ± 0.58
18.3 ± 1.2
NAa
19.3 ± 0.63
12.3 ± 0.58
21.2 ± 0.58
NA
15.6 ± 0.36
10.7 ± 0.24
23.1 ± 0.47
NA
13.9 ± 0.21
9.9 ± 0.34
13.5 ± 0.34
NA
22.4 ± 0.44
16.7 ± 0.19
13.3 ± 0.19
NA
20.6 ± 0.63
18.2 ± 0.58
13.5 ± 0.36
NA
21.4 ± 0.52
17.6 ± 0.58
9.8 ± 0.34
NA
19.7 ± 0.56
15.4 ± 0.38
11.3 ± 0.39
NA
21.4 ± 0.58
NA
22.3 ± 0.63
NA
16.1 ± 0.53
NA
17.9 ± 0.48
NA
12.3 ± 0.52
15.2 ± 0.63
19.3 ± 1.5
24.3 ± 0.86
24.2 ± 0.86
10.6 ± 0.63
12.3 ± 0.58
18.2 ± 0.53
27.4 ± 0.72
30 ± 0.67
10.2 ± 0.31
15.3 ± 0.55
15.9 ± 0.59
32.4 ± 0.67
NTb
8.8 ± 0.24
13.4 ± 0.35
14.5 ± 0.62
25.9 ± 0.54
25 ± 0.72
Ampicillin
Ciprofloxacin
aNA: No observed activity
bNT: Not tested
7
.25 (2H, d, J = 8.1 Hz, C H ), 7.71 (2H, br, NH ); 13C
158.7, 158.9 (ArC); Anal. calcd. for. C H N OS (310.37):
16 14 4
6
4
2
NMR (75 MHz, DMSO-d ): δ = 14.8 (CH ), 28.7 (CH ),
C, 61.92; H, 4.55; N, 18.05. Found: C, 61.90; H, 4.53; N,
18.00.
6
3
2
5
5.4 (OCH ), 115.3, 116.0 (CN), 77.8, 90.9, 115.5, 126.0,
3
1
29.7, 156.9, 157.7, 159.0, 160.0 (ArC); Anal. calcd. for.
C H N O S (326.37): C, 58.88; H, 4.32; N, 17.17. Found:
6-Amino-4-(ethylthio)-2-oxo-1-m-tolyl-1,2-dihydropyridine-
1
6
14
4
2
C, 58.80; H, 4.29; N, 17.15
3,5-dicarbonitrile (14f)
6
3
-Amino-4-(ethylthio)-2-oxo-1-p-tolyl-1,2-dihydropyridine-
,5-dicarbonitrile (14d)
Buff; yield 85%; mp 219 °C; IR (KBr) ν
2205, 1650 cm ; H NMR (300 MHz, DMSO-d ): δ =
3409, 3324,
max
−
1
1
6
1
.33 (3H, t, J = 7.2 Hz, ethyl CH ), 2.36 (3H, s, CH ), 3.31
3 3
White; yield 89%; mp 273 °C; IR (KBr) ν
3405, 3299,
(2H, q, J = 7.2 Hz, CH ), 7.11-7-47 (4H, m, C H ), 7.69
max
2 6 4
−
1
1
13
2
1
207, 1607 cm ; H NMR (300 MHz, DMSO-d ): δ =
(2H, br, NH2); C NMR (75 MHz, DMSO-d ): δ = 15.2
6
6
.33 (3H, t, J = 7.2 Hz, ethyl CH ), 2.38 (3H, s, CH ), 3.30
ethyl CH ), 21.3 (CH ), 29.2 (CH ), 115.7, 116.5 (CN),
3
3
3
3
2
(
7
2H, q, J = 7.2 Hz, CH ), 7.21 (2H, d, J = 7.8 Hz, C H ),
78.4, 91.4, 125.9, 129.3, 130.5, 131.0, 134.0, 140.3, 157.0,
158.3, 159.3 (ArC); Anal. calcd. for. C H N OS (310.37):
2
6
4
3
1
.36 (2H, d, J = 8.1 Hz, C H ), 7.69 (2H, br, NH ).
C
6
4
2
16 14
4
NMR (75 MHz, DMSO-d ): δ = 15.3 (ethyl CH ), 21.4
C, 61.92; H, 4.55; N, 18.05. Found: C, 61.88; H, 4.51; N,
18.02.
