Synthesis of chiral linear and macrocyclic candidates: VI. Synthesis and antibacterial activity of some macrocyclic tripeptides and linear dipeptide Schiff bases

Article abstract of DOI:10.1134/S1070363216010254

A series of macrocyclic tripeptides and linear dipeptide Schiff base derivatives has been synthesized using pyridine-3,5-dicarboxylic acid and L-phenyalanine methyl ester as starting materials. Treatment of pyridine-3,5-dicarbonyl dichloride with L-phenylalanine methyl ester gave N,N′-(pyridine-3,5-diyldicarbonyl)bis(L-phenyalanine methyl ester) which was hydrolyzed with 1N sodium hydroxide to the corresponding bis-acid, and the latter was cyclized with diamino acids to afford macrocyclic tripeptide derivatives. The reaction of the bis ester with hydrazine hydrate gave bis-hydrazide, which was condensed with aldehydes to obtain the corresponding Schiff base derivatives. The structures of the newly synthesized compounds were confirmed by IR, ¹H and ¹³C NMR, and MS spectral data and elemental analyses. The antimicrobial activities of some of the newly synthesized compounds were comparable with that of Streptomycin used as control.

Full text of DOI:10.1134/S1070363216010254

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 1, pp. 161–166. © Pleiades Publishing, Ltd., 2016.
Synthesis of Chiral Linear and Macrocyclic Candidates:
VI.1 Synthesis and Antibacterial Activity of Some Macrocyclic
Tripeptides and Linear Dipeptide Schiff Bases2
A. E. Amra,b and M. A. Al-Omara
a Pharmaceutical Chemistry Department, College of Pharmacy, Drug Exploration & Development Chair (DEDC),
King Saud University, Riyadh, 11451 Saudi Arabia
b Applied Organic Chemistry Department, National Research Center, Cairo, Dokki, 12622 Egypt
e-mail: aeamr1963@yahoo.com
Received July 2, 2015
Abstract—A series of macrocyclic tripeptides and linear dipeptide Schiff base derivatives has been
synthesized using pyridine-3,5-dicarboxylic acid and L-phenyalanine methyl ester as starting materials.
Treatment of pyridine-3,5-dicarbonyl dichloride with L-phenylalanine methyl ester gave N,N′-(pyridine-3,5-
diyldicarbonyl)bis(L-phenyalanine methyl ester) which was hydrolyzed with 1N sodium hydroxide to the
corresponding bis-acid, and the latter was cyclized with diamino acids to afford macrocyclic tripeptide
derivatives. The reaction of the bis ester with hydrazine hydrate gave bis-hydrazide, which was condensed with
aldehydes to obtain the corresponding Schiff base derivatives. The structures of the newly synthesized
1
compounds were confirmed by IR, H and 13C NMR, and MS spectral data and elemental analyses. The
antimicrobial activities of some of the newly synthesized compounds were comparable with that of
Streptomycin used as control.
Keywords: Amino acids, linear dipeptide hydrazide, macrocyclic tripeptide, Schiff bases
DOI: 10.1134/S1070363216010254
Among different areas of macrocyclic chemistry,
synthesis of azacrown derivatives has been the subject
of intense research [1–4]. Some new heterocyclic and
peptide derivatives have been studied with respect to
their anti-HIV [5], anti-inflammatory [6], analgesic
and anticonvulsant [7], anticancer [8, 9], and
antimicrobial activities [10–12]. In continuation of our
previous work, some new Schiff base derivatives have
recently been synthesized and tested as antimicrobial
and pharmacological agents [13–17]. In view of these
observations, we have synthesized a series of new
linear dipeptide Schiff bases and macrocyclic
tripeptide derivatives.
chloride gave pyridine-3,5-dicarbonyl dichloride (2),
which was reacted with L-phenylalanine methyl ester
in the presence of triethylamine to afford dimethyl
N,N′-(pyridine-3,5-diyldicarbonyl)bis[(2S)-2-amino-3-
phenylpropanoate] (3). The latter was hydrolyzed with
1N sodium hydroxide to bis-acid 4 which was cyclized
to macrocyclic tripeptide derivatives 5a and 5b by
condensation with diamino esters (L-ornithine or L-
lysine methyl ester). Finally, treatment of 3 with hydrazine
hydrate in refluxing methanol gave acid hydrazide
derivative 6 which was condensed with aromatic or
heterocyclic aldehydes to give the corresponding
Schiff bases 7a–7f and 8a–8c, respectively (Scheme 1).
