Synthesis and antimicrobial activity of some linear dipeptide pyridine and macrocyclic pentaazapyridine candidates

Article abstract of DOI:10.1515/znb-2016-0018

A series of tetracarboxamide and macrocyclic tripeptides have been prepared starting from 3,5-bis[N-(1-hydrazinyl-1-oxo-3-phenylpropan-2-yl)]pyridinecarboxamide 4 as starting material, which was synthesized from dinicotinic acid 1. Treatment of 4 with 1,4-diaminobutane, 1,6-diaminohexane, or cycloalkanone derivatives gave the corresponding macrocyclic tetracarboxamides (5a, b) and cycloalkyl hydrazone derivatives (6a-c), respectively. Additionally, the reaction of 4 with acetophenone or acetylpyridine derivatives gave the corresponding Schiff base derivatives 7a-e and 8a-c, respectively. Also, carboxylic acid hydrazide 4 was treated with acid anhydrides in glacial acetic acid to afford the corresponding diimide tetracarboxamide derivatives 9a, b, 10, and 11, respectively. The structures of newly synthesized compounds are established by physical and spectral data evidences. Some of the synthesized compounds were screened as antimicrobial agents.

Full text of DOI:10.1515/znb-2016-0018

Z. Naturforsch. 2016; aop
Mohamed E. Azab, Eman M. Flefel, Nermien M. Sabry and Abd El-Galil E. Amr*
Synthesis and antimicrobial activity of some
linear dipeptide pyridine and macrocyclic
pentaazapyridine candidates
DOI 10.1515/znb-2016-0018
Received January 16, 2016; accepted February 9, 2016
1
Introduction
Abstract: A series of tetracarboxamide and macrocyclic The naturally occurring peptide derivatives were identi-
tripeptides have been prepared starting from 3,5-bis[N- fied, and they were used in crucial roles in human physiol-
(
1-hydrazinyl-1-oxo-3-phenylpropan-2-yl)]pyridinecarbox- ogy, ion channel ligands, including actions as hormones,
amide 4 as starting material, which was synthesized from growth factors, neurotransmitters, or anti-infectives [1–3].
dinicotinic acid 1. Treatment of 4 with 1,4-diaminobutane, A series of pyridine derivatives are correlated with several
1
,6-diaminohexane, or cycloalkanone derivatives gave pharmacological properties, for example, antimycobacte-
the corresponding macrocyclic tetracarboxamides (5a, b) rial [4], anticancer [5], antiviral [6], anti-HIV [7], antifun-
and cycloalkyl hydrazone derivatives (6a–c), respectively. gal and antimicrobial [8], and anticonvulsant [9]. Also,
Additionally, the reaction of 4 with acetophenone or some pyridinecarboxamide analogs were designed and
acetylpyridine derivatives gave the corresponding Schiff used as PARP-1Q2 inhibitors [10], mycobacterium tubercu-
base derivatives 7a–e and 8a–c, respectively. Also, car- losis agents, [11] and as CB cannabinoid receptor partial
2
boxylic acid hydrazide 4 was treated with acid anhydrides agonists [12]. On the other hand, in addition, heterocyclic
in glacial acetic acid to afford the corresponding diimide compounds containing an amino acid or a peptide struc-
tetracarboxamide derivatives 9a, b, 10, and 11, respec- tural moiety showed biological [13] and antibacterial activ-
tively. The structures of newly synthesized compounds ities [14]. A branched-chain amino acid (Leu, Ile, and Val)
are established by physical and spectral data evidences. mixture has been used for treatment of hypoalbuminemia
Some of the synthesized compounds were screened as in patients with decompensated liver cirrhosis in Japan
antimicrobial agents.
[15]. In view of this concept and in continuation to our
previous work [16–24] in heterocyclic and peptide chemis-
try, we have synthesized some new linear dipeptide Schiff
bases and macrocyclic tripeptide derivatives and we have
evaluated some of them as antimicrobial agents.
Keywords: antimicrobial agents; bis-Schiff base; linear
dipeptide pyridine; macrocyclic pentaazapyridine.
2
Results and discussion
*
Corresponding author: Abd El-Galil E. Amr, Department of Applied
Organic Chemistry, National Research Center, Dokki 12622, Cairo,
Egypt; and Department of Pharmaceutical Chemistry, Drug Exploration
and Development Chair, College of Pharmacy, King Saud University,
Riyadh 11451, Saudi Arabia, e-mail: aeamr1963@yahoo.com
Mohamed E. Azab: Department of Chemistry, Faculty of Science,
University of Ain Shams, Cairo, Egypt
2.1 Chemistry
In this study, we report a series of linear dipeptide Schiff
2
2
base derivatives by using N ,N ′-(pyridine-3,5-dicarbonyl)-
di-ꢀ-phenyalaninyl hydrazide (4) as starting material,
which was synthesized from 3,5-pyridinedicarboxylic acid
according to a reported procedure [4] (Scheme 1).
Eman M. Flefel: Department of Chemistry, Faculty of Science, Taibah
University, Al-Madinah Al-Munawara 3001, Saudi Arabia; and
Department of Photochemistry, National Research Center, Dokki
Treatment of 3,5-bis-hydrazide 4 with 1,4-diaminobu-
tane or 1,6-diaminohexane afforded the corresponding
macrocyclic tetracarboxamide derivatives 5a, b. Conden-
sation of 4 with cycloalkanones in refluxing glacial acetic
acid gave the corresponding cycloalkanyl hydrazone
1
2622, Cairo, Egypt
Nermien M. Sabry: Department of Chemistry, Girls College of
Science, King Khalid University, Abha 9004, Saudi Arabia; and
Department of Applied Organic Chemistry, National Research
Center, Dokki 12622, Cairo, Egypt
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2
ꢀꢀꢀꢀꢁꢀM. E. Azab et al.: Synthesis of linear dipeptide pyridine and macrocyclic pentaazapyridine candidates
O
NH2.HCl
N
N
Cl
S
*
Ph
COOMe
O
O
Cl
O
O
TEA
OH
1
OH
Cl
2
Cl
N
N
O
O
O
O
H2NNH2·H2O
NH
NH
HN
NH
HN
O
Ph
Ph
Ph
Ph
*
*
*
*
O
HN
NH2
O
O
O
O
NH2
CH3
CH3
4
3
Scheme 1:ꢀSynthetic routes to starting compound 4.
derivatives 6a–c. Additionally, the reaction of 4 with
acetophenone or acetylpyridines gave the correspond-
ing Schiff base derivatives 7a–e and 8a–c, respectively
Scheme 2).
