Regioselective synthesis and antibacterial evaluation of novel bis-pyrimidine derivatives via a three-component reaction

Article abstract of DOI:10.1007/s00044-013-0731-0

A series of novel bis-2-phenylpyrimidines with alkyl linkages have been prepared by a three-component cyclo-condensation of benzamidine hydrochloride, β-ketoester, and dihaloalkanes. The easy work-up of the products, rapid reaction, and mild conditions are notable features of this protocol. The reaction was efficiently catalyzed in one-pot by K₂CO₃ as a base in N,N-dimethylformamide under optimized temperature (70 C) conditions providing the title compounds in moderate to high yields. The antibacterial activities of the selected products were evaluated against some strains of Gram-positive and Gram-negative bacteria. Biological data indicated that some products exhibit promising activities.

Full text of DOI:10.1007/s00044-013-0731-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0731-0
ORIGINAL RESEARCH
Regioselective synthesis and antibacterial evaluation of novel
bis-pyrimidine derivatives via a three-component reaction
•
Nosrat O. Mahmoodi Sajede Shoja
•
•
Bahman Sharifzadeh Mehdi Rassa
Received: 5 June 2013 / Accepted: 15 August 2013
Ó Springer Science+Business Media New York 2013
Abstract A series of novel bis-2-phenylpyrimidines with
alkyl linkages have been prepared by a three-component
cyclo-condensation of benzamidine hydrochloride, b-keto-
ester, and dihaloalkanes. The easy work-up of the products,
rapid reaction, and mild conditions are notable features of this
protocol. The reaction was efficiently catalyzed in one-pot by
K2CO3 as a base in N,N-dimethylformamide under optimized
temperature (70 °C) conditions providing the title com-
pounds in moderate to high yields. The antibacterial activities
of the selected products were evaluated against some strains
of Gram-positive and Gram-negative bacteria. Biological
data indicated that some products exhibit promising
activities.
(Dordoni et al., 2004) are frequently used as general
anesthetics, while methylphenobarbital (Eadie and Hooper,
2002) even now is in use as antiepileptic.
A survey of literature in the recent past reveals that
some pyrimidines are building blocks for pharmaceutical
agents (Deshmukh et al., 2009). They exhibit a wide
spectrum of pharmacophore as it acts as microbicidal
(Sedaghati et al., 2012), antihypertensive (Winter et al.,
1962), anti-tumor and anticancer agents (Desai et al., 2011;
Becan and Wagner, 2013) and DNA replication in
eukaryotic cells (Sawa and Masai, 2008). It can be sug-
gested that the bis-pyrimidine compounds would consider
as bis-drugs, and are estimated to be capable of double
therapeutic behavior.
Keywords Three-component reaction ꢀ
Antibacterial activity ꢀ Bis-pyrimidine ꢀ
Benzamidine hydrochloride ꢀ b-ketoester
Influence and pharmacological properties of alkyl link-
ages in the mono, and bis-compounds have been reported
(Maletic et al., 2011; Levi et al., 1989; Perrey et al., 2000;
Tanabe et al., 2011). For example, recently the relationship
between alkyl chain length and the antifungal (Sortino
et al., 2011), antimalarial (Fattorusso et al., 2011), anti-
tubercular (Gao et al., 2013) and antibacterial (Xu et al.,
2009) activity have been described. In addition to these,
role of alkyl chain in activity of ligands for a1-adreno-
ceptor subtypes is studied (Romeo et al., 2011). Also the
effect of alkyl chain length on plasticizer and biodegra-
dation properties was examined (Erythropel et al., 2013).
Introduction
The pyrimidine moiety turned out to be an important
pharmacophor, interacting with the synthesis and function
of nucleic acid like the cyctostaticum fluorouracil (Rose-
meyer, 2004; Goette, 1981) or the anti-HIV drug zidovu-
dine (Darbyshire et al., 2004) or potent antioxidant agents.
