Synthesis and antimicrobial activities of some newly 2,4,6-tri-substituted pyridine derivatives

Article abstract of DOI:10.1007/s11164-013-1028-0

A series of novel 2-(2-(substituted benzylidene)hydrazinyl)-N'-(substituted benzylidene)-6-chloropyridine-4-carbohydrazide (5a-e), 2-(2- cycloalkylidenehydrazinyl)-6-chloro-N'-cyclo-alkylidenepyridine-4- carbohydrazide (6a,b), 2-(2-(1-(4-substituted phenyl)ethylidene)hydrazinyl)-6- chloro-N'-(1-(4-substituted phenyl)ethylidene)pyridine-4-carbohydrazide (7a,b) and 2-(2-(1-(pyridinyl)ethylidene)hydrazinyl)-6-chloro-N'-(1-(pyridinyl) ethylidene)pyridine-4-carbo-hydrazide (8a-c) derivatives have been synthesized by treating treating 2-chloro-6-hydrazinoisonicotinic acid hydrazide 4 with selected active reagents. Their structures were confirmed by spectral and analytical data. The synthesized compounds were investigated for antimicrobial activities. The antimicrobial screening showed that many of these obtained compounds have good activities comparable to Streptomycin and Fusidic acid as reference drugs. Springer Science+Business Media Dordrecht 2013.

Full text of DOI:10.1007/s11164-013-1028-0

Res Chem Intermed
DOI 10.1007/s11164-013-1028-0
Synthesis and antimicrobial activities of some newly
2,4,6-tri-substituted pyridine derivatives
•
Osama I. Abdel Salam Nagy M. Khalifa
•
•
Said A. Said Abd El-Galil E. Amr
Received: 26 December 2012 / Accepted: 4 January 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract A series of novel 2-(2-(substituted benzylidene)hydrazinyl)-N0-(substi-
tuted benzylidene)-6-chloropyridine-4-carbohydrazide (5a–e), 2-(2-cycloalk-
ylidenehydrazinyl)-6-chloro-N’-cyclo-alkylidenepyridine-4-carbohydrazide (6a,b),
2-(2-(1-(4-substituted phenyl)ethylidene)hydrazinyl)-6-chloro-N0-(1-(4-substituted
phenyl)ethylidene)pyridine-4-carbohydrazide (7a,b) and 2-(2-(1-(pyridinyl)ethyli-
dene)hydrazinyl)-6-chloro-N0-(1-(pyridinyl) ethylidene)pyridine-4-carbo-hydrazide
(8a–c) derivatives have been synthesized by treating treating 2-chloro-6-hydrazi-
noisonicotinic acid hydrazide 4 with selected active reagents. Their structures were
confirmed by spectral and analytical data. The synthesized compounds were
investigated for antimicrobial activities. The antimicrobial screening showed that
many of these obtained compounds have good activities comparable to Strepto-
mycin and Fusidic acid as reference drugs.
Keywords Citrazinic acid ꢀ Hydrazide ꢀ Hydrazones ꢀ Antimicrobial activities
Introduction
Several publications have reported isonicotinic acid hydrazide and its derivatives as
antitubercular [1–3], virucide and bactericide [4] agents. In our previous work, we
O. I. Abdel Salam ꢀ A. E.-G. E. Amr (&)
Applied Organic Chemistry Department, National Research Center, Dokki,Cairo, Egypt
e-mail: aamr1963@yahoo.com
N. M. Khalifa ꢀ A. E.-G. E. Amr
Pharmaceutical Chemistry Department, Drug Exploration & Development Chair, College of
Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
S. A. Said
Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
123

O. I. Abdel Salam et al.
reported the synthesis, characterization, and preliminary biological activity of some
series of substituted pyridine derivatives as antimicrobial agents [5–9]. Also, we
found that certain substituted pyridine and their amide derivatives show analgesic
and anticonvulsant [10], antimicrobial [11, 12] and antitumor activities [13, 14]. In
addition, the biological and analgesic activities of many heterocyclic compounds
containing a sulfur atom have been reviewed [15–17]. On the other hand, some of
the nitrogenous candidates have promising biological [18, 19] and anticancer
activities [20, 21]. Recently, some new Schiff’s base derivatives have been
synthesized and tested as antimicrobial agents [22–24]. In continuation of our
previous work aiming at the synthesis of heterocyclic systems with remarkable
biological importance [5–13], we report here on the synthesis of some new pyridine
derivatives with different substituted at positions-2,4,6 and their antimicrobial
activities.