Finally, carboxylic acid hydrazide 4 was treated with
acid anhydrides, namely, phthalic, tetrachloro-phthalic, Melting points were determined in open glass capillary
3
Experimental section
(
3.1 Chemistry
1
,8-naphthaline, or 2,3-pyridinedicarboxylic acid anhy- tubes with an electrothermal digital melting point appa-
dride in glacial acetic acid to afford the corresponding ratus (model IA9100) and were uncorrected. Elemental
diimide tetracarboxamide derivatives 9a, b, 10, and 11, microanalysis for carbon, hydrogen, and nitrogen (Micro-
respectively (Scheme 3).
analytical Unit, National Research Center) was found
within the acceptable limits of the calculated values. IR was
recorded on a Nexus 670 FTIR Nicolet, Fourier transform
infrared spectrometer. H NMR and C NMR spectra were
run in deuterated dimethyl sulfoxide ([D ]DMSO) on Jeol
1
13
2.2 Antimicrobial activity
6
1
13
The newly synthesized compounds 5–11 were tested for 500 MHz ( H) and 125 MHz ( C) instruments. Mass spectra
their preliminary antimicrobial activity against different were run on a MAT Finnigan SSQ 7000 spectrometer, using
microorganisms representing Gram-positive (Staphylococ- the electron impact technique (EI). Analytical thin layer
cus aureus, Bacillus cereus, and Bacillus subtilis), Gram- chromatography was performed on silica gel aluminum
negative bacteria (Escherichia coli), fungi (Aspergillus sheets, 60 F254 (E. Merck). Antimicrobial activities were
niger) and yeast (Candida albicans).
evaluated in National Research Center, Dokki, Cairo, Egypt.
The obtained results (Table 1) showed that all synthe-
sized compounds exhibited both antibacterial and anti-
fungal activities on all tested microbial strains, except 3.2 Synthesis of 5a, b
for compounds 5a, 5b, 7a, 7e, 8a, 8c, 9, and 11, which
did not showed antifungal activity against C. albicans. In To a cold (–5°C) and stirred solution of the dihydrazide
terms of antifungal activities, compounds 5a, 7c, 7d, and 4 (1 mmol) in 5 ꢁ aq. HCl (3 mL) and acetic acid (3 mL),
1
0 were the most active and their activities were higher sodium nitrite solution (10%, 0.13 g, 2 mmol) was added
than that of the positive control (fusidic acid) by about at the same temperature. The reaction mixture was
.6, 2.6, 5.0, and 5.0%, respectively. Regarding antibacte- stirred for 30 min, and then it was extracted with ether.
rial activities, it can be clearly observed that compounds The ethereal part was washed with water, NaHCO , water
2
3
6
a, 6b, 7d, 8b, 10, and 11 were the highly active com- and then dried over anhydrous sodium sulfate. The cold
pounds. Among of these compounds, compound 7d was ethereal solution (–5°C) was then added to a cold (–5°C)
the most active one, where its activity reached 97.5, 92.5, dichloromethane solution of 1,4-butanediamine, or
9
5.2, and 94.7% of the positive control (chlorampheni- 1,6-hexanediamine (1 mmol, 10 mL of CH Cl ). Stirring was
2 2
col), respectively.
continued for 5 h at –5°C and at room temperature for 2
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M. E. Azab et al.: Synthesis of linear dipeptide pyridine and macrocyclic pentaazapyridine candidatesꢂꢁꢀꢀꢀꢂ3
N
O
O
NH
HN
Ph
Ph
*
*
O
O
NH
N
HN
N
O
AcOH
(
)n
n = 1, 2, 3
( )n
( )n
6a−c
a, n = 1; b, n = 2; c, n = 3
N
N
O
O
O
O
NH2
NH2
NH
HN
HN
NH
HN
Ph
Ph
Ph
Ph
*
( )n
n = 1, 3
*
*
*
O
NH
O
O
NH
HN
)n
O
NH2
NH2
AcOH
HN
(
4
5
a, b
CH3
a, n = 1; b, n = 3
N
H3C
X
O
O
AcOH
N
N
O
O
O
O
NH
HN
NH
Ph
Ph
Ph
Ph
*
*
*
*
O
NH
N
HN
N
O
O
NH
N
HN
N
O
H3C
CH3
H3C
CH3
N
N
X
X
8a−c
7a−e
a, 2-pyridyl; b, 3-pyridyl; c, 4-pyridyl
a, X = H, b, X = Me, c, X = OMe,
d, X = Cl, e X = F
Scheme 2:ꢀSynthetic routes to compounds 5a, b, 6a–c, 7a–e, and 8a–c.
h. The reaction mixture was washed with 1 ꢁ aq. HCl and (500 MHz, [D ]DMSO): δ ꢂ=ꢂ 1.40–1.48 (m, 4H, 2 CH ), 2.62–
6
2
water and then dried over anhydrous calcium chloride. 2.74 (m, 4H, 2 CH ), 3.42 (d, 4H, 2CH ), 4.05–4.10 (m, 2H, 2
2
2
The solvent was evaporated under reduced pressure and CH), 6.95–7.52 (m, 10H, 2Ph-H), 8.58, 9.05 (2s, 3H, pyr-H),
crystallized from ethanol-ether to afford the correspond- 8.72, 8.95 (2s, 4H, 4NH, exchangeable with D O). – MS (EI,
2
+
ing title compounds 5a, b, respectively.
70 eV): m/z (%) ꢂ=ꢂ 514 (12) [M] . – C H N O (513.58): calcd.
C 67.82, H 6.08, N 13.64; found C 67.70, H 6.00, N 13.57.
2
9
31
5
4
α
3
.2.1 Cyclo-(N -dinicotinoyl)-bis[ꢁ-phenylalaninyl]-1,4-
α
butanediamine (5a)
3.2.2 Cyclo-(N -dinicotinoyl)-bis[ꢁ-phenylalaninyl]-1,6-
hexanediamine (5b)
2
5
Yield 58%; m.p. 204–206°C. – [α]D ꢂ=ꢂ –110 (c ꢂ=ꢂ 0.5, DMF).