Short-acting barbiturates like thiopental sodium (pentothal)
Results and discussion
N. O. Mahmoodi (&) ꢀ S. Shoja ꢀ B. Sharifzadeh
Department of Organic Chemistry, Faculty of Sciences,
University of Guilan, PO Box 41335-1914, Rasht, Iran
e-mail: mahmoodi@guilan.ac.ir; nosmahmoodi@gmail.com
Chemistry
The most click procedure for the preparation of pyrimidi-
nones has been reported by condensation of b-dicarbonyl
compounds with the amidine or other analogs of them via
M. Rassa
Department of Biology, Faculty of Sciences, University
of Guilan, PO Box 41335-1914, Rasht, Iran
123

Med Chem Res
base catalyst (Spivey et al., 2003). Literatures researching
indicate that structural evaluations, properties, and syn-
thetic routes toward bis-pyrimidines have not been
reported.
subsequently eliminates H2O to form intermediate (3) fol-
lowed by intramolecular nucleophilic attack to the carbonyl
group leading to the cyclic product (4) which subsequently
undergoes EtOH elimination give the pyrimidinole ring of
(5). The later on tautomerization gives a pyrimidinone ring
(50), and further reaction between (50) via appropriate di-
haloalkane in the presence of base in one-pot affords target
product (6) (Scheme 2).
Following our interest in synthesis of bis-intelligent
compounds (Mahmoodi and Khodaee, 2004; Mahmoodi
et al., 2010, 2012; Rineh et al., 2007; Kiyani et al., 2009a,
b; Ghavidast et al., 2010; Zare et al., 2011; Khodaee
et al., 2013), here we report synthesis of bis-pyrimidines
capable of serving as bis-drugs. The reports that describ-
ing some lipophilicity bis-heterocyclic compounds com-
pared to their mono-heterocyclic analogues will present
superior medicinal and pharmacological activities (El-
sharief and Moussa, 2009) prompted us to design and
synthesis bis-pyrimidines 6a–i contained alkyl linkages
(Scheme 1). In general, lipophilicity is one of the most
important parameter because it is mainly involved in
pharmacokinetic processes such as absorption, distribu-
tion, metabolism, excretion, and toxicity and in ligand–
target interactions (El-Baih et al., 2006). Lipophilicity is
the molecular factor of choice in several quantitative
structure–activity relationships of diverse classes of com-
pounds (Mosmann, 1983).
All of the compounds described in Scheme 1 were
characterized by spectroscopic methods (IR, 1H NMR, 13
C
NMR) and elemental analysis.
The IR spectra of bis-pyrimidines derivatives 6a–i
revealed the presence of etheric C–O stretching vibration
bands at t 1,241–1,269 cm-1, absorption bands in the
1,621–1,670 cm-1 region corresponding to endocyclic
C=N stretching bands due to the ring closure, and peaks in
the regions 1,467–1,491 and 1,592–1,620 cm-1 which
indicate the presence of aromatic C=C groups.
1
The H NMR spectra of bis-pyrimidines 6a–i showed a
sharp singlet at region d 6–8 ppm due to the pyrimidine
rings protons. The etheric –OCH2 protons demonstrate a
signal at d 4.0–4.5 ppm as triplet for all of the compounds.
Protons bound to the aromatic rings were observed within
the expected chemical shift regions and exhibited the
expected integral values.
Intermolecular condensation of b-ketoester with ben-
zamidine hydrochloride give intermediate (2) which
Scheme1 Synthesis of bis-
pyrimidines (6a–i)
O
O
n
NH
.
HCl
O
O
N
N
N
N
(CH )
2
NH2
R
OEt
DMF / K
2CO3
R
R
6a-c ; R = Me , n = 4,5 and 6
6d-f ; R = Pr , n = 4,5 and 6
6g-i ; R = Ph , n = 4,5 and 6
70 °C / 3-4 h
Br-(CH2)n-Br
n = 4, 5 and 6
-
H
2O
HN
O
NH2
O
HN
NH
O
HN
NH
O
N
NH
OH
R
OEt
R
OEt
R
OEt
R
OEt
OH
4
3
2
-
EtOH
R = Me, Pr and Ph
I) K
2CO3
N
N
N
N
N
R
N
N
NH
O
H
C
II) Br-(CH2)n-Br
n = 4 , 5 and 6
2 n
R
O
R
O
OH
R
5'
5
6
Scheme 2 Proposed reaction mechanism for synthesis of (6a–i)
123

Med Chem Res
The 13C NMR spectra of bis-pyrimidines 6a–i showed
signals at 161.1–172.3 ppm assigned to quaternary carbons
(C2, C4, C6) of the pyrimidine ring. C5 Carbon of
pyrimidine displayed a signal at 99.9–108.2 ppm for all of
the compounds. The etheric carbons of bis-pyrimidines
appeared as a signal in the region at 61.7–68.8 ppm in all
of the compounds. The signals due to the aromatic and
aliphatic carbon groups resonate at their usual positions
(see the ‘‘Experimental’’ section).
the membranous wall of bacteria; (b) Formation of an
enzyme in bacteria that eliminate the drug compound;
(c) Bacteria causing alter the part of structure itself, that
drug compound must be affect on it.
