The Synthesis of (1,3,4-Oxadiazol-2-yl)Acrylic Acid Derivatives with Antibacterial and Protistocidal Activities

Article abstract of DOI:10.1134/S1068162018010132

A series of new 1,3,4-oxadiazol-2-yl-acrylic acids was synthesized by cyclization of 4-(2-R-hydrazino)- 4-oxo-2-butenic acids, and their antibacterial and protistocidal activities were studied. The p-substituted benzyl derivatives in the Z-form were shown to exhibit a high protistocidal activity, which exceeded that of the reference drug Baycox (toltrazuril) by several times, whereas the 3-hydroxy-2-naphthyl derivative, in addition to a very high protistocidal activity, also exhibited a moderate antibacterial activity.

Full text of DOI:10.1134/S1068162018010132

ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2018, Vol. 44, No. 2, pp. 238–243. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © L.D. Popov, A.A. Zubenko, L.N. Fetisov, Yu.D. Drobin, A.I. Klimenko, A.N. Bodryakov, S.A. Borodkin, I.E. Melkozerova, 2018, published in Bioorganicheskaya
Khimiya, 2018, Vol. 44, No. 2, pp. 225–231.
The Synthesis of (1,3,4-Oxadiazol-2-yl)Acrylic Acid Derivatives
with Antibacterial and Protistocidal Activities
L. D. Popova, 1, A. A. Zubenkob, L. N. Fetisovb, Yu. D. Drobinb, A. I. Klimenkoc, A. N. Bodryakovb,
S. A. Borodkina, and I. E. Melkozerovad
aDepartment of Chemistry, Southern Federal University, Rostov-on-Don, 344090 Russia
bNorth-Caucasian Zonal Scientific Research Veterinary Institute, Novocherkassk, 346421 Russia
cDon State Agrarian University, Persianovskii, 346493 Russia
dRostov-on-Don Basic Medical College, Rostov-on-Don, 344022 Russia
Received August 7, 2017; in final form, August 10, 2017
Abstract⎯A series of new 1,3,4-oxadiazol-2-yl-acrylic acids was synthesized by cyclization of 4-(2-R-hydra-
zino)-4-oxo-2-butenic acids, and their antibacterial and protistocidal activities were studied. The p-substi-
tuted benzyl derivatives in the Z-form were shown to exhibit a high protistocidal activity, which exceeded that
of the reference drug Baycox (toltrazuril) by several times, whereas the 3-hydroxy-2-naphthyl derivative, in
addition to a very high protistocidal activity, also exhibited a moderate antibacterial activity.
Keywords: acrylic acid, antibacterial activity, 1,3,4-oxadiazol, protistocidal activity
DOI: 10.1134/S1068162018010132
INTRODUCTION
insulin [17] and, therefore, can serve as a basis for the
development of antidiabetic products [18].
Currently, a large number of drugs displaying anti-
bacterial and protistocidal (towards monocelled pro-
tozoa) activities are known. However, normally, com-
pounds with antibacterial properties lack protisto-
cidal activity. In addition, protozoa rapidly develop
resistance to protistocidal drugs including anticoc-
cidials, which makes it necessary to search for new
agents. The compounds bearing an acrylic acid resi-
due deserve attention as potential protistocidal
agents. For example, cinnamic acid and its deriva-
tives found in plants demonstrated low toxicity and
noticeable antibacterial [1, 2] and antifungal [3, 4]
properties and are used as biologically active com-
pounds [5]. These compounds are active as antitu-
mor [6, 7] and anticancer [8, 9] agents and can serve
as tyrosinase [10], trypsin [11], lipoxygenase and cyc-
logenase [12] inhibitors. They can help in the treat-
ment of oral moniliasis (Candida albicans) [13], her-
pes [14], and regulation of sex hormones [15].
Recently, the inhibitory properties of cinnamic acid
and its derivatives towards the final products of pro-
tein glycosylation were found [16] and the com-
pounds of this type were shown to effectively release
1,3,4-Oxadiazoles and their derivatives belong to
one of the most important classes of five-membered
nitrogen-containing heterocycles due to their syn-
thetic availability and high structural variability as well
as a wide spectrum of properties useful for practice.