2
5
–
IR (film): ν ꢂ=ꢂ 3365 (NH), 3076 (CH-Ar), 2984 (CH-aliph.), Yield 60%; m.p. 194–196°C. – [α]D ꢂ=ꢂ –96 (c ꢂ=ꢂ 0.5,
662, 1535, 1234 (Cꢂ=ꢂO, amide I, II, and III) cm . – H NMR DMF). – IR (film): ν ꢂ=ꢂ 3358–3312 (NH), 3080 (CH-Ar),
–
1
1
1
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4
ꢀꢀꢀꢀꢁꢀM. E. Azab et al.: Synthesis of linear dipeptide pyridine and macrocyclic pentaazapyridine candidates
N
2975 (CH-aliph.), 1660, 1530, 1240 (Cꢂ=ꢂO, amide I, II, and
–1
1
III) cm . – H NMR (500 MHz, [D ]DMSO): δ ꢂ=ꢂ1.24–1.28
O
O
6
(
m, 4H, 2 CH ), 1.38–1.44 (m, 4H, 2CH ), 2.60–1.68 (m,
NH
NH
HN
HN
2 2
4H, 2 CH ), 3.42 (d, 4H, 2CH ), 4.08–4.20 (m, 2H, 2 CH),
Ph
Ph
*
*
2
2
O
O
O
6.96–7.55 (m, 10H, 2Ph-H), 8.62, 9.00 (2s, 3H, pyridyl-
O
N
N
H), 8.74, 8.95 (42s, H, 4NH, exchangeable with D O).
2
O O
O
O
O
+
–
MS (EI, 70 eV): m/z (%) ꢂ=ꢂ 542 (22) [M] . – C H N O
3
1
35
5
4
AcOH
(541.64): calcd. C 68.74, H 6.51, N 12.93; found C 68.62,
H 6.44, N 12.85.
10
N
O
O
O
O
NH
NH
HN
HN
Ph
Ph
3.3 Synthesis of hydrazones 6a–c
*
*
O
4
O
O
O
AcOH
To a solution of acid hydrazide 4 (1 mmol) in glacial acetic
acid (30 mL), cyclopentanone, cyclohexanone, or cyclo-
heptanone (2 mmol) was added. The reaction mixture was
refluxed for 6 h and poured onto ice water; the obtained
solid was filtered off, washed with water, dried, and crys-
tallized from the proper solvents to give the corresponding
Schiff base derivatives 6a–c, respectively.
O
N
N
O
O
O
O
O
AcOH
N
9
N
O
O
NH
HN
HN
Ph
Ph
*
*
O
NH
O
O
O
3.3.1 N,N′-Bis[1-(cyclopentanyl-1-methylhydrazonyl)-2-
N
N
O
ꢁ
-phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (6a)
O
N
N
1
1
25
Yield 82%; m.p. 178–180°C (EtOH-H O). – [α]D ꢂ=ꢂ –124
2
Scheme 3:ꢀSynthetic routes to compounds ꢈa, b, 1ꢉ, and 11.
(c ꢂ=ꢂ 0.5, DMF). – IR (film): ν ꢂ=ꢂ 3446–3367 (NH), 3085
Table 1:ꢀAntimicrobial activities of some newly synthesized compounds.
Compound
ꢂꢃ
Inhibition zone (cm)
Gram +veꢂ
Gram –ve
ꢂ
Fungi
ꢂ
Yeast
Staphylococcusꢃ
Bacillusꢃ
subtilis
Bacillusꢃ
cereus
Escherichiaꢃ
Aspergillusꢃ
Candida
albicans
aureus
coli
niger
ꢃa
ꢃb
ꢄa
ꢄb
ꢄc
ꢅa
ꢅb
ꢅc
ꢅd
ꢅe
ꢆa
ꢆb
ꢆc
9
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢄ.ꢅꢆꢃ
ꢄ.ꢅꢈꢃ
ꢄ.ꢈꢉꢃ
ꢄ.ꢈꢆꢃ
ꢄ.7ꢅꢃ
ꢄ.ꢆꢅꢃ
ꢄ.7ꢆꢃ
ꢄ.ꢅꢇꢃ
ꢄ.ꢊꢆꢃ
ꢄ.7ꢈꢃ
ꢄ.ꢆꢆꢃ
ꢄ.ꢈꢆꢃ
ꢄ.ꢅꢅꢃ
ꢄ.ꢅꢆꢃ
ꢄ.77ꢃ
ꢄ.ꢈꢉꢃ
ꢋ.ꢉꢉꢃ
–ꢃ
ꢄ.ꢇꢅꢃ
ꢄ.7ꢆꢃ
ꢄ.ꢅꢆꢃ
ꢄ.ꢈꢆꢃ
ꢄ.7ꢋꢃ
ꢄ.ꢆꢅꢃ
ꢄ.ꢅꢆꢃ
ꢄ.7ꢅꢃ
ꢄ.ꢈꢆꢃ
ꢄ.ꢇꢆꢃ
ꢄ.ꢈꢆꢃ
ꢄ.ꢈꢉꢃ
ꢄ.7ꢋꢃ
ꢄ.ꢅꢆꢃ
ꢄ.ꢈꢇꢃ
ꢄ.7ꢉꢃ
ꢋ.ꢉꢉꢃ
–ꢃ
ꢄ.ꢈꢉꢃ
ꢄ.ꢆꢆꢃ
ꢄ.ꢊꢅꢃ
ꢄ.ꢊꢋꢃ
ꢄ.ꢆꢈꢃ
ꢄ.ꢆꢉꢃ
ꢄ.7ꢇꢃ
ꢄ.7ꢆꢃ
ꢋ.ꢉꢉꢃ
ꢄ.ꢅꢆꢃ
ꢄ.ꢆꢉꢃ
ꢄ.ꢊꢆꢃ
ꢄ.ꢋꢋꢃ
ꢄ.ꢈꢌꢃ
ꢄ.ꢈꢈꢃ
ꢄ.ꢅꢆꢃ
ꢋ.ꢄꢉꢃ
–ꢃ
ꢉ.ꢅꢅꢃ
ꢉ.ꢅꢉꢃ
ꢉ.7ꢈꢃ
ꢉ.ꢈꢉꢃ
ꢉ.7ꢇꢃ
ꢉ.ꢅꢅꢃ
ꢉ.7ꢆꢃ
ꢉ.ꢈꢉꢃ
ꢉ.ꢊꢉꢃ
ꢉ.ꢅꢋꢃ
ꢉ.ꢅꢆꢃ
ꢉ.7ꢈꢃ
ꢉ.ꢅꢉꢃ
ꢉ.ꢅꢇꢃ
ꢉ.ꢊꢋꢃ
ꢉ.ꢅꢇꢃ
ꢉ.ꢊꢆꢃ
–ꢃ
ꢄ.ꢊꢆꢃ
ꢄ.7ꢉꢃ
ꢄ.ꢇꢈꢃ
ꢄ.ꢆꢅꢃ
ꢄ.ꢈꢉꢃ
ꢄ.ꢅꢈꢃ
ꢄ.ꢈꢆꢃ
ꢄ.ꢊꢆꢃ
ꢋ.ꢉꢉꢃ
ꢄ.7ꢆꢃ
ꢄ.7ꢆꢃ
ꢄ.ꢆꢆꢃ
ꢄ.7ꢆꢃ
ꢄ.ꢆꢈꢃ
ꢋ.ꢉꢉꢃ
ꢄ.7ꢆꢃ
–ꢃ
–
–
ꢉ.ꢊꢇ
ꢉ.ꢊꢋ
ꢉ.ꢊꢆ
–
ꢄ.ꢉꢆ
ꢄ.ꢉꢆ
ꢉ.ꢊꢅ
–
–
ꢄ.ꢉꢉ
–
–
ꢄ.ꢄꢉ
–
–
ꢄ.ꢊ
ꢇ0
ꢇꢇ
Chloramphenicolꢃ
fusidic acid
ꢃ
ꢄ.ꢊꢃ
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M. E. Azab et al.: Synthesis of linear dipeptide pyridine and macrocyclic pentaazapyridine candidatesꢂꢁꢀꢀꢀꢂ5
(