Structure–activity relationships
All of the synthetic derivatives prepared in the course of
this study have been evaluated for antibacterial activity
against five different standard microorganisms. Results are
reported in Table 1. In these bis-compounds, talk about this
topic is a bit complicated. This issue is examined from two
directions: influence of the modification of the substituents
on pyrimidine ring; and influence of the variation of the
length of the alkyl chain.
Pharmacological screening
The in vitro antibacterial activities of compounds 6a–i
were evaluated against Gram-positive and Gram-negative
bacteria using the cultures of five different standard
microorganisms: Escherichia coli (E. coli) ATCC 25922
and Salmonella enterica (S. enterica) ATCC 13312 as
Gram-negative models, and Staphylococcus aureus (S.
aureus) ATCC 29213, Bacillus subtilis (B. subtilis) ATCC
29213 and Micrococcus luteus (M. luteus) ATCC 29213 as
a Gram-positive model.
In general, it can be said that the alkyl linkage with
higher ‘‘n’’ lead to longer distance between the phenyl
groups, and better results can be seen; because of less steric
hindrance. However, the effect of the other substituents on
pyrimidine ring should not be ignored. For example 6f
showed strong activity against M. luteus and B. subtilis,
while 6c and 6i exhibit undesirable result against these
bacteria.
The results revealed that most of compounds 6a–i
exhibit strong activities toward M. luteus, B. subtilis
(Gram-positive bacterium), and S. enterica (a Gram-nega-
tive bacterium). All of the compounds listed in Table 1
exhibit weak antimicrobial activities against S. aureus (a
Gram-positive bacterium). Also the results indicate that
compounds 6e, 6f, and 6i have moderate growth-inhibiting
activity against E. coli.
In other hand, the smaller size of drug compounds,
because the more solubility in phospholipid, lead to greater
penetration power to the membranous wall of the bacteria,
and thus more favorable effect is observed. Of course the
kind of bacteria is very decisive. For example 6a and 6g
demonstrate strong activities against M. luteus and B.
subtilis, while those activities against the S. enterica are not
favorable. The activity of 6d against these bacteria is not
desirable too.
In fact, the weakness in some of the results in Table 1 is
the biological point of view due to the following factors;
(a) The target compound is not capable to penetrating to
Table 1 Antimicrobial activity
of the compounds (6a–i)
Entry Compound
Conc. of
Antimicrobial activity (zone of inhibition in mm)
compound
in DMSO
lg/0.1 mL
Gram-negative
Gram-positive
Escherichia Salmonella Staphylococcus Bacillus Micrococcus
coli
enterica
aureus
subtilis luteus
1
6a
6b
6c
6d
6e
6f
12
12
12
12
12
12
12
12
12
–
–
9
16
13
10
–
–
–
16
9
–
15
–
2
3
–
–
10
13
13
22
16
14
11
12
14
–
4
–
–
12
14
16
18
13
12
10
16
–
5
10
8
–
6
–
10
–
7
6g
6h
6i
–
–
8
–
14
12
8
–
9
13
16
12
–
–
10
11
12
Erythromycin 15
21
23
–
Tetracycline
DMSO
30
–
7
–
123

Med Chem Res
1
Experimental
623; H NMR (400 MHz, CDCl3) (d/ppm): 8.13 (d, 4H,
Ar–H, J = 8.8 Hz), 7.74 (t, 4H, Ar–H, J = 9.4 Hz), 7.55
(t, 2H, Ar–H, J = 7.8 Hz), 6.17 (s, 2H, H5 of pyrimidine),
4.20 (t, 4H, –OCH2–, J = 11.6 Hz), 2.50 (s, 6H, substi-
tuted-CH3), 1.61–1.70 (m, 4H, –CH2–), 1.39–1.49 (m, 2H,
–CH2–); 13C NMR (100 MHz, CDCl3) (d/ppm): 169.92
(C4 of pyrimidine), 167.57 (C6 of pyrimidine), 166.75 (C2
of pyrimidine), 128.87–137.44 (Ar–C), 107.25 (C5 of
pyrimidine), 61.74 (OCH2), 29.93 (CH2), 28.91 (substi-
tuted-CH3), 24.33 (CH2). Molecular weight: 440.55, Anal.
calcd. for C27H28N4O2: C, 73.61; H, 6.41; N, 12.72 %.