They display various biological activities [19, 20] and
are widely used in different areas of medicinal chemis-
try [21] and pesticide chemistry [22, 23].
The presence of an acrylic acid residue and a het-
erocyclic fragment in one molecule may result in an
increased biological activity. We prepared and studied
some derivatives of (1,3,4-oxadiazol-2-yl)acrylic acid.
The data about compounds of this type have been poor
[24–29], their biological activity has not been studied.
RESULTS AND DISCUSSION
Derivatives of (1,3,4-oxadiazol-2-yl)acrylic acid
were synthesized by the scheme shown below as
described in [24]. The reaction of maleic anhydride (II)
with hydrazides (I) resulted in hydrazides (III), which
cyclized into 1,3,4-oxadiazoles (IV) in the presence of
POCl3.
1
Corresponding author: e-mail: ldpopov@mail.ru.
238

THE SYNTHESIS OF (1,3,4-Oxadiazol-2-yl)ACRYLIC ACID DERIVATIVES
239
H
N
N
H
N
N
O
C
C
R
C
R
C
C
H
O
C
O
OH
H
O
HO
Z(cis) form
E(trans) form
Fig. 1. Isomeric forms of 1,3,4-oxadiazol-2-yl acrylic acids.
O
O
O
O
+
O
CH CH COOH
C
R
C
NH NH
R
C
NH NH2
(Ia−m)
(II)
(IIIa−m)
O
N N
POCl3
DMF
CH CH COOH
R
O
(IVa−m)
Scheme 1. а: R = 2-furyl, b: R = 2,7а-dihydro-1,3-benzothiazol-2-ylsulfanylmethyl, c: R= 4-tolyl, d: R = 4-methoxyphe-
nyl, e: R = 2-methoxyphenyl, f: R = 4-chlorophenyl, g: R = 4-bromophenyl, h: R = 4-nitrophenyl, i: R = 2Н-thiophen-2-yl,
j: R = 3-hydroxy-2-naphtyl, k: R = 2,6-dihydroxyphenyl, l: R = 2-hydroxyphenyl, m: R = phenoxymethyl.
Due to the presence of a double –СН=СН– bond, duction of halogen atoms into the benzene ring: the
compounds (IVа–m) can exist in the form of either
trans(E) and/or cis(Z) isomers (Fig. 1). The discrimi-
nation of these isomers is rather simple and is based on
the coupling constant value (J) of ethylene protons.
activity of compounds (IVf) and (IVg) was, by a hun-
dred times and more, higher than that of the com-
pounds with methyl and methoxy groups (compounds
(IVc–e)). Probably, this difference can be associated
with the isomer type (Z-isomers were more active)
rather than with the nature of the substituent at the
para-position of the benzene ring. The most active
compound was the naphthyl derivative with a hydroxyl
group (IVj), which was also isolated in the Z form. It
could lyse protozoa cells at a concentration of
0.48 μg/mL, whereas the reference Baycox was only
effective at a concentration of 62.5 μg/mL. Other Z-iso-
mers obtained, for example, furyl derivative (IVa), did
not manifest any antiprotozoal activity. This fact can
be explained by the redistribution of electron density
in the oxadiazole cycle, which, most probably, pro-
vides the high antibacterial activity of the compounds
of this type. Thus, the search of antiprotozoal com-
pounds within this class, especially Z-isomers, seems
to be promising.
The larger constant (J ~ 16 Hz) corresponds to the
E-isomer, and for the Z-isomer this constant is con-
siderably lower. The difference in coupling constants
for compounds of this type was first reported in [24].
In all cases the reactions yielded a mixture of E- and
Z-isomers, an increase in the reaction time resulting in
an increase in the content of the E-isomer. With the
goal of obtaining one isomer, we used the maximal
time described in [24]. However, according to the
1H NMR data some of the compounds (IVa, b, e, f, g,
j, k, m) were isolated as Z-isomers, others (IVc, d, h, i, l), as
E-isomers. The J values for E-isomers were similar to
those described in [24], in contrast to Z-isomers, whose
J values were lower by two times (J ~ 6 Hz). In addition,
in the 1H NMR spectra of all the compounds synthe-
sized we observed a proton resonance of a carboxyl
group at 11.5–13.5 ppm, which disappeared after deu-
teration. The shape and position of resonances of all
other protons completely coincided with the proposed
structures.