CH-Ar), 2982 (CH-aliph.), 1661, 1521, 1314 (Cꢂ=ꢂO, amide 3.4 Synthesis of compounds 7a–e and 8a–c
–1
1
I, II, and III) cm . – H NMR (500 MHz, [D ]DMSO): δ ꢂ=ꢂ
6
1
.28–1.34 (m, 16H, 2 cyclopentyl-H), 3.36 (d, 4H, 2CH ), A mixture of 4 (1 mmol) and a substituted acetophe-
2
4
.62–4.73 (m, 2H, 2CH), 6.98–7.52 (m, 10H, 2Ph-H), 7.90, none (acetophenone, 4-methyl-, 4-methoxy-, 4-chloro-,
8
.64 (2s, 4H, 4NH, exchangeable with D O), 8.68, 9.12 (2s, 4-fluoroacetophenone) or an acetylpyridine (2-acetyl-,
2
3
H, pyr-H). – 13C NMR (125 MHz, [D ]DMSO): δ ꢂ=ꢂ 41.35 3-acetyl-, 4-acetylpyridine, 2 mmol) in glacial acetic acid
6
(
(
(
2C, 2CH ), 53.14 (2C, 2CH), 125.66, 127.70, 128.64, 139.44 (30 mL) was refluxed for 4–7 h. The reaction mixture
2
12C, 2Ph-C), 131.46, 141.23, 152.36 (5C, Pyr-C), 167.18 was poured into ice water, and then neutralized with
2C, 2Cꢂ=ꢂO), 176.64 (2C, 2Cꢂ=ꢂO), 26.04, 36.86, 186.74 (10C, 1 ꢁ aq. sodium carbonate. The obtained solid was filtered
+
cyclopentyl-C). – MS (EI, 70 eV): m/z (%) ꢂ=ꢂ 622 (6) [M] . off, washed with water, dried, and crystallized from the
–
C H N O (621.72): calcd. C 67.61, H 6.32, N 15.77; found proper solvent to give the corresponding Schiff bases 7a–e
35
39
7
4
C 67.52, H 6.22, N 15.69.
and 8a–c, respectively.
3
.3.2 N,N′-Bis[1-(cyclohexanyl-1-methylhydrazonyl)-2-ꢁ-
3.4.1 N,N′-Bis[(1-phenyl-1-methyl-hydrazonyl-2-ꢁ-
phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (6b)
phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (7a)
2
5
25
Yield 66%; m.p. 206–208°C (AcOH-H O). – [α] ꢂ=ꢂ –116 Yield 75%; m.p. 242–244°C (DMF-H O). – [α]D ꢂ=ꢂ –98 (c ꢂ=ꢂ
2
D
2
(
c ꢂ=ꢂ 0.5, DMF). – IR (film): ν ꢂ=ꢂ 3565–3432 (NH), 3084 0.5, DMF). – IR (film): ν ꢂ=ꢂ 3367–3342 (NH), 3078 (CH-Ar),
CH-Ar), 2974 (CH-aliph.), 1664, 1525, 1318 (Cꢂ=ꢂO, amide 2990 (CH-aliph.), 1652, 1537, 1254 (CO, amide I, II, and III)
(
–1
1
–1
1
I, II, and III) cm . – H NMR (500 MHz, [D ]DMSO): δ ꢂ=ꢂ cm . – H NMR (500 MHz, [D ]DMSO): δ ꢂ=ꢂ 1.04 (s, 6H,
6
6
1
.25–1.36 (m, 20H, 2 cyclohexyl-H), 3.42 (d, 4H, 2CH ), 2CH ), 3.24 (d, 4H, 2CH ), 4.68–4.75 (m, 2H, 2CH), 7.05–7.68
2
3
2
4
.65–4.70 (m, 2H, 2CH), 6.96–7.54 (m, 10H, 2Ph-H), 7.96, (m, 20H, 4Ph-H), 8.54, 8.65 (2s, 4H, 4NH, D O exchange-
2
1
3
8
3
.68 (2s, 4H, 4NH, exchangeable with D O), 8.76, 9.10 (2s, able), 8.75, 9.08 (2s, 3H, pyr-H). – C NMR (125 MHz, [D ]
2
6
H, Pyr-H). – 13C NMR (125 MHz, [D ]DMSO): δ ꢂ=ꢂ 41.36 DMSO): δ ꢂ=ꢂ 14.43 (2C, 2CH ), 41.22 (2C, 2CH ), 53.98 (2C,
6
3
2
(
(
2
2C, 2CH ), 53.32 (2C, 2CH), 125.65, 127.74, 128.67, 139.48 2CH), 125.56, 127.72, 128.55, 139.35 (12C, 2Ph-C), 127.82,
2
12C, 2Ph-C), 131.42, 141.28, 152.33 (5C, Pyr-C), 167.24 (2C, 128.55, 130.70, 133.36 (12C, 2Ph-C), 131.72, 140.34, 151.86
Cꢂ=ꢂO), 176.44 (2C, 2Cꢂ=ꢂO), 23.22, 26.86, 28.14, 161.33 (12C, (5C, pyr-C), 167.42 (2C, 2CO), 168.35 (2C, 2Cꢂ=ꢂN), 176.98 (2C,
+
+
cyclohexyl-C). – MS (EI, 70 eV): m/z (%) ꢂ=ꢂ 650 (22) [M] . – 2CO, hydrazone). – MS (EI, 70 eV): m/z (%) ꢂ=ꢂ 694 (16) [M] .