Linear dipeptide Schiff base derivatives 7a–7f and
8a–8c were synthesized using N3,N5-bis[(2S)-1-
hydrazinyl-1-oxo-3-phenylpropan-2-yl]pyridine-3,5-
dicarboxamide (5) as starting material. Treatment of
pyridine-3,5-dicarboxylic acid (1) with thionyl
Fourteen newly synthesized compounds have been
tested for their antibacterial activity against Bacillus
subtilis, Staphylococcus aureus, and Escherichia coli
according to the bioassay technique for antibiotics [18]
specified in the US Pharmacopeia. The tested derivatives
demonstrated high activities at a concentration of
50 μg/mL. Streptomycin was used as antibacterial
reference drug. The results are summarized in table.
1 For communication V, see [1].
2 The text was submitted by the authors in English.
161

162
AMR, AL-OMAR
Scheme 1.
N
O
O
NH2·HCl
N
N
, Et3N
COOMe
Ph
SOCl2
NH
HN
O
O
O
O
Ph
Ph
Cl
N
Cl
OH
OH
O
OMe
MeO
O
2
3
1
COOMe
NH2
O
O
H2N
( )n
1 N NaOH, MeOH
N
NH
HN
HO
Mixed anhydride method (a)
Ph
Ph
O
O
O
OH
O
NH
NH
HN
4
Ph
Ph
O
HN
( )n
5a, 5b
O
N
COOMe
O
O
COOMe
H2N
( )n
N2H4 · H2O
NH2
NH
NH
HN
HN
Ph
Ph
Azide method (b)
O
O
NH2
NH2
6
N
O
O
NH
HN
ArCHO
Ph
Ph
6
O
NH
N
HN
N
O
Ar
Ar
7a–7f, 8a–8c
5, n = 1 (a), 2 (b); 7, Ar = Ph (a), 4-MeC6H4 (b), 4-MeOC6H4 (c), 3,4,5-(MeO)3C6H2 (d), 4-ClC6H4 (e), 4-FC6H4 (f);
8, Ar = pyridin-2-yl (a), pyridin-3-yl (b), pyridin-4-yl (c).
EXPERIMENTAL
were obtained at the Microanalytical Unit, NRC and
were within the acceptable limits. The IR spectra were
recorded on a Nicolet Nexus 670 FTIR spectrometer.
The 1H and 13C NMR spectra were run in DMSO-d6 on
a JEOL instrument (Tokyo, Japan) at 500 and 125 MHz,
respectively. The mass spectra (electron impact, 70 eV)
The melting points were determined in open glass
capillary tubes with an Electro Thermal IA9100 digital
melting point apparatus and are uncorrected. The
elemental analyses for carbon, hydrogen, and nitrogen
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 1 2016

SYNTHESIS OF CHIRAL LINEAR AND MACROCYCLIC CANDIDATES: VI.
163
Antibacterial activities of compounds 3–8
Inhibition zone, cm
were obtained on a Finnigan MAT SSQ 7000 spectro-
meter. Analytical thin-layer chromatography (TLC)
was performed on silica gel 60 F254 plates (Merck).
Comp.
no.