Also, the compounds under study manifested antibac-
terial properties, but the most effective compound (IVj)
was 3–8 times less active than furazolidone.
All the synthesized compounds (IVa–m) were
tested for biological activity (Table 1).
Toxicity. We did not find the effect of acute toxicity
for compounds (IVf, g, j–l) at a dose of 0.3 g/kg body
weight when administered in the stomach of labora-
tory rats. The compounds can be preliminarily
As seen from the table, most of the compounds
under study displayed a noticeable antiprotozoal activ-
ity against the Colpoda steinii model. A dramatic
increase in the activity was observed after the intro- referred to as moderately toxic drugs.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 44 No. 2 2018

240
POPOV et al.
N N
O
Table 1. Biological activity of (1,3,4-oxadiazol-2-yl)acrylic acid derivatives (IVa–m)
R
CH CH COOH
Activity, μg/mL towards
Code
(IVa)
(IVb)
R
St. aureus
E. coli
C. steinii
250.0
250.0
250.0
500.0
O
N
250.0
500.0
CH2
S
S
(IVc)
(IVd)
250.0
250.0
250.0
250.0
500.0
500.0
CH3
OCH3
(IVe)
500.0
500.0
500.0
OCH3
(IVf)
(IVg)
(IVh)
250.0
250.0
250.0
250.0
250.0
250.0
31.25
1.95
Cl
Br
500.0
NO2
(IVi)
(IVj)
250.0
31.25
250.0
31.25
31.25
0.48
S
OH
OH
(IVk)
(IVl)
250.0
250.0
62.5
OH
OH
250.0
250.0
250.0
250.0
15.6
62.5
(IVm)
CH2
O
Reference Baycox
–
–
62.5
–
compounds
Furazolidone
Water
3.9
–
12.5
–
–
Definitions: (–) death (inhibition) of the test culture not found.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
Vol. 44
No. 2
2018

THE SYNTHESIS OF (1,3,4-Oxadiazol-2-yl)ACRYLIC ACID DERIVATIVES
241
EXPERIMENTAL
3.60; N 11.60. С12Н10N2О4. Calc., %: С 58.55; Н 4.06;
N 11.37.
1H NMR spectra (δ, ppm, J, Hz) were recorded on
a Bruker DPX-250 spectrometer (working frequency
250 MHz) in DMSO-d6 using tetramethylsilane as a
standard. Melting points were measured in an open
capillary on a Chimlabpribor PTP device. Element
analysis was carried out on an Elementar Vario Micro
cube CHNS-analyzer. The reaction course and the
product purity were monitored by TLC on Silufol
UV-254 plates.
(Z)-3-[5-(2-Methoxyphenyl)-1,3,4-oxadiazol-2-yl]-
acrylic acid (IVe). Colorless crystals. The yield 55%.
1
mp 195–196°C. Н NMR: 3.98 (s, 3Н, ОСН3), 6.93
(d, 1Н, arom., J 8.4), 7.13 (dd, 1Н, arom., J 8.4, 8.4),
7.25 (d, 1Н, СН=СН, J 5.7), 7.58 (dd, 1Н, arom.,
J 8.4, 8.4), 7.89 (d, 1Н, СН=СН, J 5.7), 7.95 (d, 1Н,
arom., J 8.4), 11.44 (s, 1Н, СООН). Found, %: С
58.90; Н 3.60; N 11.60. С12Н10N2О4. Calc., %: С
58.55; Н 4.06; N 11.37.
(Z)-3-[5-(2-Furyl)-1,3,4-oxadiazol-2-yl]acrylic
acid (IVа). A solution of maleic anhydride (0.02 mol)
in СН3СООН (4 mL) was added to a solution of 2-
furoic acid hydrazide (0.02 mol) in СН3СООН
(5 mL). Immediately, the mixture was warmed and a
white precipitate was formed. The mixture was stirred
for 1.5 h at room temperature. The precipitate was sep-
arated and washed twice with acetic acid and ethanol.