C H N O (649.78): calcd. C 68.39, H 6.67, N, 15.09; found – C H N O (693.79): calcd. C 70.98, H 5.67, N 14.13; found
37
43
7
4
41 39
7
4
C 68.30, H 6.60, N 15.00.
C 70.90, H 5.60, N 14.05.
3
.3.3 N,N′-Bis[1-(cycloheptanyl-1-methylhydrazonyl)-2-ꢁ- 3.4.2 N,N′-Bis[1-(4-methylphenyl-1-methylhydrazonyl)-2-ꢁ-
phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (6c) phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (7b)
2
5
25
Yield 72%; m.p. 232–234°C (EtOH). – [α]D ꢂ=ꢂ –112 (c ꢂ=ꢂ 0.5, Yield 68%; m.p. 226–228°C (AcOH-H O). – [α]D ꢂ=ꢂ –105
2
DMF). – IR (film): ν ꢂ=ꢂ 3554–3428 (NH), 3090 (CH-Ar), 2978 (c ꢂ=ꢂ 0.5, DMF). – IR (film): ν ꢂ=ꢂ 3388–3335 (NH), 3082 (CH-
(
CH-aliph.), 1661, 1526, 1318 (Cꢂ=ꢂO, amide I, II, and III) Ar), 2985 (CH-aliph.), 1653, 1534, 1252 (CO, amide I, II, and
–1
1
–1
1
cm . – H NMR (500 MHz, [D ]DMSO): δ ꢂ=ꢂ 1.20–1.36 (m, III) cm . – H NMR (500 MHz, [D ]DMSO): δ ꢂ=ꢂ 1.00 (s, 6H,
6
6
2
4H, 2 cycloheptyl-H), 3.31 (d, 4H, 2CH ), 4.62–4.71 (m, 2CH ), 2.23 (s, 6H, 2CH ), 3.26 (d, 4H, 2CH ), 4.65–4.72 (m,
2
3
3
2
2
H, 2CH), 6.99–7.56 (m, 10H, 2Ph-H), 7.94, 8.66 (2s, 4H, 2H, 2CH), 7.12–7.72 (m, 18H, 4Ph-H), 8.65, 8.78 (2s, 4H, 4NH,
1
3
4
NH, exchangeable with D O), 8.79, 9.18 (2s, 3H, Pyr-H). D O exchangeable), 8.72, 9.12 (2s, 3H, pyr-H). – C NMR
2
2
13
–
C NMR (125 MHz, [D ]DMSO): δ ꢂ=ꢂ 41.48 (2C, 2CH ), (125 MHz, [D ]DMSO): δ ꢂ=ꢂ 14.22, 23.45 (4C, 4CH ), 41.25
6
2
6
3
5
3.15 (2C, 2CH), 125.76, 127.54, 128.62, 139.50 (12C, 2Ph-C), (2C, 2CH ), 54.10 (2C, 2CH), 125.62, 127.70, 128.58, 139.45
2
1
32.13, 141.18, 152.42 (5C, Pyr-C), 167.24 (2C, 2Cꢂ=ꢂO), 175.98 (12C, 2Ph-C), 128.74, 129.08, 130.86, 140.35 (12C, 2Ph-C),
(
2C, 2Cꢂ=ꢂO), 23.56, 25.42, 29.70, 183.84 (14C, cycloheptyl- 131.84, 140.38, 151.85 (5C, pyr-C), 167.36 (2C, 2CO), 168.45
+
C). – MS (EI, 70 eV): m/z (%) ꢂ=ꢂ 678 (15) [M] . – C H N O
(2C, 2Cꢂ=ꢂN), 176.95 (2C, 2CO, hydrazone). – MS (EI, 70 eV):
3
9
47
7
4
+
(
6
677.83): calcd. C 69.10, H 6.99, N 14.46; found C 69.00, H m/z (%) ꢂ=ꢂ 722 (8) [M] . – C H N O (721.84): calcd. C 71.55,
43
43
7
4
.90, N 14.40.
H 6.00, N 13.58; found C 71.48, H 5.92, N 13.50.
Unauthenticated
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6
ꢀꢀꢀꢀꢁꢀM. E. Azab et al.: Synthesis of linear dipeptide pyridine and macrocyclic pentaazapyridine candidates
3
.4.3 N,N′-Bis[1-(4-methoxylphenyl-1-
164.78 (12C, 2Ph-C), 131.76, 140.38, 151.80 (5C, pyr-C), 167.41
methylhydrazonyl)-2-ꢁ-phenylalaninyl]-3,5-
(2C, 2CO), 168.52 (2C, 2Cꢂ=ꢂN), 176.82 (2C, 2CO, hydrazone).
+
(diaminocarbonyl)pyridine (7c)
– MS (EI, 70 eV): m/z (%) ꢂ=ꢂ 730 (25) [M] . – C H F N O
41
37
2
7
4
(
729.77): calcd. C 67.48, H 5.11, N 13.44; found C 67.40, H
2
5
Yield 78%; m.p. 268–270°C (dioxane). – [α]D ꢂ=ꢂ –78 (c ꢂ=ꢂ 5.05, N 13.40.