Found C, 73.62; H, 6.47; N, 12.70 %.
Materials and equipments
Chemicals materials were purchased from Fluka, Merck,
and Aldrich. Melting points were measured on an Elec-
trothermal 9100 apparatus. IR spectra were determined on
a Shimadzo IR-470 spectrometer. All H NMR and 13C
1
NMR data were recorded in CDCl3 using a Bruker Avance
400 and 100-MHz spectrometer. Chemical shifts are
reported in ppm (d) using deuterated solvents as internal
references. Elemental analysis was made by a Carlo-Erba
EA1110 CNNO-S analyzer and agreed with the calculated
values.
1,6-Bis((6-methyl-2-phenylpyrimidin-4-yl)oxy)hexane
(6c) Orange oil; yield 89 %; IR (mmax/cm-1): 3411, 2962,
2890, 1668, 1602, 1514, 1491, 1420, 1244, 893, 776, 679,
General procedure for the synthesis of 1,4-bis((6-
alkyl or phenyl-2-phenylpyrimidin-4-yl)oxy) alkane
derivatives (6a–i)
1
628; H NMR (400 MHz, CDCl3) (d/ppm): 8.44 (d, 4H,
Ar–H, J = 9.2 Hz), 7.69 (t, 4H, Ar–H, J = 7.4 Hz), 7.55
(t, 2H, Ar–H, J = 7.8 Hz), 6.19 (s, 2H, H5 of pyrimidine),
4.29 (t, 4H, –OCH2–, J = 11.2 Hz), 2.16 (s, 6H, substi-
tuted-CH3), 1.61–1.70 (m, 4H, –CH2–), 1.45 (t, 4H, –CH2–,
J = 12.4 Hz); 13C NMR (100 MHz, CDCl3) (d/ppm):
169.95 (C4 of pyrimidine), 167.67 (C6 of pyrimidine),
163.82 (C2 of pyrimidine), 127.40–137.78 (Ar–C), 104.64
(C5 of pyrimidine), 64.14 (OCH2), 29.30 (CH2), 24.11
(substituted-CH3), 21.73 (CH2), Molecular weight: 454.57,
Anal. calcd. for C28H30N4O2: C, 73.98; H, 6.65; N,
12.33 %. Found C, 73.96; H, 6.66; N, 12.34 %.
A 25 mL round bottom flask was charged with benzami-
dine hydrochloride (31.7 mg, 0.203 mmol), b-ketoester
derivatives (0.184 mmol), powdered K2CO3 (63.7 mg,
0.461 mmol), and a stir bar. The flask was sealed and
charged with DMF (1.5 mL) followed by dihaloalkane
(0.23 mmol). With vigorous stirring, the reaction mixture
was heated to 70 °C for 2–4 h, and reaction progress was
monitored by TLC. Upon completion of the reaction, the
reaction mixture was diluted with EtOAc (10 mL), and
washed with sat. aq NaHCO3 (10 mL) and brine (10 mL).
The combined aqueous phases were back-extracted with
EtOAc (5 mL), and the combined organic phases were
dried over Na2SO4, filtered, and concentrated in vacuum to
afford the title compound as near colorless oil that slowly
solidified upon standing.