Bacillus Staphylococcus Escherichia
Dimethyl N,N′-(pyridine-3,5-diyldicarbonyl)bis
[(2S)-2-amino-3-phenylpropanoate] (3). A solution
of 2 mmol of L-phenylalanine methyl ester hydro-
chloride in 15 mL of methylene chloride was cooled to
–10°C, 1 mmol of pyridine-3,5-dicarbonyl dichloride
(2) was added under stirring, and 2 mmol of triethyl-
amine was than added under stirring until pH ~8. The
mixture was stirred for 3 h at –10°C and for 12 h at
room temperature, washed with water, 1 N aqueous
HCl, 1 N sodium hydrogen carbonate, and water again,
dried over anhydrous calcium chloride, and evaporated
to dryness. Yield 90%, mp 142–144°C. IR spectrum, ν,
cm–1: 3487 (NH), 3087 (C–Harom), 2967 (C–Haliph),
1748 (C=O, ester), 1655 (C=O, amide I), 1533 (δN–H,
subtilis
aureus
coli
3
1.87
1.85
1.86
1.86
1.76
1.96
1.83
1.62
1.85
1.74
1.75
1.78
1.86
1.68
2.00
1.77
1.65
1.96
1.78
1.97
1.95
1.58
1.75
1.92
1.75
1.65
1.86
1.74
1.67
2.00
0.68
0.72
0.65
0.84
0.86
0.90
0.75
0.65
0.75
0.76
0.60
0.75
0.76
0.78
0.95
4
5a
5b
6
7a
7b
7c
7d
7e
7f
8a
8b
8c
1
amide II), 1254 (C–N, amide III). H NMR spectrum,
δ, ppm: 3.22 d (4H, CH2), 3.68 s (6H, OCH3), 4.70–
4.76 m (2H, CH), 7.05–7.51 m (10H, Harom), 8.52 s
(2H, NH, D2O exchangeable), 8.68 s and 9.12 s (3H,
pyridine). 13C NMR spectrum, δC, ppm: 42.45 (2C,
CH2), 52.18 (2C, OCH3), 53.32 (2C, CH); 125.46,
127.48, 128.56, 139.44 (12C, Ph); 131.65, 140.12,
151.95 (5C, pyridine); 168.02 (2C, C=O), 171.88 (2C,
C=O, ester). Mass spectrum: m/z 489 (Irel 8%) [M]+.
Found, %: C 66.14; H 5.50; N 8.50. C27H27N3O6.
Calculated, %: C 66.25; H 5.56; N 8.58.
Streptomycin
N,N′-(Pyridine-3,5-diyldicarbonyl)bis[(2S)-2-
amino-3-phenylpropanoic acid] (4). A solution of
1 mmol of 3 in 15 mL of methanol was cooled to –5°C,
25 mL of 1 N sodium hydroxide was added dropwise
under stirring, and the mixture was stirred for 3 h at
–5°C and for 12 h at room temperature. The mixture
was concentrated, cooled, and acidified with 1 N
aqueous HCl to pH ~3, and the precipitate was filtered
off, washed with cold water, dried, and recrystallized
from ethanol. Yield 86%, mp 232–234°C. IR spectrum,
ν, cm–1: 3586–3398 (OH, NH), 3084 (C–Harom), 2978
(C–Haliph), 1723 (C=O, acid), 1654 (C=O, amide), 1532
[δ(N–H)], 1255 (C–N). 1H NMR spectrum, δ, ppm: 3.18
d (4H, CH2), 4.72–4.75 m (2H, CH), 7.02–7.56 s (10H,
Ph), 8.56 s (2H, NH, D2O exchangeable), 8.65 s and
9.10 s (3H, pyridine), 11.96 s (2H, OH, D2O exchangeable).
13C NMR spectrum, δC, ppm: 41.68 (2C, CH2), 54.02
(2C, CH); 125.34, 127.45, 128.42, 139.32 (12C, Ph);
131.68, 140.16, 151.90 (5C, pyridine); 167.76 (2C,
C=O), 173.86 (2C, C=O, acid). Mass spectrum: m/z 461
(Irel 65%) [M]+. Found, %: C 65.00; H 4.95; N 9.02.
C25H23N3O6. Calculated, %: C 65.07; H 5.02; N 9.11.
Macrocyclic tripeptide methyl esters Va and Vb
(general procedures). a. Mixed anhydride method. A
solution of 1 mmol of 4 and 2 mmol of triethylamine
in 20 mL of methylene chloride was cooled to –15°C,
a solution of 0.2 mL (2 mmol) of ethyl chloroformate
in 20 mL of methylene chloride was added under
stirring over a period of 20 min, and a solution of
1 mmol of L-ornithine or L-lysine methyl ester (free
base) in 20 mL of methylene chloride was then added
at –15°C. The mixture was stirred for 3 h at –15°C and
for 12 h at room temperature, washed with water, 1 N
sodium hydrogen carbonate, 1 N aqueous HCl, and
water again, dried over anhydrous calcium chloride,
and evaporated to dryness. The oily residue was
solidified by treatment with anhydrous diethyl ether–n-
hexane mixture. The crude product was purified by
crystallization from ethanol–n-hexane.
b. Azide method. The procedure was the same as
reported in [19].