6
3
(
CH ), 29.2 (CH ), 115.7, 116.5 (CN), 78.3, 91.5, 128.7,
3 2
1
31.3, 131.5, 139.9, 157.2, 158.3, 159.4 (ArC); Anal. calcd.
for. C H N OS (310.37): C, 61.92; H, 4.55; N, 18.05.
Found: C, 62.99; H, 4.54; N, 17.39.
3-Amino-7-(3-nitrophenyl)-4-oxo-4,6-dihydro-1H-
pyrazolo[3,4-d][1,2,4]-triazolo[1,5-a]pyridine-9-
carbonitrile (15)
1
6
14
4
6
3
-Amino-4-(ethylthio)-2-oxo-1-o-tolyl-1,2-dihydropyridine-
,5-dicarbonitrile (14e)
A mixture of 10f (0.001 mol) and hydrazine hydrate (0.01
mol) was dissolved in ethanol (20 mL) and few drops of
piperidine were added. The mixture was refluxed for 1 h.
The resulting precipitated solid was filtered off and
recrystallized from ethanol.
Yellow; yield 84%; mp 194 °C; IR (KBr) ν
2
1
3423, 3307,
max
−
1
1
211, 1626 cm ; H NMR (300 MHz, DMSO-d ): δ =
6
.33 (3H, t, J = 7.2 Hz, ethyl CH ), 2.01 (3H, s, CH ), 3.33
3
3
(
2H, q, J = 7.2 Hz, CH ), 7.26–7.44 (4H, m, C H ), 7.80
Buff; yield 77%; mp 317 °C; IR (KBr) ν
2196, 1660 cm ; H NMR (300 MHz, DMSO-d ): δ =
3387, 3260,
max
2
6
4
1
3
−1
1
(
2H, br, NH2); C NMR (75 MHz, DMSO-d ): δ = 15.2
6
6
(
ethyl CH ), 17.0 (CH ), 29.3 (CH ), 115.6, 116.3 (CN),
5.18 (2H, br, NH ), 7.76–8.85 (4H, m, C H ), 11.40 (1H,
3
3
2
2
6
4
7
6.1, 91.2, 128.4, 128.9, 130.7, 132.1, 133.0, 136.2, 156.6,

Medicinal Chemistry Research
Table 2 Antibacterial activities
Sample
Gram negative bacteria
(
gram negative bacteria) of the
synthesized compounds
P. aeruginosa
E. coli
S. marcescens
S. typhimurium
1
1
1
1
1
1
1
1
1
1
1
1
1
0a
0b
0c
0d
0e
2a
2b
4a
4b
4c
4d
4e
4f
NAa
NA
21.9 ± 1.2
8.3 ± 0.58
23.5 ± 0.63
NA
14.1 ± 0.65
12.6 ± 0.54
21.5 ± 0.88
NA
13.2 ± 0.58
11.2 ± 0.44
20.2 ± 0.73
NA
NA
NA
NA
23.2 ± 0.19
15.4 ± 0.44
11.4 ± 0.36
NA
24.3 ± 0.42
15.7 ± 0.47
11.5 ± 0.43
NA
19.5 ± 0.35
16.6 ± 0.62
10.8 ± 0.46
NA
NA
NA
NA
NA
23.2 ± 1.5
NA
28.1 ± 0.76
NA
23.4 ± 0.77
NA
NA
NA
10.6 ± 0.62
13.3 ± 1.2
20.3 ± 1.2
23.4 ± 0.61
12.6 ± 0.38
12.9 ± 0.63
15.7 ± 0.45
19.3 ± 0.42
9.7 ± 0.37
13.2 ± 0.58
17.4 ± 0.61
24.1 ± 0.51
NA
NA
Ciprofloxacin
20.6 ± 0.73
aNA: No observed activity
br, NH); Anal. calcd. for. C H N O (336): C, 50.01; H,
2–6 h. The turbidity of the bacterial suspension should be
equal to or greater than the turbidity of a McFarland Stan-
dard 0.5. After that, 1 mg of the each tested compound
(antimicrobial agent) was dissolved in 1 mL DMSO and
two-fold serial dilution was done using broth medium. A
fixed volume of the prepared bacterial inoculum was added
to each tube and incubated for at 37 °C 16–20 h. The MIC is
defined as the lowest concentration of the antimicrobial
agent that inhibits visible growth of the tested isolate as
observed with the unaided eye (Wiegand et al. 2008).