Results and discussion
2-Chloro-6-hydrazinoisonicotinic acid hydrazide (4) was synthesized using as
starting material according to the reported procedure [6, 25]. Chlorination of 2,6-
dihydroxyisonicotinic acid (citrazinic acid) (1) with phosphorus oxychloride in the
presence of TEA afforded the corresponding 2,6-dichloroisonicotinic acid (2),
which was esterified with absolute ethanol in the presence of concentrated sulfuric
acid to afford ethyl 2,6-dichloro-isonicotinate (3). The ester 3 was treated with
hydrazine hydrate in refluxing ethanol to afford 2-chloro-6-hydrazino isonicotinic
acid hydrazide (4) in pure form and good yield (Scheme 1).
Additionally, bis-Schiff base derivatives 5a–e were synthesized via simple
condensation of the hydrazide 4 with appropriate substituted aromatic aldehydes,
O
O
Cl
HO
OH
OH
POCl3
TEA
N
N
Cl
2
OH
1
O
EtOH/H2SO4
O
Cl
NH2
N
H
Cl
Et
O
NH2NH2.H2O
EtOH
N
N
HN
NH2
Cl
3
4
Scheme 1 Synthetic route for starting material 4
123

2,4,6-tri-substituted pyridine derivatives
namely, 2,6-dichlorobenzaldehyde, 3,4-dichlorobenzaldehyde, 2-chloro-6-flouro-
benzaldehyde, 2-methoxybenzaldehyde, or 3,4,5-trimethoxy-benzaldehyde in re-
fluxing absolute ethanol. Also, condensation of hydrazide 4 with selected active
ketones, namely, cycloalkanone (cyclohexanone or cycloheptanone), substituted
acetophenone or acetyl pyridine derivatives in refluxing ethanol in the presence a
X
O
Cl
N
O
N
H
Cl
N
N
CH3
N
H
CH3
N
(
)n
HN
N
HN
N
(
)n
7a,b
X
6a,b
a, X = OMe, b, X = NO2
a, n = 1, b, n = 2
X
COCH3
O
(
)n
O
Cl
NH2
N
H
N
CHO
HN
COCH3
4
NH2
X
N
EtOH
O
O
Z
X
Cl
Y
N
Cl
N
N
H
N
H
X
N
N
CH3
CH3
HN
HN
N
X
N
Y
Z
X
5a-e
8a-c
a, X = 2,6-Cl2; b, X = 3,4-Cl2;
c, X = 2-Cl,6-F d, X = 2-OMe;
e, X = 3,4,5-OMe3
a, X = N, Y = Z = C
b, X = Z = C, Y = N
c, X = Y = C, Z = N
Scheme 2 Synthetic route for the target compounds 5–8
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O. I. Abdel Salam et al.
few drops of glacial acetic acid afforded the corresponding condensed derivatives
6a,b, 7a,b and 8a–c, respectively (Scheme 2).
Antimicrobial activity
The newly synthesized compounds (5–8) have been tested for their preliminary
antimicrobial activity against Bacillus subtilis (NRRL B-543) and Staphylococcus
aureus (NRRL B-313) (as Gram-positive bacteria), and Esherishia coli (NRRL
B-558) (as Gram-negative bacteria), while Candida albicans (NRRL Y-477) and
Aspergillus niger (NRRL Y-3) (as fungi). The antimicrobial activity was measured
at 50 l/mL of the tested compounds using the bioassay sensitivity technique of
antibiotics specified in the United States Pharmacopoeia [26]. The degree of
inhibition is measured in comparison with that of Streptomycin and Fusidic acid
taken as standards at the same concentration. The results are summarized in Table 1.