Methyl (4S,7S,13S)-4,13-dibenzyl-2,5,12,15-
tetraoxo-3,6,11,14,18-pentaazabicyclo[14.3.1]icosa-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 1 2016

164
AMR, AL-OMAR
1(20),16,18-triene-7-carboxylate (5a). Yield 74 (a),
52% (b); mp 185–187°C. IR spectrum, ν, cm–1: 3398
(NH), 3076 (C–Harom), 2968 (C–Haliph), 1748 (C=O,
ester), 1653 (C=O, amide), 1532 [δ(N–H)], 1254 (C–N).
1H NMR spectrum, δ, ppm: 1.50–1.42 m (2H, CH2),
1.72–1.86 m (2H, CH2), 3.16–3.20 m (2H, CH2), 3.38
d (4H, CH2), 3.64 s (3H, OCH3), 4.32 t (1H, CH),
4.66–4.70 m (2H, CH), 7.02–7.55 m (10H, Ph), 8.58 s
and 9.05 s (3H, pyridine), 8.75 s and 8.93 s (4H, NH,
D2O exchangeable). 13C NMR spectrum, δC, ppm:
22.18, 27.78, 39.42 (3C, CH2); 42.34 (2C, CH2), 52.82
(2C, CH), 53.56 (C7), 54.45 (OCH3); 124.56, 128.38,
129.44, 138.75 (12C, Ph); 131.68, 140.34, 152.09 (5C,
pyridine); 167.65 and 169.96 (4C, C=O, amide),
171.45 (C=O, ester). Mass spectrum: m/z 572 (Irel
24%) [M]+. Found, %: C 65.02; H 5.74; N 12.20.
C31H33N5O6. Calculated, %: C 65.14; H 5.82; N 12.25.
9.08 s (3H, pyridine). 13C NMR spectrum, δC, ppm:
41.54 (2C, CH2), 54.00 (2C, CH); 125.54, 127.42,
128.57, 139.44 (12C, Ph); 131.58, 140.14, 151.92 (5C,
pyridine); 167.62 (2C, C=O), 170.84 (2C, C=O,
hydrazide). Mass spectrum: m/z 489 (Irel 32%) [M]+.
Found, %: C 61.24; H 5.50; N 19.92. C25H27N7O4.
Calculated, %: C 61.34; H 5.56; N 20.03.
N3,N5-Bis{(2S)-1-[(arylmethylidene)hydrazinyl]-
1-carbonyl-3-phenylpropan-2-yl}pyridine-3,5-
dicarboxamides 7a–7f and 8a–8c (general proce-
dure). A mixture of 1 mmol of 6 and 2 mmol of the
corresponding aromatic aldehyde (see legend to
Scheme 1) in 30 mL of ethanol containing 2 mL of
triethylamine was refluxed for 3–6 h. The mixture was
then poured into ice water, and the precipitate was
filtered off, washed with water, dried, and re-
crystallized from appropriate solvent.
N3,N5-Bis[(2S)-1-(benzylidenehydrazinyl)-1-
carbonyl-3-phenylpropan-2-yl]pyridine-3,5-di-
carboxamide (7a). Yield: 62%, mp 212–214°C. IR
spectrum, ν, cm–1: 3354–3332 (NH), 3070 (C–Harom),
2980 (C–Haliph), 1654 (C=O), 1535 [δ(N–H)], 1256
Methyl (4S,7S,14S)-4,14-dibenzyl-2,5,13,16-tetra-
oxo-3,6,12,15,19-pentaazabicyclo[15.3.1]docosa-
1(21),17,19-triene-7-carboxylate (5b). Yield 65 (a),
50% (b); mp 192–194°C. IR spectrum, ν, cm–1: 3378
(NH), 3085 (C–Harom), 2990 (C–Haliph), 1752 (C=O,
ester), 1655 (C=O, amide), 1534 [δ(N–H)], 1257 (C–N).
1H NMR spectrum, δ, ppm: 1.55–1.28 m (4H, CH2),
1.78–1.85 m (2H, CH2), 3.02–3.22 m (2H, CH2), 3.35
d (4H, CH2), 3.62 s (3H, OCH3), 4.25 t (1H, CH),
4.65–4.70 m (2H, CH), 7.05–7.53 m (10H, Ph), 8.55 s
and 9.08 s (3H, pyridine), 8.76 s and 8.96 s (4H, NH,
D2O exchangeable). 13C NMR spectrum, δC, ppm:
20.18, 29.38, 34.37, 39.15 (4C, CH2); 42.15 (2C, CH2),
52.85 (2C, CH), 53.52 (C7), 54.33 (OCH3); 124.35,
128.32, 129.41, 138.77 (12C, Ph); 131.66, 140.30,
152.08 (5C, pyridine); 167.70 and 169.98 (4C, C=O,
amide), 171.42 (C=O, ester). Mass spectrum: m/z 586
(Irel 16) [M]+. Found, %: C 65.55; H 5.94; N 11.90.