1,4-Bis((2-phenyl-6-propylpyrimidin-4-yl)oxy)butane (6d)
Deep yellow oil; yield 79 %; IR (mmax/cm-1): 3407, 2958,
2877, 1658, 1612, 1503, 1476, 1401, 1269, 891, 786, 684,
1
623; H NMR (400 MHz, CDCl3) (d/ppm): 8.44 (d, 4H,
Ar–H, J = 9.2 Hz), 7.58–7.79 (m, 6H, Ar–H), 6.02 (s, 2H,
H5 of pyrimidine), 4.02 (t, 4H, –OCH2–, J = 11.0 Hz),
2.53 (t, 4H, –CH2–, J = 12.8 Hz), 1.49–1.87 (m, 8H, –
CH2–), 0.86 (t, 6H, –CH3 of substituted Pr, J = 14.2 Hz);
13C NMR (100 MHz, CDCl3) (d/ppm): 172.31 (C4 of
pyrimidine), 172.06 (C6 of pyrimidine), 168.24 (C2 of
pyrimidine), 129.12–134.18 (Ar–C), 102.57 (C5 of
pyrimidine), 67.83 (OCH2), 43.48 (CH2), 27.21 (CH2),
22.14 (CH2), 19.43 (CH3 of substituted Pr); Molecular
weight: 482.63, Anal. calcd. for C30H34N4O2: C, 74.66; H,
7.10; N, 11.61 %. Found C, 74.64; H, 7.12; N, 11.65 %.
1,4-Bis((6-methyl-2-phenylpyrimidin-4-yl)oxy)butane (6a)
Pale orange oil; yield 88 %; IR (mmax/cm-1): 3396, 2949,
2872, 1663, 1603, 1505, 1467, 1389, 1257, 882, 773, 680,
1
608; H NMR (400 MHz, CDCl3) (d/ppm): 8.38 (d, 4H,
Ar–H, J = 8.0 Hz), 7.75 (t, 4H, Ar–H, J = 7.4 Hz), 7.55
(t, 2H, Ar–H, J = 7.8 Hz), 6.20 (s, 2H, H5 of pyrimidine),
4.51 (t, 4H, –OCH2–, J = 10.4 Hz), 2.55 (s, 6H, substi-
tuted-CH3), 1.55 (t, 4H, –CH2–, J = 14.4 Hz); 13C NMR
(100 MHz, CDCl3) (d/ppm): 169.79 (C4 of pyrimidine),
166.97 (C6 of pyrimidine), 163.82 (C2 of pyrimidine),
128.63–133.26 (Ar–C), 100.61 (C5 of pyrimidine), 68.75
(OCH2), 29.81 (CH2), 28.10 (substituted-CH3). Molecular
weight: 426.52, Anal. calcd. for C26H26N4O2: C, 73.22; H,
6.14; N, 13.14 %. Found C, 73.18; H, 6.19; N, 13.17 %.
1,5-Bis((2-phenyl-6-propylpyrimidin-4-yl)oxy)pentane
(6e) Yellow oil; yield 76 %; IR (mmax/cm-1): 3405, 2942,
2879, 1670, 1620, 1501, 1479, 1421, 1269, 902, 790, 674,
1
623; H NMR (400 MHz, CDCl3) (d/ppm): 8.65 (d, 4H,
Ar–H, J = 9.2 Hz), 7.76 (t, 4H, Ar–H, J = 8.0 Hz), 7.56
(t, 2H, Ar–H, J = 8.2 Hz), 6.09 (s, 2H, H5 of pyrimidine),
4.02 (t, 4H, –OCH2–, J = 10.2 Hz), 2.70 (t, 4H, –CH2–,
J = 12.6 Hz), 1.33–1.82 (m, 10H, –CH2–), 0.95 (t, 6H,
1,5-Bis((6-methyl-2-phenylpyrimidin-4-yl)oxy)pentane
(6b) Yellow oli; yield 85 %; IR (mmax/cm-1): 3408, 2054,
2883, 1659, 1598, 1516, 1474, 1390, 1241, 879, 771, 672,
123

Med Chem Res
–CH3 of substituted Pr, J = 14.2 Hz); 13C NMR
(100 MHz, CDCl3) (d/ppm): 168.15 (C4 of pyrimidine),
167.23 (C6 of pyrimidine), 162.29 (C2 of pyrimidine),
129.67–135.98 (Ar–C), 99.98 (C5 of pyrimidine), 65.91
(OCH2), 44.66 (CH2), 29.31 (CH2), 22.13 (CH2), 21.04
(CH2), 12.19 (CH3 of substituted Pr); Molecular weight:
496.65, Anal. calcd. for C31H36N4O2: C, 74.97; H, 7.31; N,
11.28 %. Found C, 74.96; H, 7.32; N, 11.26 %.
weight: 564.69, Anal. calcd. for C37H32N4O2: C, 78.70; H,
5.71; N, 9.92 %. Found C, 78.68; H, 5.70; N, 9.91 %.