.5, DMF). – IR (film): ν ꢂ=ꢂ 3374–3328 (NH), 3080 (CH-Ar),
988 (CH-aliph.), 1654, 1535, 1255 (CO, amide I, II, and III)
0
2
3
.4.6 N,N′-Bis[1-(2-pyridyl-1-methylhydrazonyl)-2-ꢁ-
–1
1
cm . – H NMR (500 MHz, [D ]DMSO): δ ꢂ=ꢂ 1.12 (s, 6H, 2CH ),
6
3
phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (8a)
3
.32 (d, 4H, 2CH ), 2.68 (s, 6H, 2OCH ), 4.62–4.68 (m, 2H,
2
3
2
CH), 6.95–7.65 (m, 18H, 4Ph-H), 8.68, 8.82 (2s, 4H, 4NH,
2
5
Yield 65%; m.p. 217–219°C (AcOH-H O). – [α] ꢂ=ꢂ –92 (c ꢂ=ꢂ
13
2
D
D O exchangeable), 8.74, 9.10 (2s, 3H, pyr-H). – C NMR
2
0
.5, DMF). – IR (film): ν ꢂ=ꢂ 3454–3324 (NH), 3088 (CH-Ar),
(
125 MHz, [D ]DMSO): δ ꢂ=ꢂ 14.36 (2C, 2CH ), 41.34 (2C, 2CH ),
6
3
2
2
974 (CH-aliph.), 1655, 1534, 1253 (Cꢂ=ꢂO, amide I, II, and
5
4.18 (2C, 2CH), 55.32 (2C, 2OCH ), 125.65, 127.73, 128.54,
3
–1
1
III) cm . – H NMR (500 MHz, [D ]DMSO): δ ꢂ=ꢂ 0.99 (s, 6H,
6
1
39.42 (12C, 2Ph-C), 113.95, 125.78, 129.94, 162.48 (12C,
2
CH ), 3.62 (d, 4H, 2CH ), 4.64–4.70 (m, 2H, 2CH), 7.02–7.60
3
2
2
Ph-C), 131.76, 140.42, 151.80 (5C, pyr-C), 167.43 (2C, 2CO),
(
(
8
m, 10H, 2Ph-H), 7.75–8.56 (m, 6H, 2-pyridyl-H), 8.65, 8.92
1
68.35 (2C, 2Cꢂ=ꢂN), 176.88 (2C, 2CO, hydrazone). – MS (EI,
2s, 4H, 4NH, D O exchangeable), 8.80 (s, 2H, pyridyl-H),
+
2
7
0 eV): m/z (%) ꢂ=ꢂ 754 (12) [M] . – C H N O (753.84): calcd.
43
43
7
6
13
.75, 9.08 (2s, 3H, 3,5-pyridyl-H). – C NMR (125 MHz, [D ]
6
C 68.51, H 5.75, N 13.01; found C 68.40, H 5.70, N 12.90.
DMSO): δ ꢂ=ꢂ 13.65 (2C, 2 CH ), 41.82 (2C, 2CH ), 53.74 (2C,
3
2
2
1
CH), 125.35, 127.62, 128.55, 139.58 (12C, 2Ph-C), 122.88,
26.12, 131.68, 135.84, 140.32, 148.65, 152.28, 154.48 (15C,
3.4.4 N,N′-Bis[1-(4-chlorophenyl-1-methylhydrazonyl)-2-ꢁ-
3
pyr-C), 144.98 (2C, 2Cꢂ=ꢂN), 167.72 (2C, 2CO), 176.85 (2C,
phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (7d)
+
2
CO, hydrazone). – MS (EI, 70 eV): m/z (%) ꢂ=ꢂ 696 (10) [M] .
–
C H N O (695.76): calcd. C 67.32, H 5.36, N 18.12; found
2
5
39 37 9 4
Yield 64%; m.p. 234–236°C (AcOH). – [α]D ꢂ=ꢂ –86 (c ꢂ=ꢂ 0.5,
DMF). – IR (film): ν ꢂ=ꢂ 3398–3354 (NH), 3085 (CH-Ar), 2978
C 67.21, H 5.30, N 18.05.
–
1
(
CH-aliph.), 1654, 1535, 1252 (CO, amide I, II, and III) cm .
1
–
H NMR (500 MHz, [D ]DMSO): δ ꢂ=ꢂ 1.10 (s, 6H, 2CH ), 3.26 3.4.7 N,N′-Bis[1-(3-pyridyl-1-methylhydrazonyl)-2-ꢁ-
6
3
(
d, 4H, 2CH ), 4.65–4.70 (m, 2H, 2CH), 7.15–7.72 (m, 18H,
phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (8b)
2
4
Ph-H), 8.52, 8.68 (2s, 4H, 4NH, D O exchangeable), 8.76,
2
13
25
9
1
.14 (2s, 3H, pyr-H). – C NMR (125 MHz, [D ]DMSO): δ ꢂ=ꢂ Yield 55%; m.p. 241–243°C (EtOH). – [α]D ꢂ=ꢂ –75 (c ꢂ=ꢂ 0.5,
6
4.52 (2C, 2CH ), 41.28 (2C, 2CH ), 53.85 (2C, 2CH), 125.64, DMF). – IR (film): ν ꢂ=ꢂ 3415–3332 (NH), 3075 (CH-Ar), 2982
3
2
–1
1
1
(
27.70, 128.62, 139.38 (12C, 2Ph-C), 128.82, 129.55, 131.65, (CH-aliph.), 1652, 1534, 1255 (CO, amide I, II, and III) cm .
1
36.35 (12C, 2Ph-C), 131.80, 140.40, 151.82 (5C, pyr-C), 167.45 – H NMR (500 MHz, [D ]DMSO): δ ꢂ=ꢂ 1.05 (s, 6H, 2CH ), 3.75
6
3
2C, 2CO), 168.48 (2C, 2Cꢂ=ꢂN), 176.86 (2C, 2CO, hydrazone). (d, 4H, 2CH ), 4.60–4.66 (m, 2H, 2CH), 7.00–7.58 (m, 10H,
2
+
–
MS (EI, 70 eV): m/z (%) ꢂ=ꢂ 763 (32) [M] . – C H Cl N O
2Ph-H), 7.70–8.50 (m, 6H, pyridyl-H), 8.65, 8.86 (2s, 4H,
41
37
2
7
4
(
762.68): calcd. C 64.57, H 4.89, Cl 9.30, N 12.86; found C 4NH, D O exchangeable), 8.75, 9.10 (2s, 3H, 3,5-pyridyl-H),
2
1
3
6
4.50, H 4.80, Cl 9.22, N 12.80.