C32H35N5O6. Calculated, %: C 65.63; H 6.02; N 11.96.
1
(C–N). H NMR spectrum, δ, ppm: 3.36 d (4H, CH2),
4.65–4.72 m (2H, CH), 6.98–7.65 m (22H, Ph,
CH=N), 8.63 s and 8.96 s (4H, NH, D2O ex-
changeable), 8.78 s and 9.02 s (3H, pyridine). 13C
NMR spectrum, δC, ppm: 41.65 (2C, CH2), 53.86 (2C,
CH); 125.43, 127.56, 128.53, 139.48 (12C, Ph);
127.75, 128.25, 131.00, 133.14 (12C, Ph); 131.66,
140.23, 152.01 (5C, pyridine); 142.67 (2C, CH=N),
167.54 (2C, C=O), 176.84 (2C, C=O, hydrazide). Mass
spectrum: m/z 666 (Irel 10%) [M]+. Found, %: C 70.25;
H 5.21; N 14.64. C39H35N7O4. Calculated, %: C 70.36;
H 5.30; N 14.73.
N3 ,N5 -Bis{(2S)-1-carbonyl-1-[(4-methyl-
phenylmethylidene)hydrazinyl]-3-phenylpropan-2-
yl}pyridine-3,5-dicarboxamide (7b). Yield 74%, mp
224–226°C. IR spectrum, ν, cm–1: 3378–3343 (N–H),
3076 (CHarom), 2984 (CHaliph), 1656 (C=O), 1534
N3,N5-Bis[(2S)-1-hydrazinyl-1-carbonyl-3-
phenylpropan-2-yl]pyridine-3,5-dicarboxamide (6).
A mixture of 1 mmol of 3 and 8 mmol of hydrazine
hydrate in 10 mL of methanol was heated for 10 h
under reflux. The mixture was evaporated under
reduced pressure to dryness, the residue was ground
with diethyl ether, and the precipitate was filtered off
and recrystallized from dioxane. Yield 78%, mp 256–
258°C. IR spectrum, ν, cm–1: 3485–3380 (NH, NH2),
3080 (C–Harom), 2986 (CHaliph), 1653 (C=O), 1531
1
[δ(N–H)], 1253 (C–N). H NMR spectrum, δ, ppm:
2.24 s (6H, CH3), 3.35 d (4H, CH2), 4.62–4.68 m (2H,
CH), 7.10–7.58 m (20H, Harom, CH=N), 8.68 s and
8.95 s (4H, NH, D2O exchangeable), 8.75 s and 9.08 s
(3H, pyridine). 13C NMR spectrum, δC, ppm: 23.78
(2C, CH3), 41.65 (2C, CH2), 53.86 (2C, CH); 125.65,
127.48, 128.50, 139.52 (12C, Carom); 128.78, 128.95,
129.35, 140.54 (12C, Carom); 131.68, 140.36, 152.12
(5C, pyridine); 142.55 (2C, CH=N), 167.65 (2C,
C=O), 176.72 (2C, C=O, hydrazide). Mass spectrum:
m/z 694 (Irel 12%) [M]+. Found, %: C 70.90; H 5.60; N
1
[δ(N–H)], 1254 (C–N). H NMR spectrum, δ, ppm:
3.24 d (4H, CH2), 4.12 s (4H, NH2, D2O exchangeable),
4.70–4.74 m (2H, CH), 7.00–7.55 m (10H, Ph), 8.60 s
and 8.94 s (4H, NH, D2O exchangeable), 8.72 s and
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SYNTHESIS OF CHIRAL LINEAR AND MACROCYCLIC CANDIDATES: VI.
165
14.07. C41H39N7O4. Calculated, %: C 70.98; H 5.67; N
14.13.
128.12, 129.45, 131.48, 135.82 (12C, Carom); 131.46,
140.54, 152.24 (5C, pyridine); 142.65 (2C, CH=N),
167.36 (2C, C=O), 176.53 (2C, C=O, hydrazide). Mass
spectrum: m/z 735 (Irel 8%) [M]+. Found, %: C 63.65;
H 4.46; Cl 9.54; N 13.23. C39H33Cl2N7O4. Calculated,
%: C 63.76; H 4.53; Cl 9.65; N 13.35.