Without additional purification, the resulting acylhy-
(Z)-3-[5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-
acrylic acid (IVf). Colorless crystals. The yield 48%.
1
mp 179°C. Н NMR: 6.93 (d, 1Н, СН=СН, J 5.7),
7.56 (d, 2Н, arom., J 8.4), 7.88 (d, 2Н, arom., J 8.4),
7.94 (d, 1Н, СН=СН, J 5.7), 11.83 (s, 1Н, СООН).
Found, %: С 52.40; Н 3.20; Cl 13.80; N 11.50. С11Н7-
ClN2О3. Calc., %: С 52.72; Н 2.79; Cl 14.17; N 11.17.
(Z)-3-[5-(4-Bromophenyl)-1,3,4-oxadiazol-2-yl]-
drazide was subjected to the reaction with a solution of acrylic acid (IVg). Colorless crystals. The yield 66%.
1
POCl3 (0.02 mol) in DMF (7 mL). The solution was
stirred for 2 h at room temperature and poured into
Н2О (50 mL). The precipitate was separated, washed
twice with water and recrystallized from ethanol to
give colorless crystals (72%); mp 205–206°C.
1Н NMR: 6.78 (s, 1Н, fur.), 6.84 (d, 1Н, СН=СН, J
5.5), 7.42 (s, 1 Н, fur.), 7.48 (d, 1Н, СН=СН, J 5.5),
8.11 (s, 1Н, fur.), 13.24 (s, 1Н, СООН). Found, %: С
52.10; Н 3.00; N 13.40. С9Н6N2О4. Calc., %: С 52.43;
Н 2.93; N 13.59.
mp 252°C. Н NMR: 6.93 (d, 1 Н, СН=СН, J 5.7),
7.70 (d, 2Н, arom., J 8.4), 7.80 (d, 2Н, arom., J 8.4),
7.94 (d, 1Н, СН=СН, J 5.7), 11.83 (s, 1Н, СООН).
Found, %: С 45.20; Н 2.50; Br 26.50; N 10.00.
С11Н7BrN2О3. Calc., %: С 44.78; Н 2.37; Br 27.08; N
9.49.
(Е)-3-[5-(4-Nitrophenyl)-1,3,4-oxadiazol-2-yl]-
acrylic acid (IVh). Colorless crystals. The yield 79%.
1
mp 223–224°C. Н NMR: 6.73 (d, 1Н, СН=СН, J
12.6), 6.96 (d, 1Н, СН=СН, J 12.6), 8.21 (d, 2Н,
arom., J 9.0), 8.45 (d, 2Н, arom., J 9.0), 13.45 (s, 1Н,
СООН). Found, %: С 50.80; Н 2.20; N 16.50.
С11Н7N3О5. Calc., %: С 50.59; Н 2.68; N 16.09.
Compounds (IVb)–(IVm) were prepared similarly
to compound (IVа).
(Z)-3-[5-(2,7а-Dihydro-1,3-benzothiazol-2-ylsul-
fanylmethyl)-1,3,4-oxadiazol-2-yl]acrylic acid (IVb).
Colorless crystals. The yield 68%. mp 197–198°C.
1Н NMR: 4.38 (s, 2Н, СН2), 6.92 (d, 1Н, СН=СН,
J 5.7), 7.35 (dd, 1Н, arom., J 8.1, 8.1), 7.48 (dd, 1Н,
arom., J 8.1, 8.1), 7.84 (d, 1Н, arom., J 8.1), 7.90 (d,
1Н, СН=СН, J 5.7), 8.02 (d, 1Н, arom., J 8.1), 11.88
(s, 1Н, СООН). Found, %: С 48.90; Н 2.50; N 12.40;
S 14.60. С13Н9N3О3S2. Calc., %: С 48.89; Н 2.84; N
13.16; S 20.08.
(Е)-3-[5-(2Н-Thiophen-2-yl)-1,3,4-oxadiazol-2-
yl]acrylic acid (IVi). Colorless crystals. The yield 80%.