9.18 (s, 2H, pyridyl-H-2). – C NMR (125 MHz, [D ]DMSO):
6
δ ꢂ=ꢂ 12.98 (2C, 2CH ), 41.68 (2C, 2CH ), 53.84 (2C, 2CH),
3
2
1
25.64, 127.58, 128.72, 139.67 (12C, 2Ph-C), 122.56, 125.52,
3.4.5 N,N′-Bis[1-(4-fluorophenyl-1-methylhydrazonyl)-2-ꢁ- 136.92, 150.75, 151.24 (10C, 3-Pyridyl-C), 131.48, 140.65,
phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (7e)
152.32 (5C, 3,5-pyridyl-C), 167.05 (2C, 2CO), 168.42 (2C,
2
Cꢂ=ꢂN), 176.78 (2C, 2CO, hydrazone). – MS (EI, 70 eV): m/z
2
5
+
Yield 70%; m.p. 216–218°C (AcOH). – [α] ꢂ=ꢂ –116 (c ꢂ=ꢂ 0.5, (%) ꢂ=ꢂ 696 (35) [M] . – C H N O (695.76): calcd. C 67.32, H
DMF). – IR (film): ν ꢂ=ꢂ 3378–3342 (NH), 3080 (CH-Ar), 2972 5.36, N 18.12; found C 67.20, H 5.28, N 18.05.
D
39 37
9
4
–
1
(
CH-aliph.), 1652, 1533, 1254 (CO, amide I, II, and III) cm .
1
–
H NMR (500 MHz, [D ]DMSO): δ ꢂ=ꢂ 1.15 (s, 6H, 2CH ), 3.24
6
3
(
d, 4H, 2CH ), 4.68–4.72 (m, 2H, 2CH), 7.10–7.75 (m, 18H, 3.4.8 N,N′-Bis[1-(4-pyridyl-1-methylhydrazonyl)-2-ꢁ-
2
4
Ph-H), 8.68, 8.70 (2s, 4H, 4NH, D O exchangeable), 8.75,
phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (8c)
2
13
9
1
.10 (2s, 3H, pyr-H). – C NMR (125 MHz, [D ]DMSO): δ ꢂ=ꢂ
6
2
5
4.56 (2C, 2CH ), 41.32 (2C, 2CH ), 53.88 (2C, 2CH), 125.58, Yield 62%; m.p. 255–257°C (MeOH). – [α] ꢂ=ꢂ –102 (c ꢂ=ꢂ 0.5,
3
2
D
1
27.64, 128.60, 139.44 (12C, 2Ph-C), 114.65, 128.62, 129.68, DMF). – IR (film): ν ꢂ=ꢂ 3410–3330 (NH), 3078 (CH-Ar), 2986
Unauthenticated
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M. E. Azab et al.: Synthesis of linear dipeptide pyridine and macrocyclic pentaazapyridine candidatesꢂꢁꢀꢀꢀꢂ7
–
1
1
(
CH-aliph.), 1653, 1532, 1251 (CO, amide I, II, and III) cm . – H NMR (500 MHz, [D ]DMSO): δ ꢂ=ꢂ 3.40 (d, 4H, 2CH ),
6
2
1
–
H NMR (500 MHz, [D ]DMSO): δ ꢂ=ꢂ 0.98 (s, 6H, 2CH ), 3.78 4.45–4.52 (m, 2H, 2CH), 7.12–7.86 (m, 22H, Ar-H), 8.57, 9.02
6
3
(
d, 4H, 2CH ), 4.62–4.65 (m, 2H, 2CH), 6.98–7.46 (m, 10H, (2s, 3H, pyr-H), 8.60, 8.78 (2s, 4H, 4NH, exchangeable
2
1
3
2
4
–
Ph-H), 7.78, 8.70 (d, 8H, pyridyl-H), 8.68, 8.88 (2s, 4H, with D O). – C NMR (125 MHz, [D ]DMSO): δ ꢂ=ꢂ 41.45 (2C,
2
6
NH, D O exchangeable), 8.78, 9.12 (2s, 3H, 3,5-pyridyl-H). 2CH ), 53.12 (2C, 2 CH), 122.12, 124.65, 127.95, 130.10, 136.86,
2
2
13
C NMR (125 MHz, [D ]DMSO): δ ꢂ=ꢂ 13.12 (2C, 2CH ), 41.60 137.35 (20C, naphthyl-C), 125.60, 127.54, 128.54, 139.68 (12C,
6
3
(
(
1
(
2C, 2CH ), 53.80 (2C, 2CH), 125.60, 127.50, 128.65, 139.60 2Ph-C), 131.62, 140.18, 152.17 (5C, pyr-C), 158.55 (4C, 4 CO-
2
12C, 2Ph-C), 123.65, 136.52, 148.65 (10C, pyridyl-C), 131.55, imide), 167.24, 170.26 (4C, 4 CO-amide). – MS (EI, 70 eV):
+
40.32, 152.44 (5C, 3,5-pyridyl-C), 167.00 (2C, 2CO), 168.30 m/z (%) ꢂ=ꢂ 850 (8) [M] . – C H N O (849.84): calcd. C
49
35
7
8
2C, 2Cꢂ=ꢂN), 176.84 (2C, 2CO, hydrazone). – MS (EI, 70 eV): 69.25, H 4.15, N 11.54; found C 69.12, H 4.05, N 11.43.
+
m/z (%) ꢂ=ꢂ 696 (16) [M] . – C H N O (695.76): calcd. C
3
9
37
9
4
6
7.32, H 5.36, N 18.12; found C 67.18, H 5.24, N 18.08.
α
3
.5.3 N -Dinicotinoyl-bis[ꢁ-phenylalaninylpyrrolo[3,4-b]
pyridine-5,7-dione-imide] (11)
3
.5 Synthesis of ꢈ–11
2
5
Yield 68%; m.p. 234–236°C. – [α]D ꢂ=ꢂ –96 (c ꢂ=ꢂ 0.5, DMF).
A mixture of 4 (1 mmol) and dicarboxylic acid anhydride – IR (film): ν ꢂ=ꢂ 3445–3313 (NH), 3083 (CH-Ar), 2992 (CH-
–1
derivatives (phthalic anhydride, tetrachlorophthalic aliph.), 1653, 1535, 1252 (Cꢂ=ꢂO, amide I, II, and III) cm .