N3,N5-Bis{(2S)-1-carbonyl-1-[(4-methoxy-
phenylmethylidene)hydrazinyl]-3-phenylpropan-2-
yl}pyridine-3,5-dicarboxamide (7c). Yield 72%, mp
238–240°C. IR spectrum, ν, cm–1: 3365–3315 (N–H),
3073 (C–Harom), 2990 (C–Haliph), 1653 (C=O), 1534
N3 ,N5 -Bis{(2S)-1-carbonyl-1-[(4-fluoro-
phenylmethylidene)hydrazinyl]-3-phenylpropan-2-
yl}pyridine-3,5-dicarboxamide (7f). Yield 55%, mp
232–234°C. IR spectrum, ν, cm–1: 3412–3345 (N–H),
3080 (C–Harom), 2986 (C–Haliph), 1655 (C=O), 1534
1
[δ(N–H)] 1256 (C–N). H NMR spectrum, δ, ppm:
3.48 d (4H, CH2), 3.62 s (6H, OCH3), 4.60–4.66 m
(2H, CH), 6.92–7.55 m (20H, Harom, CH=N), 8.64 s
and 8.90 s (4H, NH, D2O exchangeable), 8.76 s and
9.06 s (3H, pyridine). 13C NMR spectrum, δC, ppm:
42.05 (2C, CH2), 53.76 (2C, CH), 55.75 (2C, OCH3);
125.60, 127.42, 128.62, 139.58 (12C, Carom); 114.12,
125.78, 129.48, 162.64 (12C, Carom); 131.57, 140.32,
152.18 (5C, pyridine), 142.44 (2C, CH=N), 167.45
(2C, C=O), 176.66 (2C, C=O, hydrazide). Mass
spectrum: m/z 726 (Irel 15%) [M]+. Found, %: C 67.74;
H 5.35; N 13.42. C41H39N7O6. Calculated, %: C 67.85;
H 5.42; N 13.51.
1
[δ(N–H)], 1256 (C–N). H NMR spectrum, δ, ppm:
3.64 d (4H, CH2), 4.68–4.70 m (2H, CH), 7.12–7.58 m
(20H, Harom, CH=N), 8.68 s and 8.84 s (4H, NH, D2O
exchangeable), 8.75 s and 9.10 s (3H, pyridine). 13C
NMR spectrum, δC, ppm: 42.08 (2C, CH2), 53.75 (2C,
CH); 125.54, 127.36, 128.60, 139.50 (12C, Carom);
114.92, 128.45, 129.42, 164.56 (12C, Carom); 131.55,
140.65, 152.53 (5C, pyridine); 142.77 (2C, CH=N),
167.56 (2C, C=O), 175.98 (2C, C=O, hydrazide). Mass
spectrum: m/z 702 (Irel 32%) [M]+. Found, %: C 66.64;
H 4.65; N 13.90. C39H33F2N7O4. Calculated, %: C
66.75; H 4.74; N 13.97.
N3,N5-Bis{(2S)-1-carbonyl-3-phenyl-1-[(3,4,5-
trimethoxyphenylmethylidene)hydrazinyl]propan-
2-yl}pyridine-3,5-dicarboxamide (7d). Yield 56%,
mp 212–214°C. IR spectrum, ν, cm–1: 3405–3335
(N–H), 3083 (C–Harom), 2976 (C–Haliph), 1655 (C=O),
N3,N5-Bis{(2S)-1-carbonyl-3-phenyl-1-[(pyridin-
2-ylmethylidene)hydrazinyl]propan-2-yl}pyridine-
3,5-dicarboxamide (8a). Yield 52%, mp 182–184°C.