1,6-Bis((2,6-diphenylpyrimidin-4-yl)oxy)hexane (6i) Cream
oil; yield 74 %; IR (mmax/cm-1): 3390, 2958, 2881, 1667,
1610, 1503, 1472, 1265, 898, 768, 686, 615; 1H NMR
(400 MHz, CDCl3) (d/ppm): 7.99 (d, 4H, Ar–H,
J = 6.4 Hz), 7.83 (d, 4H, Ar–H, J = 8.8 Hz), 7.38–7.59
(m, 14H, Ar–H and H5 of pyrimidine), 4.06 (t, 4H,
–OCH2–, J = 11.6 Hz), 2.06–2.12 (m, 4H, –CH2–),
1.66–1.72 (m, 4H, –CH2–); 13C NMR (100 MHz, CDCl3)
(d/ppm): 170.09 (C4 of pyrimidine), 166.98 (C6 of
pyrimidine), 162.54 (C2 of pyrimidine), 128.79–138.97
(Ar–C), 106.11 (C5 of pyrimidine), 62.51 (OCH2), 37.88
(CH2), 22.75 (CH2); Molecular weight: 578.72, Anal.
calcd. for C38H34N4O2: C, 78.87; H, 5.92; N, 9.68 %.
Found C, 78.86; H, 5.91; N, 9.67 %.
1,6-Bis((2-phenyl-6-propylpyrimidin-4-yl)oxy)hexane (6f)
Pale orange oil; yield 81 %; IR (mmax/cm-1): 3419, 2951,
2921, 1646, 1596, 1509, 1480, 1400, 1259, 788, 669, 617;
1H NMR (400 MHz, CDCl3) (d/ppm): 8.66 (d, 4H, Ar–H,
J = 8.8 Hz), 7.62–7.79 (m, 6H, Ar–H), 6.09 (s, 2H, H5 of
pyrimidine), 4.03 (t, 4H, –OCH2–, J = 12.4 Hz), 2.73 (t,
4H, –CH2–, J = 14.0 Hz), 1.88–1.96 (m, 4H, –CH2–),
1.38–1.50 (m, 8H, –CH2–), 0.95 (t, 6H, –CH3 of substituted
Pr, J = 14.2 Hz); 13C NMR (100 MHz, CDCl3) (d/ppm):
171.93 (C4 of pyrimidine), 169.98 (C6 of pyrimidine),
164.13 (C2 of pyrimidine), 129.09–133.28 (Ar–C), 100.33
(C5 of pyrimidine), 68.89 (OCH2), 45.02 (CH2), 29.87
(CH2), 28.93 (CH2), 25.46 (CH2), 18.75 (CH3 of substi-
tuted Pr); Molecular Weight: 510.68, Anal. calcd. for
C32H38N4O2: C, 75.26; H, 7.50; N, 10.97 %. Found C,
75.24; H, 7.54; N, 10.95 %.
Antibacterial activity
A sterilized glass tube (5 mm diameter) was used asepti-
cally to make wells on plates. The antibacterial activity of
compounds was assayed biologically using the Agar well-
diffusion method. A colony of each standard test organism
was sub-cultured in order to obtain fresh bacteria on the
nutrient agar plates at 37 °C for 18 h. To preparations of
suspensions of microorganisms (0.5 McFarland), one to
two colonies from each plate was dissolved in isotonic
saline solution. Then Mueller–Hinton agar (Merck) plates
were prepared according to manufacturers’ instructions in
order to evaluate the antibacterial activities of compounds.
The sterile Mueller–Hinton agar plates were inoculated
with the bacteria.
1,4-Bis((2,6-diphenylpyrimidin-4-yl)oxy)butane
(6g)
Cream oil; yield 71 %; IR (mmax/cm-1): 3336, 2962, 2591,
1657, 1609, 1504, 1479, 1250, 783, 675, 628; H NMR
1
(400 MHz, CDCl3) (d/ppm): 8.00 (d, 4H, Ar–H,
J = 7.6 Hz), 7.83 (d, 4H, Ar–H, J = 8.8 Hz), 7.56–7.63
(m, 8H, Ar–H), 7.37–7.44 (m, 6H, Ar–H and H5 of
pyrimidine), 4.06 (t, 4H, –OCH2–, J = 10.8 Hz),
2.07–2.12 (m, 4H, –CH2–); 13C NMR (100 MHz, CDCl3)
(d/ppm): 170.19 (C4 of pyrimidine), 168.10 (C6 of
pyrimidine), 167.22 (C2 of pyrimidine), 128.17–137.38
(Ar–C), 100.91 (C5 of pyrimidine), 62.04 (OCH2), 29.42
(CH2); Molecular weight: 550.66, Anal. calcd. for
C36H30N4O2: C, 78.52; H, 5.49; N, 10.17 %. Found C,
78.50; H, 5.44; N, 10.16 %.