14
8
8
3
2
.40; N, 33.32. Found: C, 50.00; H, 2.44; N, 33.58.
Antimicrobial evaluation
Antimicrobial tests were carried out by diffusion agar
technique. A bottomless cylinder containing a measured
quantity of the sample (100 μL, 5 mg/mL) is placed on a
plate (9 cm diameter) containing a solid bacterial medium
(
nutrient agar broth) or fungal medium (Sabouraud dextrose
agar), which has been heavily seeded with a spore sus-
8
pension of the tested organism (1 × 10 CFU/mL of tested
6
bacteria on nutrient agar broth and 1 × 10 CFU/mL of fungi
Results and discussion
on Sabouraud dextrose agar media). After incubation for 24
h for bacteria and 5 days for fungi, the diameter of the clear
zone of inhibition surrounding the sample was measured
and used to indicate the inhibitory power of the sample
against a particular tested organism. The solvent used was
DMSO. Ampicillin and Ciprofloxacin were used as the
standard for antibacterial activity and Amphotericin B was
used as the standard for antifungal activity. After incubation
time, antimicrobial activity was evaluated by measuring the
zone of inhibition against the tested organisms and com-
pared with that of the standard as summarized in Tables 1–
Chemistry
Reaction of 2,2-dicyanoethene-1,1-bis(ethylthiolate) 2,
prepared by malononitrile, carbon disulfide, and ethyl
iodide in the presence of sodium ethoxide, with N-cya-
noacetohydrazide 3 at room temperature for 24 h in the
presence of KOH-dioxane produced the corresponding N-
[4-(ethyllthio)-2-oxopyridin 6, Scheme 1. The structure of 6
was established by IR spectrum and revealed absorption
band by cm− at 3490 and 3208 for NH , 2211 for CN and
1619 for C=O groups. Its H NMR spectrum showed by δ
1
2
1
3
.
triplet peak at 1.25 ppm and quartet at 3.24 ppm for CH3
Minimum inhibition concentration (MIC)
measurement
and CH of the SCH CH group, respectively, and two
2
2
3
broad peaks at 5.54 ppm and 8.40 ppm for two NH groups.
2
Furthermore, the reaction of 2 with N’-[(aryl)-methylene]-2-
cyanoacetohydrazides 7a–f, was carried out by treating 7a–f
with one equivalent of compound 2 in KOH-dioxane at
room temperature for 24 h and obtained the corresponding
7-(ethylthio)-3,5-dihydro[1,2,4]triazolo[1,5-a]pyridines
For each strain, three to five isolated colonies were selected
from the fresh agar plate and were transferred into a tube
containing 3–4 mL of sterile broth medium. The bacterial
suspension was mixed well and incubated at 35–37 °C for

Medicinal Chemistry Research
NC
NC
NC
NC
SNa
SNa
O
2
C H ONa - CS
2
2 5
C H I
2
5
Dioxane-KOH
RT-12h
2
NC
N
Ar
RT
EtOH - 1h,
N
H
1
7
O
SC H
2
5
NC
NH2
SC H
2
5
SC H
2 5
NC
H
N
H
NC
NC
SC H
2 5
3
NC
HN
H
NC
N
H
CN
O
Dioxane - KOH
RT,12h
CN
O
CN
O
N
HN
NH2
2 5
SC H
N
HN
N
4
2
N
Ar
Ar
9
8
SC H
SC H
2 5
2
5
NC
HN
H
CN
O
NC
H N
CN
SC H
2
5
N
NH2
N
NH2
O
2
NC
CN
ArCHO
6
5
6
N
NH
O
N
Scheme 1 A synthetic pathway for N-amino-4-(ethylthi)-pyridine-2-
one (6)
Ar
1
0
1
1
0a–f with 70–82% yield, Scheme 2. The formation of
0a–f from 2 and 7a–f is assumed to proceed via inter-
7,10
Ar
7,10
Ar
4-CH -C H
6 4
6 4
3-NO -C H
2 6 4
a
b
c
C H
d
e
f
6
5
3
mediate Michael adducts 8 and 9, which cyclized to yield
the novel triazolopyridine derivatives 10. The structure of
1
4-Cl-C H
4-F-C H
6
4
6
4-OCH -C H
3
4
1
13
0a–f was confirmed by H NMR, C NMR, IR, and ele-
Scheme 2 Synthetic pathways for 7-(Ethylthio)-5-oxo-[1,2,4]triazolo
1,5-a]pyridines (10a–f)
1
mental analysis. For example, H NMR spectrum of com-
[
pound 10b, showed a triplet peak at 1.24 ppm for CH2,
quartet at 3.18 ppm for CH , and two doublets at 7.57 ppm
3
and 8.15 ppm for the benzene ring. The absence of proton
of –CH=N– group in H NMR spectrum proved the
also be prepared by the reaction of the corresponding 1,6-
diamino-2-oxo-4-(ethylthio)-1,2-dihydropyridine-3-carbo-
nitriles 6 with benzene sulfonyl chloride in KOH-dioxane.