IR spectrum, ν, cm–1: 3368–3298 (N–H), 3088 (C–Harom),
2976 (C–Haliph), 1652 (C=O), 1532 [δ(N–H)], 1252
1
1535 [δ(N–H)], 1255 (C–N). H NMR spectrum, δ,
ppm: 3.65 d (4H, CH2), 3.65 s (18H, OCH3), 4.65–4.70
m (2H, CH), 6.78–7.52 m (16H, Harom, CH=N), 8.65 s
and 8.91 s (4H, NH, D2O exchangeable), 8.74 s and
9.12 s (3H, pyridine). 13C NMR spectrum, δC, ppm:
41.78 (2C, CH2), 54.32 (2C, CH); 55.92, 55.98 (6C,
OCH3); 125.55, 127.63, 128.68, 139.44 (12C, Carom);
105.98, 127.82, 141.08, 150.04 (12C, Carom); 131.66,
140.32, 152.18 (5C, pyridine); 142.62 (2C, CH=N),
167.42 (2C, C=O), 176.42 (2C, C=O, hydrazide). Mass
spectrum: m/z 846 (Irel 15%) [M]+. Found, %: C 63.80;
H 5.53; N 11.50. C45H47N7O10. Calculated, %: C 63.89;
H 5.60; N 11.59.
1
(C–N). H NMR spectrum, δ, ppm: 3.56 d (4H, CH2),
4.66–4.68 m (2H, CH), 7.04–7.55 m (12H, Ph,
CH=N), 7.78–8.52 m (8H, C5H4N), 8.63 s and 8.96 s
(4H, NH, D2O exchangeable), 8.78 s and 9.02 s (3H,
C5H3N). 13C NMR spectrum, δC, ppm: 41.74 (2C,
CH2), 53.76 (2C, CH); 125.40, 127.58, 128.56, 139.54
(12C, Ph); 122.98, 125.75, 135.32, 148.55, 152.16
(10C, C5H4N); 131.43, 140.34, 152.24 (5C, C5H3N);
140.68 (2C, CH=N), 167.64 (2C, C=O), 176.65 (2C,
C=O, hydrazide). Mass spectrum: m/z 668 (Irel 18%)
[M]+. Found, %: C 66.46; H 4.90; N 18.80.
C37H33N9O4. Calculated, %: C 66.55; H 4.98; N 18.88.
N3 ,N5 -Bis{(2S)-1-carbonyl-1-[(4-chloro-
phenylmethylidene)hydrazinyl]-3-phenylpropan-2-
yl}pyridine-3,5-dicarboxamide (7e). Yield 70%, mp
256–258°C. IR spectrum, ν, cm–1: 3398–3332 (N–H),
3066 (C–Harom), 2976 (C–Haliph), 1652 (C=O), 1532
N3,N5-Bis{(2S)-1-carbonyl-3-phenyl-1-[(pyridin-
3-ylmethylidene)hydrazinyl]propan-2-yl}pyridine-
3,5-dicarboxamide (8b). Yield 62%, mp 204–206°C.
IR spectrum, ν, cm–1: 3398–3312 (NH), 3080 (C–Harom),
2970 (C–Haliph), 1653 (C=O), 1535 [δ(N–H)], 1256
1
[δ(N–H)], 1253 (C–N). H NMR spectrum, δ, ppm:
3.65 d (4H, CH2), 4.64–4.68 m (2H, CH), 7.04–7.62 m
(20H, Harom, CH=N), 8.71 s and 8.88 s (4H, NH, D2O
exchangeable), 8.78 s and 9.12 s (3H, pyridine). 13C
NMR spectrum, δC, ppm: 42.12 (2C, CH2), 53.68 (2C,
CH); 125.61, 127.44, 128.66, 139.54 (12C, Carom);
1
(C–N). H NMR spectrum, δ, ppm: 3.73 d (4H, CH2),
4.62–4.65 m (2H, CH), 7.10–7.54 m (12H, Ph,
CH=N), 7.68–8.56 m (6H, C5H4N), 8.63 s and 8.94 s
(4H, NH, D2O exchangeable), 9.12 s (2H, C5H4N),
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 1 2016

166
AMR, AL-OMAR
8.76 s and 9.08 s (3H, C5H3N). 13C NMR spectrum, δC,
ppm: 41.84 (2C, CH2), 53.72 (2C, CH); 125.52,
127.55, 128.58, 139.64 (12C, Ph); 123.48, 129.54,
136.82, 150.78, 151.34 (10C, C5H4N); 131.36, 140.42,
152.13 (5C, C5H3N); 142.55 (2C, CH=N), 166.98 (2C,
C=O), 176.72 (2C, C=O, hydrazide). Mass spectrum:
m/z 668 (Irel 18%) [M]+. Found, %: C 66.44; H 4.88; N
18.82. C37H33N9O4. Calculated, %: C 66.55; H 4.98; N
18.88.