1
mp 234–235°C. Н NMR: 6.85 (d, 1Н, СН=СН, J
15.9), 7.32 (dd, 1Н, thioph., J 4.8, 3.6), 7.43 (d, 1Н,
СН=СН, J 15.9), 7.96 (dd, 1Н, thioph., J 3.6, 1.2),
8.01 (dd, 1Н, thioph., J 4.8, 1.2), 13.24 (s, 1Н,
СООН). Found, %: С 48.90; Н 2.50; N 12.40; S
14.60. С9Н6N2О3S. Calc., %: С 48.66; Н 2.70; N
12.60; S 14.43.
(Z)-3-[5-(3-Hydroxy-2-naphtyl)-1,3,4-oxadiazol-
2-yl]acrylic acid (IVj). Colorless crystals. The yield
71%. mp 192–195°C. 1Н NMR: 6.95 (d, 1Н,
СН=СН, J 5.7), 7.33 (s, 1Н, arom.), 7.36 (dd, 1Н,
arom., J 7.5, 7.5), 7.52 (dd, 1Н, arom., J 7.5, 7.5), 7.76
(d, 1Н, arom., J 8.1), 7.99 (2Н, arom. + СН=СН,
J 5.7), 8.66 (s, 1Н, arom.), 11.97 (s, 1Н, ОН), 12.05 (s,
1Н, СООН). Found, %: С 63.40; Н 3.90; N 10.30.
С15Н10N2О4. Calc., %: С 63.85; Н 3.54; N 9.92.
(Е)-3-[5-(p-Tolyl)-1,3,4-oxadiazol-2-yl]acrylic acid
(IVc). Colorless crystals. The yield 84%. mp 212–
1
213°C. Н NMR: 2.40 (s, 3Н, СН3), 6.92 (d, 1Н,
СН=СН, J 15.9), 7.42 (d, 2Н, arom., J 8.1), 7.43 (d,
1Н, СН=СН, J 15.9), 8.01 (d, 2Н, arom., J 8.1), 13.25
(s, 1Н, СООН). Found, %: С 62.90; Н 3.90; N 11.80.
С12Н10N2О3. Calc., %: С 62.63; Н 4.35; N 12.17.
(Е)-3-[5-(4-Methoxyphenyl)-1,3,4-oxadiazol-2-
yl]acrylic acid (IVd). Colorless crystals. The yield 90%.
(Z)-3-[5-(2,6-Dihydroxyphenyl)-1,3,4-oxadiazol-
1
mp 227–228°C. Н NMR: 3.85 (s, 3Н, ОСН3), 6.90 2-yl]acrylic acid (IVk). Colorless crystals. The yield
(d, 1Н, СН=СН, J 16.2), 7.15 (d, 2Н, arom., J 9.0), 59%. mp 250–255°C. 1Н NMR: 6.43 (d, 2Н, arom., J
7.43 (d, 1Н, СН=СН, J 16.2), 8.05 (d, 2Н, arom., J 8.4), 6.98 (d, 1Н, СН=СН, J 5.7), 7.27 (dd, 1Н,
9.0), 13.20 (s, 1Н, СООН). Found, %: С 58.90; Н arom., J 8.4, 8.4), 7.99 (d, 1Н, СН=СН, J 5.7), 12.16
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 44 No. 2 2018

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POPOV et al.
(s, 1Н, СООН), 12.64 (s, 2Н, ОН). Found, %: С isms were found, was regarded as the one containing
53.50; Н 2.80; N 11.50. С11Н8N2О5. Calc., %: С 53.25; the compound under study at a minimal protistocidal
concentration. The following solutions were taken as
controls:
—Control medium (boiled tap water and sterile
distilled water), 5 wells.
—Control solvent (70% DMSO (50 μL) and dis-
tilled water (5 mL); then, serial dilutions similarly to
those for the tested compounds), 12 wells.
Н 3.22; N 11.29.