Experimental
Melting points were uncorrected and determined in open glass capillaries using in
Electrothermal IA 9000 Series digital melting point apparatus (Electrothermal,
Essex, UK.). Elemental analyses were performed with all final compounds with an
Elementar Vario EL (Microanalytical Unit, Cairo University, Cairo, Egypt), and
Table 1 Antimicrobial activity of the new synthesized compounds 5–8
Comp. no.
Inhibition zone diameter (mm)
Gram-positive bacteria
Gram-negative bacteria
Fungi
B. subtilis
S. aureus
E. coli
C. albicans
A. niger
5a
15
20
12
11
19
20
10
14
13
14
16
15
21
–
14
15
13
12
10
18
15
21
22
22
15
22
22
–
21
20
13
14
22
18
10
16
11
12
15
14
21
–
11
16
19
10
17
12
14
10
15
11
18
15
–
15
18
18
15
15
12
14
10
16
15
19
16
–
5b
5c
5d
5e
6a
6b
7a
7b
8a
8b
8c
Streptomycin
Fusidic acid
17
18
123

2,4,6-tri-substituted pyridine derivatives
were in good agreement ( 0.4 %) with the calculated values. The IR spectra (KBr)
were recorded on an FT IR-8201 PC spectrophotometer (Schimadzu, Japan). The
NMR spectra were measured with a Jeol 270 MHz spectrometer (FTGNM-EX 270;
Japan) in DMSO-d6 as solvent. The chemical shifts were recorded relative to TMS.
The mass spectra (EI) were run at 70 eV with a Finnegan SSQ 7000 spectrometer
(Thermoinstrument System, USA), m/z values are indicated in Dalton. TLC (Silica
gel, aluminum sheets 60 F254; Merck, Darmstadt, Germany) was used for tracing the
reactions. Antimicrobial screening was carried out in Department of Microbial
Chemistry, National Research Center, Cairo, Egypt.
Synthesis of 2-(2-(substituted benzylidene)hydrazinyl)-N0-(substituted
benzylidene)-6-chloropyridine-4-carbohydrazide (5a–e)
A mixture of the hydrazide derivative 4 (0.554 g, 1 mmol) and the appropriate
aldehydes, namely, 2,6-dichloro-, 3,4-dichloro-, 2-chloro-6-flouro-, 2-methoxy- or
3,4,5-trimethoxybenzaldehydes (2 mmol) in absolute ethanol (50 mL) was heated
under reflux for 6 h. The reaction mixture was poured onto ice-water, the
obtained solid was collected by filtration, washed with water and crystallized
from a proper solvent to afford the corresponding Schiff base derivatives 5a–e,
respectively.
2-(2-(2,6-Dichlorobenzylidene)hydrazinyl)-N’-(2,6-dichlorobenzylidene)-
6-chloropyridine-4-carbohydrazide (5a)
Yield 82 %, mp 184-186 °C (AcOH/H2O). IR (KBr, cm-1): 3233 (NH), 1665
1
(C=O); H NMR (DMSO-d6, ppm): d = 6.86–7.40 (m, 6H, Ar–H), 8.10–8.32 (m,
4H, pyr-H ? 2CH = N), 8.75, 10.45 (2 s, 2H, 2NH, exchangeable with D2O); 13C
NMR (DMSO-d6, ppm): d = 108.05, 112.08, 146.98, 149.35, 153.86 (5C, pyr-C),
126.42, 129.56, 132.48, 134.15 (12C, Ar–C), 142.68 (2CH=N), 162.70 (CO); MS,
m/z (%): 515 [M?, 12] and 186 (100). Anal. Calcd. for C20H12Cl5N5O (515.61): C,
46.59; H, 2.35; N, 13.58; Cl, 34.38. Found: C, 46.52; H, 2.30; N, 13.50; Cl, 34.32.