When compound 2 is treated with cyanoacetanilides 13 at
room temperature for 24 h in the presence of KOH-dioxane,
14a–f were obtained in excellent yield, Scheme 3. Com-
pound 10f reacted with hydrazine in refluxing ethanol in
presence of catalytic amount of piperidine to give the cor-
responding pyrazolo[4,3-c][1,2,4]triazolo[1,5-a]pyridines
15. The structure of compound 15 was established on the
basis of spectral data and elemental analysis as outlined in
Scheme 3. Its IR spectrum showed absorption band at 3387
1
cyclization of adduct 9 and the formation of triazolopyridine
derivatives 10. Compounds 10 can also be prepared by the
reaction of the corresponding N-[4-(ethyllthio)-2-oxopyr-
idin-1 6 with substituted aromatic aldehydes. In order to
explore the reactivity of cyanoketene dithioacetal 2 with
other classes of substituted cyanoacetohydrazide, com-
pound 2 reacted with cyanoaceto-N-phenylsulfonyl-hydra-
zide 11a, b at room temperature for 24 h in the presence of
KOH-dioxane to give the corresponding N-[4-(ethylthio)-2-
oxopyridin-1(2H)-yl]benzene-sulfonamide 12a, b, Scheme
and 3260 cm− for NH , band at 2196 cm for CN and
1
−1
3
. The structures of compounds 12a, b were established on
2
band at 1660 cm− for C=O groups. Furthermore, the for-
1
the basis of spectroscopic data and elemental analysis,
1
Scheme 3. IR of 12b revealed absorption band at 3409 and
mation of compound 15 was confirmed by H NMR, two
−
1
−1
−1
3
283 cm for NH , 2214 cm for CN and 1609 cm for
broad signals at 5.18 ppm and 11.40 ppm for NH and NH,
2
2
1
C=O groups. Its H NMR spectrum displayed triplet peak
respectively, and multiplet at 7.76–8.85 ppm for the ben-
zene ring. The disappearance of triplet and quartet peaks for
CH and CH , respectively, and the presence of broad peaks
at 1.24 ppm for CH , singlet peak at 2.32 ppm for CH of
2
3
tosyl group, quartet peak at 3.17 ppm for CH , two doublet
3
3
2
1
peaks at 7.15 ppm and 7.58 ppm for the benzene ring and a
at 5.18 ppm for NH and 11.40 ppm for NH groups in H
2
broad singlet peak at 7.82 ppm for NH. Compounds 12 can
NMR spectrum proved the formation of pyrazol ring.