3. Bradshaw, J.S., Krakowiak, K.E., and Izatt, R.M.,
Tetrahedron, 1992, vol. 48, p. 4475.
4. Izatt, R.M., Pawlak, K., Bradshaw, J.S., and Bruening R.L.,
Chem. Rev., 1995, vol. 95, p. 2529.
5. Elwahy, A.H. M., J. Heterocycl. Chem., 2003, vol. 40,
p. 1.
6. Mohamed, S.F., Flefel, E.M., Amr, A.E., and Abd El-
Shafy, D.N., Eur. J. Med. Chem., 2010, vol. 45, p. 1494.
7. Said, S.A., Amr, A.E., Sabry, N.M., and Abdalla, M.M.,
Eur. J. Med. Chem., 2009, vol. 44, p. 4787.
N3,N5-Bis{(2S)-1-carbonyl-3-phenyl-1-[(pyridin-
4-ylmethylidene)hydrazinyl]propan-2-yl}pyridine-
3,5-dicarboxamide (8c). Yield 55%, mp 218–220°C.
IR spectrum, ν, cm–1: 3406–3344 (NH), 3077 (C–Harom),
2976 (C–Haliph), 1655 (C=O), 1533 [δ(N–H)], 1254
8. Fakhr, I.M., Amr, A.E., Sabry, N.M., and Abdalah, M.M.,
Arch. Pharm., 2008, vol. 341, p. 174.
9. Ouf, N.H., Amr, A.E., and Sakran, M.I., Med. Chem.
Res., 2015, vol. 24, p. 1514.
1
10. Amr, A.E., Ali, K.A., and Abdalla, M.M., Eur. J. Med.
Chem., 2009, vol. 44, p. 902.
11. Al-Salahi, R.A., Al-Omar, M.A., and Amr, A.E.,
Molecules, 2010, vol. 15, p. 6588.
12. Moustafa, A.H., Assy, M.G., Amr, A.E., and Saber, R.M.,
(C–N). H NMR spectrum, δ, ppm: 3.84 d (4H, CH2),
4.60–4.66 m (2H, CH), 7.08–7.56 m (12H, Ph,
CH=N), 7.72 s and 8.65 s (8H, C5H4N), 8.56 s and
8.94 s (4H, NH, D2O exchangeable), 8.78 s and 9.12 s
(3H, C5H3N). 13C NMR spectrum, δC, ppm: 41.68 (2C,
CH2), 53.70 (2C, CH); 125.50, 127.58, 128.62, 139.68
(12C, Ph); 123.34, 143.04, 148.87 (10C, C5H4N);
131.44, 140.56, 152.18 (5C, C5H3N); 142.68 (2C,
CH=N), 167.16 (2C, C=O), 176.66 (2C, C=O, hydra-
zide). Mass spectrum: m/z 668 (Irel 32%) [M]+. Found,
%: C 66.45; H 4.86; N 18.84. C37H33N9O4. Calculated,
%: C 66.55; H 4.98; N 18.88.
Curr. Org. Chem., 2011, vol. 15, p. 1661.
13. Abdel-Salam, O.I., Al-Omar, M.A., and Amr, A.E.,
Curr. Org. Synth., 2012, vol. 9, p. 406.
14. Khayyat, S. and Amr, A.E., Molecules, 2014, vol. 19,
p. 10698.
15. Khayyat, S., Amr, A.E., Abd El-Salam, O.I., Al-Omar, M.A.,
and Abdalla, M.M., Int. J. Pharmacol., 2015, vol. 11,
no. 5, p. 423.
16. Amr, A.E., Abd El-Salam, O.I., and Al-Omar, M.A.,
ACKNOWLEDGMENTS
Russ. J. Gen. Chem., 2015, vol. 85, no. 5, p. 1161.
The authors thank the Deanship of Scientific
Research at King Saud University for financial support
through the Research Group project no. RGP-172.
17. Ibrahim, A.A., Mohamed, A.M, Amr, A.E., and Al-
Omar, M.A., Russ. J. Gen. Chem., 2015, vol. 85, no. 6,
p. 1506. DOI: 10.1134/S1070363215060250.
18. Azab, M.E. and Amr, A.E., Russ. J. Gen. Chem., 2015,
vol. 85, no. 6, p. 1513. DOI: 10.1134/S1070363215050262.
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