2-(2-(3,4-Dichlorobenzylidene)hydrazinyl)-N’-(2,6-dichlorobenzylidene)-
6-chloropyridine-4-carbohydrazide (5b)
Yield 68 %, mp 200-204 °C (EtOH). IR (KBr, cm-1): 3352 (NH), 1660 (C=O); 1H
NMR (DMSO-d6, ppm): d = 6.92–7.55 (m, 4H, Ar–H), 7.72 (s, 2H, Ar–H),
8.08–8.36 (m, 4H, pyr-H ? 2CH=N), 8.82, 10.36 (2s, 2H, 2NH, exchangeable with
D2O); 13C NMR (DMSO-d6, ppm): d = 108.15, 112.22, 147.05, 149.42, 154.02
(5C, pyr-C), 126.86, 129.35, 129.56, 132.62, 132.70, 134.65 (12C, Ar–C), 143.55
(2CH=N), 171.80 (CO); MS, m/z (%): 515 [M?, 18] and 215 (100). Anal. Calcd. for
C20H12Cl5N5O (515.61): C, 46.59; H, 2.35; N, 13.58; Cl, 34.38. Found: C, 46.53; H,
2.28; N, 13.52; Cl, 34.34.
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O. I. Abdel Salam et al.
2-(2-(2-Chloro-6-flourobenzylidene)hydrazinyl)-N0-(2,6-dichlorobenzylidene)-
6-chloropyridine-4-carbohydrazide (5c)
Yield 75 %, mp 175–177 °C (AcOH/H2O). IR (KBr, cm-1): 3348 (NH), and 1665
1
(C=O); H NMR (DMSO-d6, ppm): d = 6.88–7.55 (m, 6H, Ar–H), 8.14–8.35 (m,
4H, pyr-H ? 2CH=N), 8.78, 10.32 (2s, 2H, 2NH, exchangeable with D2O); 13C
NMR (DMSO-d6, ppm): d = 107.98, 112.04, 147.14, 149.40, 153.88 (5C, pyr-C),
113.65, 117.82, 124.80, 133.50, 134.52, 161.00 (12C, Ar–C), 143.64 (2CH=N),
171.86 (CO); MS, m/z (%): 483 [M??1, 6] and 199 (100). Anal. Calcd. for
C20H12Cl3F2N5O (482.70): C, 49.76; H, 2.51; N, 14.51; Cl, 22.03. Found: C, 49.70;
H, 2.46; N, 14.44; Cl, 21.96.
2-(2-(2-Methoxybenzylidene)hydrazinyl)-N0-(2,6-dichlorobenzylidene)-
6-chloropyridine-4-carbohydrazide (5d)
Yield 92 %, mp 222–224 °C (MeOH). IR (KBr, cm-1): 3332 (NH) and 1664
1
(C=O); H NMR (DMSO-d6, ppm): d = 3.72 (s, 6H, 2OCH3), 6.84-7.45 (m, 8H,
Ar–H), 8.02-8.40 (m, 4H, pyr-H ? 2CH=N), 8.76, 10.28 (2s, 2H, 2NH, exchange-
able with D2O); 13C NMR (DMSO-d6, ppm): d = 55.14 (2OCH3), 107.86, 112.05,
147.14, 149.32, 154.10 (5C, pyr-C), 112.66, 115.82, 120.90, 130.98, 132.02, 157.10