1
anhydride, 1,8-naphthalenedicarboxylic acid anhydride, – H NMR (500 MHz, [D ]DMSO): δ ꢂ=ꢂ 3.45 (d, 4H, 2CH ),
6
2
or 2,3-pyridinedicarboxylic acid anhydride, 2 mmol) was 4.50–4.61 (m, 2H, 2CH), 6.94–7.48 (m, 10H, 2Ph-H), 8.62,
refluxed in glacial acetic acid (50 mL) for 6 h. The reaction 9.05 (2s, 3H, pyr-H), 7.96–8.32 (m, 4H, pyr-H), 8.95 (t, 2H,
mixture was poured into ice water; the obtained precipi- pyr-H), 8.68, 8.75 (2s, 4H, 4NH, exchangeable with D O).
2
1
3
tate was collected by filtration, washed with water, dried, – C NMR (125 MHz, [D ]DMSO): δ ꢂ=ꢂ 42.28 (2C, CH ), 52.87
6
2
and crystallized from DMF-H O to give the corresponding (2C, 2 CH), 124.32, 128.36, 129.43, 138.76 (12C, 2Ph-C), 127.21,
2
bisimide hexacarboxamide derivatives 9–11, respectively. 128.05, 131.66, 137.94, 140.12, 145.12, 152.10, 152.56 (15C,
pyr-C), 164.63, 164.95 (4C, 4 CO-Imide), 169.48, 170.34 (4C,
+
4
CO-amide). – MS (EI, 70 eV): m/z (%) ꢂ=ꢂ 752 (20) [M] .
α
3
.5.1 N -Dinicotinoyl-bis(ꢁ-phenylalaninyl-isoindoline-
– C H N O (751.70): calcd. C 62.31, H 3.89, N 16.77; found
39 29 9 8
1
,3-dione-imide) (ꢈ)
C 62.20, H 3.80, N 16.70.
2
5
Yield 72%; m.p. 256–258°C. – [α] ꢂ=ꢂ –117 (c ꢂ=ꢂ 0.5, DMF).
D
–
IR (film): ν ꢂ=ꢂ 3398–3343 (NH), 3078 (CH-Ar), 2986 (CH-
3
.6 Antimicrobial activity
–1
1
aliph.), 1653, 1533, 1254 (Cꢂ=ꢂO, amide I, II, and III) cm . – H
NMR (500 MHz, [D ]DMSO): δ ꢂ=ꢂ 3.40 (d, 4H, 2CH ), 4.56–
6
2
The antimicrobial activities of the synthesized com-
pounds were determined by the agar diffusion method as
recommended by the National Committee for Clinical Lab-
oratory Standards [25]. The concentrations of the tested
compounds (10 μg mL ) were used according to modified
Kirby–Bauer’s disk diffusion method [26]. The degree of
inhibition is measured in comparison with that of Chlo-
ramphenicol and fusidic acid taken as standards.
4
.63 (m, 2H, 2CH), 7.08–8.05 (m, 18H, 4Ph-H), 8.45, 9.00
(
2s, 3H, pyr-H), 8.64, 8.75 (2s, 4H, 4NH, D O exchangea-
2
13
ble). – C NMR (125 MHz, [D ]DMSO): δ ꢂ=ꢂ 40.84 (2C, 2CH ),
6
2
5
3.03 (2C, 2 CH), 124.34, 127.42, 128.22, 138.86 (12C, 2Ph-C),
–1
1
27.24, 131.22, 131.86, (12C, 2 Phth-C), 131.65, 140.14, 152.13
(
5C, pyr-C), 164.56 (4C, 4 CO-imide), 167.12, 170.15 (4C, 4
+
CO-amide). – MS (EI, 70 eV): m/z (%) ꢂ=ꢂ 750 (14) [M] .
–
C H N O (749.72): calcd. C 65.68, H 4.17, N 13.08; found
41 31 7 8
C 65.60, H 4.10, N 13.00.
4
Conclusions
α
3
.5.2 N -Dinicotinoyl-bis(ꢁ-phenylalaninylbenzo[de]
isoquinoline-1,3(2H)-dione-imide) (1ꢉ)
In the present work, a series of tetracarboxamide and
macrocyclic tripeptides have been prepared starting from
2
5
Yield 65%; m.p. 264–266°C. – [α]D ꢂ=ꢂ –68 (c ꢂ=ꢂ 0.5, DMF). 3,5-bis[N-(1-hydrazinyl-1-oxo-3-phenylpropan-2-yl)]pyridi-
–
IR (film): ν ꢂ=ꢂ 3416–3332 (NH), 3073 (CH-Ar), 2987 (CH- necarboxamide as starting material. Some of the synthe-
–1
aliph.), 1655, 1535, 1255 (Cꢂ=ꢂO, amide I, II, and III) cm . sized compounds were screened as antimicrobial agents.
Unauthenticated
Download Date | 5/15/16 9:35 AM

8
ꢀꢀꢀꢀꢁꢀM. E. Azab et al.: Synthesis of linear dipeptide pyridine and macrocyclic pentaazapyridine candidates
Acknowledgments: The authors would like to extend
their sincere appreciation to the Deanship of Scientific
Research at King Saud University for its funding of this
research through the Research Group project no. RGP-172.
[10] Q. Zhu, X. Wang, Z. Chu, G. He, G. Dong, Y. Xu, Bioorg. Med.
Chem. Lett. 2ꢉ13, 23, 1993.
[
11] V. Klimešová, P. Herzigová, K. Palát, M. Macháček, J.
Stolaříková, H. M. Dahse, U. Möllmann, ARKIVOC 2ꢉ12, (iii), 90.
12] M. A. Tabrizi, P. G. Baraldi, G. Saponaro, A. R. Moorman, R.
Romagnoli, D. Preti, S. Baraldi, C. Corciulo, F. Vincenzi, P. A.
Borea, K. Varani, J. Med. Chem. 2ꢉ13, 56, 1098.
13] A. Fukumizu, Y. Tsuda, K. Wanaka, M. Tada, S. Okamoto, A.
Hijikata-Okunomiya, Y. Okada, Chem. Pharm. Bull. 1ꢈꢈꢈ, 47,
[
[
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Z. Naturforsch.ꢂ
ꢂ2016 | Volume x | Issue x(b)
Graphical synopsis
Mohamed E. Azab, Eman M. Flefel,
Nermien M. Sabry, Abd El-Galil E. Amr
Synthesis and antimicrobial activity
of some linear dipeptide pyridine and
macrocyclic pentaazapyridine candi-
dates
DOI 10.1515/znb-2016-0018
Z. Naturforsch. 2016; x(x)b: xxx–xxx
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