Medicinal Chemistry Research
O
H
N
(RCMB 05036), Geotrichum candidum (RCMB 052006)
and Syncephalastrum racemosum (RCMB 005003) strains
of fungi, (ii) Streptococcus pneumoniae (RCMB 010010),
Staphylococcus aureus (RCMB 010028), Bacillis subtilis
(RCMB 010067) and Enterococcus faecalis (RCMB
010068) strains of Gram-positive bacteria, and (iii) Pseu-
domonas aeruginosa (RCMB 010043), Escherichia coli
(RCMB 010052), Serratia marcescens (RCMB 010071)
and Salmonella typhimurium (RCMB 010072) strains as
gram-negative bacteria. Antimicrobial tests were carried out
at the Regional Center for Mycology and Biotechnology,
Antimicrobial Activity Unit, Al-Azhar University, Cairo,
Egypt. Amphotericin B, Ampicillin and Ciprofloxacin were
used as standard. The results were recorded for each tested
compound as inhibition diameter zones in millimeters
O
S
O
Dioxane-KOH
RT - 12h
NC
Ar
2
N
H
11
SC H
2
5
NC
CN
Ar.SO Cl - EtOH
2
6
1
h
H N
N
O
2
NH
O S O
Ar
1
1,12
Ar
a
b
C H
6
5
4-CH -C H
3
6 4
1
2
SC H
2
5
CN
O
NC
2
NC
Ar
(mm) ± standard deviation and are summarized in Tables 1–
N
H
Dioxane-KOH
RT - 12h
N
Ar
14
O
3. The MIC measurements were determined for the most
active compounds 10c, 10e, and 14b by using twofold serial
dilution method and the results were all summarized in
Table 4.
Most of the synthesized compounds except 10d, 14a,
and 14c were shown to possess moderate to good anti-
microbial activity against most of the tested organisms
except P. aeruginosa as compared to Amphotericin B and
Ciprofloxacin. The most active compound was found to be
H N
2
13
1
3,14
Ar
13,14
Ar
4-CH -C H
6 4
a
b
c
C H
d
e
f
6
5
6
3
4-Cl-C H
4
3 6 4
2-CH -C H
4-OCH -C H
3-CH -C H
3
6
4
3
6
4
HN N
14b, which has 4-chlorobenzene at N1 showing interesting
NC
N
NH2
NH NH - Pip.-EtOH
2
2
10f
antibacterial and antifungal activities. It was shown to have
close activity to Amphotericin B against A. fumigatus
(Inhibition Zone 22.3 ± 0.44 mm; MIC 125 µg/mL), similar
activity to Ciprofloxacin against E. coli (Inhibition Zone
1h
N
NH
O
1
5
2
(
3.2 ± 1.5 mm; MIC 250 µg/mL) and S. typhimurium
Inhibition Zone 23.4 ± 0.77 mm; MIC 250 µg/mL) and
higher activity than Ciprofloxacin against S. marcescens
Inhibition Zone 28.1 ± 0.76 mm; MIC 62.5 µg/mL) as
NO
2
Scheme 3 Synthetic pathways for N-arylsulfonylamino-2-pyridones
12a, b), N-aryl-2-pyridones (14a–f) and pyrazolo[3,4-d][1,2,4]-tria-
(
(
clearly shown in Tables 1–3. Alternatively, pyridone deri-
vatives fused with triazol moiety such as 10c and 10e
showed marked activities toward Gram-negative bacteria,
Table 2, as compared to Ciprofloxacin. Both 10c and 10e
have higher activity than Ciprofloxacin against S. marces-
cens with inhibition zone 21.5 ± 0.88 and 24.3 ± 0.42 mm,
respectively, but lower than 14b, and similar activity to
Ciprofloxacin against E. coli. Comparing both 10c and 10e
to Amphotericin B, Table 3, showed slightly lower activ-
ities for the former against A. fumigatus with inhibition zone
21.3 ± 1.5 and 21.3 ± 0.58 mm, respectively. Despite the
fact that several drugs such as sulfamethoxazole and sul-
fadimidine, which contain sulfonamide group are well
known as antimicrobial agents, the synthesized pyridone
derivatives containing the N-sulfonylamino group, 12a and
12b, surprisingly showed low activities against all tested
organisms as compared to Amphotericin B and Cipro-
floxacin standard.
zolo[1,5-a]pyridine-9-carbonitrile (15)
Antimicrobial evaluations
Some bacteria and fungi have shown resistance to existing
antimicrobial agents. Pyridone derivatives are important
scaffolds which exhibit promising antimicrobial activities
(
Darwish et al. 2014, Shah et al. 2013). This promoted us to
develop new pyridone derivatives as antibacterial and
antifungal agents. The aim of our work is to synthesize
different series of pyridine bearing an ethylsulfanyl group at
C4 with different substitutes at N1. Additionally, we studied
the anti (bacterial and fungal) activities of these derivatives
and the influence of the various substituents at N1 position.