(12C, Ar–C), 144.04 (2CH=N), 172.12 (CO); MS, m/z (%): 438 [M?, 6] and 107
(100). Anal. Calcd. for C22H20ClN5O3 (437.88): C, 60.34; H, 4.60; N, 15.99; Cl,
8.10. Found: C, 60.30; H, 4.55; N, 15.93; Cl, 8.00.
2-(2-(3,4,5-Trimethoxybenzylidene)hydrazinyl)-N0-(2,6-dichlorobenzylidene)-
6-chloropyridine-4-carbohydrazide (5e)
Yield 78 %, mp 215–217 °C (DMF/EtOH). IR (KBr, cm-1): 3238 (NH), 1662
(C=O); 1H NMR (DMSO-d6, ppm): d = 3.72 (s, 18H, 6OCH3), 7.38 (s, 4H, Ar–H),
7.88–8.25 (m, 4H, pyr-H ? 2CH=N), 8.76, 10.40 (2s, 2H, 2NH, exchangeable with
D2O); 13C NMR (DMSO-d6, ppm): d = 55.12 (4C, 4OCH3), 58.74 (2C, 2OCH3),
108.00, 112.02, 146.96, 149.32, 153.88 (5C, pyr-C), 105.10, 127.32, 140.66, 152.78
(12C, Ar–C), 142.78 (2CH=N), 163.22 (CO); MS, m/z (%): 558 [M?, 38] and 235
(100). Anal. Calcd. for C26H28ClN5O7 (557.98): C, 55.97; H, 5.06; N, 12.55; Cl,
6.35. Found: C, 55.92; H, 5.00; N, 12.50; Cl, 6.30.
Synthesis of 2-(2-cycloalkylidenehydrazinyl)-6-chloro-
N0-cycloalkylidenepyridine-4-carbo-hydrazide (6a,b)
To a solution of cyclohexanone or cycloheptanone (2 mmol) in absolute ethanol
(50 mL) in the presence of few drops glacial acetic acid, compound 4 (0.34 g,
1 mmol) was added with stirring. The reaction mixture was heated under reflux for
6 h, and evaporated under reduced pressure to dryness. The obtained residue was
solidified with n-hexane, and the solid formed was filtered off, dried and crystallized
from the proper solvent to give the corresponding title compounds 6a,b,
respectively.
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2,4,6-tri-substituted pyridine derivatives
2-(2-Cyclohexylidenehydrazinyl)-6-chloro-N0-cyclohexylidenepyridine-
4-carbohydrazide (6a)
Yield 65 %, mp 156–158 °C (EtOH). IR (KBr, cm-1): 3345 (NH), 2934 (CH-
aliphatic), 1665 (C=O); 1H NMR (DMSO-d6, ppm): d = 1.58–1.65 (m, 12H, 6CH2,
hexyl rings), 2.15–2.28 (m, 8H, 4CH2, hexyl ring), 7.98, 8.10 (2s, 2H, pyr-H), 8.86,
10.46 (2s, 2H, 2NH, exchangeable with D2O); 13C NMR (DMSO-d6, ppm):
d = 23.85, 26.45, 35.10, 161.45 (12C, hexane ring), 106.05, 111.32, 146.50,
148.90, 153.04 (5C, pyr-C), 163.14 (CO); MS, m/z (%): 361 [M?, 14] and 154
(100). Anal. Calcd. for C18H24ClN5O (361.86): C, 59.74; H, 6.68; N, 19.35; Cl,
9.80. Found: C, 59.70; H, 6.62; N, 19.29; Cl, 9.74.
2-(2-Cycloheptylidenehydrazinyl)-6-chloro-N’-cycloheptylidenepyridine-
4-carbohydrazide (6b)
Yield 72 %, mp. 205-207 °C (EtOH/ether). IR (KBr, cm-1): 3356 (NH), 2945 (CH-
aliphatic), 1662 (C=O); 1H NMR (DMSO-d6, ppm): d = 1.62–1.72 (m, 16H, 8CH2,
heptyl ring), 2.10-2.32 (m, 8H, 4CH2, heptyl ring), 8.05, 8.12 (2s, 2H, pyr-H), 8.94,
10.56 (2s, 2H, 2NH, exchangeable with D2O); 13C NMR (DMSO-d6, ppm):
d = 23.78, 28.40, 33.18, 175.55 (14C, heptane rings), 106.12, 110.96, 146.32,
149.06, 153.12 (5C, pyr-C), 162.96 (CO); MS, m/z (%):390 [M?, 10] and 250 (100).
Anal. Calcd. for C20H28ClN5O (389.92): C, 61.61; H, 7.24; N, 17.96; Cl, 9.09.