0.01 g of test samples was dissolved in 1 mL dimethyl
sulfoxide (DMSO) to obtain a stock solution. A concentra-
tion of 1 mg/mL or 100 lg/0.1 mL of each sample was
prepared. 0.1 mL of prepared samples was dropped into
each respective labeled well aseptically. The inoculated
plates were left on the table for 1 h to allow the each sample
to diffuse into the agar. For comparison, erythromycin and
tetracycline were used as a positive control and DMSO as a
negative control. Test organism growth may be affected by
the inhibitory action of the test compound and so, a clear
zone around the disk appeared as an indication of the inhi-
bition of the test organism growth. The results of our tests
were presented as the inhibition zones, given in millimeters
(mm). Measurements were obtained after 24 h for bacteria.
1,5-Bis((2,6-diphenylpyrimidin-4-yl)oxy)pentane (6h) Pale
yellow oil; yield 69 %; IR (mmax/cm-1): 3393, 2942, 2874,
1651, 1592, 1509, 1480, 1247, 886, 778, 679, 603; 1H
NMR (400 MHz, CDCl3) (d/ppm): 8.00 (d, 4H, Ar–H,
J = 7.6 Hz), 7.82 (d, 4H, Ar–H, J = 8.8 Hz), 7.52–7.56
(m, 8H, Ar–H), 7.36–7.43 (m, 6H, Ar–H and H5 of
pyrimidine), 4.07 (t, 4H, –OCH2–, J = 10.2 Hz),
1.82–1.91 (m, 4H, –CH2–), 1.59–1.67 (m, 2H, –CH2–); 13
C
NMR (100 MHz, CDCl3) (d/ppm): 170.12 (C4 of pyrimi-
dine), 168.03 (C6 of pyrimidine), 161.14 (C2 of pyrimi-
dine), 128.97–137.93 (Ar–C), 108.22 (C5 of pyrimidine),
65.09 (OCH2), 36.18 (CH2), 29.26 (CH2); Molecular
Conclusion
In conclusion, this three-component, one-pot protocol for
first time provides a regioselective, fast, and practical
123

Med Chem Res
Fattorusso C, Persico M, Basilico N, Taramelli D, Fattorusso E, Scala
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method for the preparation of novel 1,4-bis((6-alkyl or
phenyl-2-phenylpyrimidin-4-yl)oxy)alkane from a variety
of benzamidine hydrochloride, b-ketoester, and dihaloalk-
anes in good yields. This allows the rapid assessment of
pharmacological activities of these novel bis-pyrimidine
derivatives. The simplicity, high atom economy, easy
execution, simple workup, and good yields, together with
the use of inexpensive starting materials and an environ-
mentally friendly procedure, are features of this procedure.
Most of the compounds prepared as part of this study
exhibited good antibacterial activity against M. luteus,
B. subtilis and S. enterica.
Gao C, Ye TH, Wang NY, Zeng XX, Zhang LD, Xiong Y, You XY,
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Synthesis and structure–activity relationships evaluation of
benzothiazinone derivatives as potential anti-tubercular agents.
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Photochromic behavior of several new synthesized bis-1,3-
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Supporting information
1
This file demonstrates the FT-IR, H NMR, and 13C NMR
spectra of compounds 6a–i.
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platelet-activating factor and their effects on the mammalian
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Acknowledgments The authors are grateful to the Research Council
of University of Guilan for financial support of this research work.
Mahmoodi NO, Khodaee
Z (2004) One-pot diastereoselective
synthesis of new racemic and achiral spirohydantoins. Mende-
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M, Sharifzadeh B (2010) NMR structural elucidation and
photochromic behavior of new 1,3-diazabicyclo[3.1.0]hex-3-
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