The synthesized pyridone derivatives 10a–e, 12a, b and
1
4a–f bearing fused triazole, N-sulfonylamino and N-aryl
moieties, respectively, were individually tested against (i)
Aspergillus fumigatus (RCMB 02568), Candida albicans

Medicinal Chemistry Research
Table 3 Antifungal activities of
the synthesized compounds
Sample
Fungi
A. fumigatus
C. albicans
G. candidum
S. racemosum
1
1
1
1
1
1
1
1
1
1
1
1
1
0a
0b
0c
0d
0e
2a
2b
4a
4b
4c
4d
4e
4f
20.6 ± 1.2
9.3 ± 0.58
21.3 ± 1.5
NAa
18.3 ± 0.58
11.2 ± 0.58
20.2 ± 1.2
NA
10.3 ± 0.32
11.7 ± 0.32
12.2 ± 0.33
NA
10.9 ± 0.28
10.3 ± 0.34
13.9 ± 0.52
NA
21.3 ± 0.58
16.3 ± 0.44
14.9 ± 0.25
NA
20.3 ± 0.58
18.2 ± 0.73
14.7 ± 0.58
NA
20.8 ± 0.54
15.8 ± 0.52
9.7 ± 0.42
NA
22.3 ± 0.64
18.5 ± 0.58
8.9 ± 0.31
NA
22.3 ± 0.44
NA
20.3 ± 0.19
NA
17.6 ± 0.58
NA
15.4 ± 0.38
NA
13.3 ± 0.62
12.3 ± 1.2
17.8 ± 0.58
23.7 ± 1.2
15.2 ± 0.53
13.2 ± 0.58
16.3 ± 1.2
25.4 ± 0.58
11.9 ± 0.47
10.5 ± 0.32
16.3 ± 0.52
28.7 ± 0.27
10.1 ± 0.42
10.8 ± 0.23
19.6 ± 0.58
26.3 ± 0.34
Amphotericin B
aNA: No observed activity
Table 4 The minimum
Sample
Gram positive bacteria
inhibitory concentration (MIC,
µg/mL) of the most active
compounds 10c, 10e, and 14b
S. pneumoniae
S. aureus
B. subtilis
E. faecalis
1
1
1
0c
0e
4b
1000
250
500
500
1000
1000
1000
31.25
1000
500
1000
1000
31.25
500
Ampicillin
31.25
62.5
Gram Negative Bacteria
P. aeruginosa
E. coli
S. marcescens
S. typhimurium
1
1
1
0c
0e
4b
NA
NA
NA
125
250
125
500
250
125
1000
250
250
62.5
31.25
Ciprofloxacin
31.25
31.25
Fungi
A. fumigatus
C. albicans
G. candidum
S. racemosum
1
1
1
0c
0e
4b
500
500
500
1000
1000
1000
31.25
500
1000
1000
31.25
500
125
500
Amphotericin B
31.25
31.25
Structural–activity relationship (SAR) of the synthesized
compounds and their antimicrobial activities showed quite
interesting observations. Firstly, the variation of the sub-
stituents on the aryl moieties of the triazol ring system fused
with the pyridone derivatives had a profound effect on the
compounds, 10a–e, activities as shown in Tables 1–3. It
was noticed that the presence of electron withdrawing
groups such as fluoride, 10e, exhibited activities close to
that of the standard. The presence of electron donating
group such as methyl group on the benzene ring 10d did not
result in noticeable activity of the analog against all
organisms while unsubstituted benzene ring 10a resulted in
moderate activity against A. fumigatus, S. pneumonia and E.
coli and low activity toward other organisms. Secondly,
similar observation was also noticed regarding the presence
of methyl group on the benzene ring of pyridone derivatives
with N-sulfonylamino, 12b. It lowered the activity toward
all organisms as compared to the case of unsubstituted

Medicinal Chemistry Research
benzene ring, 12a. Thirdly, the presence of electron with-
drawing group such as Cl on the aryl moiety of compound
thioglycosides and their corresponding pyrazolopyrimidine and
pyrazolopyridine thioglycosides. Tetrahedron 73:5853–5861
Elgemeie GH, Abu-Zaied MA, Nawwar GA (2018) First novel
synthesis of triazole thioglycosides as ribavirin analogues.