Found: C, 61.54; H, 7.20; N, 17.88; Cl, 9.02.
2-(2-(1-(4-Substituted phenyl)ethylidene)hydrazinyl)-6-chloro-N0-(1-
(4-substituted phenyl) ethylidene)pyridine-4-carbohydrazide (7a,b)
A mixture of 4 (0.34 g, 1 mmol) and substituted acetophenone derivatives, namely,
p-methoxy- or p-nitroacetophenenone (2 mmol) in absolute ethanol (100 mL), was
refluxed for 6 h in the presence of glacial acetic acid (2 mL). The reaction mixture
was concentrated under reduced pressure, and the solid formed was collected by
filtration, dried and purified by crystallization from the proper solvent to give the
corresponding title compounds 7a,b, respectively.
2-(2-(1-(4-Methoxyphenyl)ethylidene)hydrazinyl)-6-chloro-N0-(1-
(4-methoxyphenyl)ethylidene) pyridine-4-carbohydrazide (7a)
Yield 55 %, mp 234–236 °C (DMF/H2O). IR (KBr, cm-1): 3376 (NH), 2952 (CH-
1
aliphatic), 1665 (C=O); H NMR (DMSO-d6, ppm): d = 1.72 (s, 6H, 2CH3), 3.65
(s, 6H, 2OCH3), 6.95-7.72 (m, 8H, Ar–H), 7.96, 8.08 (2s, 2H, pyr-H), 9.10, 10.76
(2s, 2H, 2NH, exchangeable with D2O); 13C NMR (DMSO-d6, ppm): d = 17.60
(2CH3), 56.76 (2OCH3), 114.08, 126.25, 129.64, 162.75 (12C, Ar–C), 168.55
(2C=N), 105.98, 112.05, 146.18, 148.76, 152.98 (5C, pyr-C), 163.35 (CO); MS, m/z
(%): 466 [M?, 10] and 191 (100). Anal. Calcd. for C24H24ClN5O3 (465.93): C,
61.87; H, 5.19; N, 15.03; Cl, 7.61. Found: C, 61.80; H, 5.15; N, 14.96; Cl, 7.55.
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O. I. Abdel Salam et al.
2-(2-(1-(4-Nitrophenyl)ethylidene)hydrazinyl)-6-chloro-N0-(1-
(4-nitrophenyl)ethylidene) pyridine-4-carbohydrazide (7b)
Yield 62 %, mp 245-247 °C (DMF/H2O). IR (KBr, cm-1): 3366 (NH), 2968 (CH-
1
aliphatic), 1668 (C=O); H NMR (DMSO-d6, ppm): d = 1.68 (s, 6H, 2CH3), 6.98-
7.88 (m, 8H, Ar–H), 8.02, 8.12 (2s, 2H, pyr-H), 9.15, 10.84 (2s, 2H, 2NH,
exchangeable with D2O); 13C NMR (DMSO-d6, ppm): d = 17.42 (2CH3), 119.10,
129.28, 138.86, 149.72 (12C, Ar–C), 169.25 (2C=N), 105.85, 112.14, 146.08,
148.66, 153.92 (5C, pyr-C), 164.15 (CO); MS, m/z (%): 496 [M?, 24] and 196
(100). Anal. Calcd. for C22H18ClN7O5 (495.87): C, 53.29; H, 3.66; N, 19.77; Cl,
7.15. Found: C, 53.24; H, 3.60; N, 19.70; Cl, 7.07.
(2-(2-(1-(Pyridinyl)ethylidene)hydrazinyl)-6-chloro-N0-
(1-(pyridinyl)ethylidene)-pyridine-4-carbohydrazide (8a–c)
To a hot solution of acetylpyridine, namely, 2-acetyl-, 3-acetyl- or 4-acetylpyridine
derivatives (2 mmol) in absolute ethanol (100 mL), hydrazide of 4 (0.34 g, 1 mmol)
was added with stirring. The reaction mixture was refluxed for 5 h, and, after
cooling, the reaction mixture was poured into ice-water. The obtained solid was
separated by filtration, washed with water, dried and crystallized from the proper
solvent to give the corresponding title compounds 8a–c, respectively.