(Е)-3-[5-(2-Hydroxymethyl)-1,3,4-oxadiazol-2-yl]-
acrylic acid (IVl). Colorless crystals. The yield 72%. mp
197–198°C. 1Н NMR: 6.66 (d, 1Н, СН=СН, J 12.6),
6.91 (d, 1Н, СН=СН, J 12.6), 7.02 (dd, 1Н, arom., J
7.8, 7.5), 7.08 (d, 1Н, arom., J 8.1), 7.47 (dd, 1Н,
arom., J 8.1, 7.5), 7.71 (d, 1Н, arom., J 7.8), 10.26 (s,
1Н, ОН), 13.30 (s, 1Н, СООН). Found, %: С 57.30;
Н 3.80; N 11.60. С11Н8N2О4. Calc., %: С 56.92; Н
3.45; N 12.06.
(Z)-3-[5-(Phenoxymethyl)-1,3,4-oxadiazol-2-yl]-
acrylic acid (IVm). Colorless crystals. The yield 64%.
mp 210–211°C. Н NMR: 4.75 (s, 2Н, СН2), 6.85–
6.90 (m, arom., 3Н), 6.93 (d, 1Н, СН=СН, J 6.3),
7.26 (dd, 2Н, arom., J 8.1, 8.1), 7.87 (d, 1Н, СН=СН,
J 6.3), 11.62 (s, 1Н, СООН). Found, %: С 60.10; Н
4.00; N 11.10. С12Н10N2О4. Calc., %: С 60.47; Н 3.90;
N 10.85.
The protistocidal activity was assessed as described
in [30] using C. steinii protozoa (a field isolate from the
collection of the laboratory of parasitology of the
North Caucasus Zonal Research Veterinary Institute).
The experiments were performed in microplates for
immunoassays. As a medium for protozoa, a mixture
of boiled tap water and sterile distilled water in equal
volumes was used. Primary dilutions were carried out
in distilled water in the presence of DMSO. Serial
dilutions were prepared as follows.
Solution 1. The compound (5 mg) was dissolved
under stirring in 70% DMSO (50 μL) and distilled
water was added in portions (5 mL) to a concentration
of 1000 μg/μL.
Solutions 2–12. A mixture of boiled tap water and ster-
ile distilled water in equal volumes (150 μL) was added
with an eight-channel automatic pipette to wells 2–12;
then solution 1 (150 μL) was added to well 2 and the
mixture was stirred. The resulting solution (150 μL)
was transferred to well 3 and the procedure was
repeated up to well 12. After stirring, the solution
(150 μL) from well 12 was removed and a three-day
C. steinii culture (30 μL) was added to each of the
wells. Solution 1 (150 μL) and the protozoa suspen-
sion (30 μL) were added to well 1. The protozoa sus-
pension was prepared in the way, so that 10 to 15 active
individuals could be seen upon microscopy at low-
power magnification. After the protozoa addition, the
plate was covered with a cap and kept at room tem-
perature (20–22°C) for 18–20 h.
The results were assessed as follows. An aliquot
(30 μL) was taken from the last well after stirring using
an automatic autopipette, transferred it to a clean slide
and examined by low magnitude microscopy (10 × 15).
The presence or absence of live organisms was
recorded. Examination was performed from the right
to the left. The first well, where no live microorgan-
—Reference Baycox (toltrazuril).
The antibacterial (bacteriostatic) activity was evalu-
ated by a twofold serial dilutions technique. As test
cultures for the assessment of antimicrobial activity of
chemotherapeutic drugs, two standard strains, Staph-
ylococcus aureus P-209 and Escherichia coli 078 strain
(a field strain), were used. The cultures were grown for
a day at 37°C on an agar Luria–Bertani medium (LB).
Solutions of the tested compounds at various concen-
trations (2 mL) prepared by twofold serial dilutions in
the liquid nutrient medium [31–34] were added to the
bacterial suspensions (2 mL) at a concentration of
500000 microorganisms/mL. The considered biobur-
den was 250000 microorganisms/mL. The resulting
solutions were incubated for 18 h at 37°C. The
medium containing 250000 microorganisms/mL
served a positive control. The medium lacking bacteria
served a negative control. The reference compound
was furazolidone.
1
ACKNOWLEDGMENTS
NMR spectra were recorded in the Educational
and Scientific Laboratory of Resonance Spectroscopy
of the Department of Chemistry of Natural and High-
Molecular-Weight Compounds of the Southern Fed-
eral University and in the Center of Collective Use
Molecular Spectroscopy of the Southern Federal Uni-
versity.
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