Nucleosides & Nucleotides 37:112–123
Elgemeie GH, El-Ezbawy SR, El-Aziz HA (2001) The design and
synthesis of structurally related mercaptopurine analogues: reac-
tion of dimethyl N-cyano-dithioiminocarbonate with 5-
aminopyrazoles. Synth Commun 31:3453–3458
1
4b showed the highest antibacterial activity of all com-
pounds toward three of the tested Gram-negative bacteria.
Finally, in case of pryidone derivatives 14d–f, the position
of the methyl group on the aryl moiety varied the activity of
the corresponding derivative. Compound 14f with methyl
group on the meta position showed higher antimicrobial
activity than both 14d and 14e with methyl group on the
para and ortho positions, respectively. In addition and
specifically in case of the tested fungi, the presence of
methyl group on the para position of the benzene ring
caused the increase in the activity of compound 14d as
compared to that of the same compound with ortho-sub-
stituted methyl group, 14e, Table 3. However, in case of the
tested Gram-positive and Gram-negative bacteria, the
activity of 14d showed opposite behavior, Tables 1, 2.
Elgemeie GH, Elghandor AH, Abd-Elaziz GW (2003) Novel synthesis
of heterocyclic ketene N,N-, N,O-, and N,S-acetals using cyano-
ketene dithioacetals. Synth Commun 33:1659–1664
Elgemeie GH, Elghandor AH, Abd-Elaziz GW (2004) Potassium 2-
cyanoethylene-1-thiolate:
a new preparative route to 2-
cyanoketene S,N-acetals and pyrazole derivatives. Synth Com-
mun 34:3281–3291
Elgemeie GH, Elghandor AH, Elzanate AM, Ahamed SA (2006)
Novel 1,3-dithiolanes using sodium α-cyano-ketene dithiolates.
Synth Commun 36:755–764
Elgemeie GH, Elzanate AM, Elghandor AH, Ahamed SA (2002)
Novel intramolecular cyclization of pyrazolone ketene S,N-acet-
als for the construction of methylsulfanylpyrazolo[4,3-b]pyr-
idines. Synth Commun 32:3509–3517
Elgemeie GH, Jones PG (2002) N-[3-Cyano-2-oxo-5,6,7,8-tetra-
Conclusion
hydroquinoline-1(2H)-yl]-4-methylbenzenesulfonamide.
Cryst E58:1250–1251
Acta
Elgemeie GH, Jones PG (2004) 6-Amino-4-(methylsulfanyl)-2-oxo-1-
tolyl-1,2-dihydropyridine-3,5-dicarbonitrile. Acta Cryst
0:2107–2109
Elgemeie GH, Jones PG (2016) Crystal structure of 1-amino-2-oxo-
2,5,6,7,8,9-hexahydro-1H-cyclohepta[b]pyridine-3-carbonitrile.
Acta Cryst E72:1239–1241
In summary, new series of N-substituted derivatives of 4-
ethylsulfanyl-2-pyridones and triazolopyridines were syn-
thesized, characterized by spectral analysis and evaluated
for their in vitro antimicrobial activities. The antimicrobial
results showed that three compounds (10c, 10e, and 14b)
were the most active antimicrobial agents in this study.
E
6
Elgemeie GH, Mahmoud MA, Jones PG (2002) N-(3-Cyano-2-oxo-
2
,5,6,7,8,9-hexahydro-1H-cyclohepta[b]pyridin-1-yl)-4-methyl-
benzenesulfonamide. Acta Cryst E58:1293–1295
Compliance with ethical standards
Fassihi A, Abedi D, Saghaie L, Sabet R, Fazeli H, Bostaki G, Deilami
O, Sadinpour H (2009) Synthesis, antimicrobial evaluation and
QSAR study of some 3-hydroxy-pyridine-4-one and 3-
hydroxypyran-4-one derivatives Eur J Med Chem 44:2145–
Conflict of interest The authors declare that they have no conflict of
interest.
2
157.
NSC690376), 391347 (NSC690377), 391348 (NSC690378),
91349 (NSC690379), 391350 (NSC690380), 391351
https://pubchem.ncbi.nlm.nih.gov/compound/391346
(
3
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