2-(2-(1-(Pyridin-2-yl)ethylidene)hydrazinyl)-6-chloro-N0-(1-(pyridin-
2-yl)ethylidene)pyridine-4-carbohydrazide (8a)
Yield 72 %, mp 215-217 °C (AcOH/H2O). IR (KBr, cm-1): 3360 (NH), 2958 (CH-
1
aliphatic), 1665 (C=O); H NMR (DMSO-d6, ppm): d = 1.74 (s, 6H, 2CH3), 7.76-
8.65 (m, 10H, pyr-H), 9.25, 10.75 (2s, 2H, 2NH, exchangeable with D2O); 13C
NMR (DMSO-d6, ppm): d = 17.12 (2CH3), 146.12 (2C = N), 107.12, 111.75,
122.65, 125.88, 129.15, 145.54, 147.85, 149.07, 152.76, 153.68 (15C, pyr-C),
163.95 (CO); MS, m/z (%):407 [M?, 16] and 162 (100). Anal. Calcd. for
C20H18ClN7O (407.85): C, 58.90; H, 4.45; N, 24.04; Cl, 8.69. Found: C, 58.84; H,
4.40; N, 23.97; Cl, 8.62.
2-(2-(1-(Pyridin-3-yl)ethylidene)hydrazinyl)-6-chloro-N’-(1-(pyridin-
3-yl)ethylidene)pyridine-4-carbohydrazide (8b)
Yield 58 %, mp 196–198 °C (AcOH). IR (KBr, cm-1): 3334 (NH), 2963 (CH-
aliphatic), 1664 (C=O); 1H NMR (DMSO-d6, ppm): d = 1.68 (s, 6H, 2CH3),
7.66–8.72 (m, 8H, pyri-H), 9.10 (s, 2H, pyr-H), 9.55, 10.84 (2s, 2H, 2NH,
exchangeable with D2O); 13C NMR (DMSO-d6, ppm): d = 16.98 (2CH3), 166.05
(2C=N), 106.24, 112.34, 122.60, 125.82, 129.25, 145.50, 147.82, 149.00, 153.15,
153.78 (15C, pyr-C), 163.98 (CO); MS, m/z (%):407 [M?, 16] and 273 (100). Anal.
Calcd. for C20H18ClN7O (407.85): C, 58.90; H, 4.45; N, 24.04; Cl, 8.69. Found: C,
58.83; H, 4.37; N, 23.98; Cl, 8.63.
123

2,4,6-tri-substituted pyridine derivatives
2-(2-(1-(Pyridin-4-yl)ethylidene)hydrazinyl)-6-chloro-N0-(1-(pyridin-
4-yl)ethylidene)pyridine-4-carbohydrazide (8c)
Yield 64 %, mp 184–186 °C (DMF/H2O). IR (KBr, cm-1): 3344 (NH), 2974 (CH-
1
aliphatic), 1666 (C=O); H NMR (DMSO-d6, ppm): d = 1.65 (s, 6H, 2CH3), 7.86-
8.72 (m, 10H, pyr-H), 9.76, 10.80 (2s, 2H, 2NH, exchangeable with D2O); 13C
NMR (DMSO-d6, ppm): d = 16.98 (2CH3), 166.56 (2C=N), 106.15, 110.85,
123.65, 137.86, 146.22, 148.45, 149.16, 153.30 (15C, pyr-C), 164.02 (CO); MS, m/z
(%):407 [M?, 8] and 169 (100). Anal. Calcd. for C20H18ClN7O (407.85): C, 58.90;
H, 4.45; N, 24.04; Cl, 8.69. Found: C, 58.86; H, 4.40; N, 24.00; Cl, 8.65.
Acknowledgment The authors extend their appreciation to the Deanship of Scientific Research at King
Saud University for funding the work through the research group project No. RGP-VPP-0172.
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