Synthesis and anti(myco)bacterial activity of novel 5,5-diphenylpyrrolidine N-aroylthiourea derivatives and a functionalized hexahydro-1H-pyrrolo[1,2-c]imidazole

Article abstract of DOI:10.1007/s00044-017-1907-9

In this paper, five novel 5,5-diphenylpyrrolidine N-aroylthiourea derivatives were synthesized by stereoselective cycloaddition of N-diphenylmethylene-protected glycine methyl ester and methyl acrylate, and subsequent coupling with aroylisothiocyanates. The cis-stereochemistry of one of the heterocyclic thiourea derivatives was characterized by single crystal X-ray diffraction studies. The compounds showed antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Aeromonas hydrophila, Escherichia. coli and Acinetobacter baumannii with minimum inhibitory concentration values in the range of 62.5–1000 μg/mL against these bacterial strains. Antimycobacterial activity of the compounds was investigated against the M. tuberculosis H37Rv strain and all compounds exhibited antimycobacterial activity with a minimum inhibitory concentration value of 80 μg/mL. Additionally, methyl 5,5-diphenylhexahydro-1-oxo-3-thioxo-1H-pyrrolo[1,2-c]imidazole-6-carboxylate was synthesized by cyclization reaction of the 5,5-diphenylpyrrolidine N-aroylthiourea derivatives in the presence of hydrazine monohydrate and exhibited antibacterial activity with a minimum inhibitory concentration value of 62.5 μg/mL against the same bacterial strains and exhibited antimycobacterial activity with a minimum inhibitory concentration value of 80 μg/mL against the M. tuberculosis H37Rv strain.

Full text of DOI:10.1007/s00044-017-1907-9

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-017-1907-9
ORIGINAL RESEARCH
Synthesis and anti(myco)bacterial activity of novel 5,5-
diphenylpyrrolidine N-aroylthiourea derivatives and a
functionalized hexahydro-1H-pyrrolo[1,2-c]imidazole
Duygu Erşen1 Mahmut Ülger2 Sven Mangelinckx3 Müge Gemili1 Ertan Şahin4
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1
Yahya Nural
Received: 14 July 2016 / Accepted: 24 April 2017
© Springer Science+Business Media New York 2017
Abstract In this paper, five novel 5,5-diphenylpyrrolidine
N-aroylthiourea derivatives were synthesized by stereo-
selective cycloaddition of N-diphenylmethylene-protected
glycine methyl ester and methyl acrylate, and subsequent
coupling with aroylisothiocyanates. The cis-stereochemistry
of one of the heterocyclic thiourea derivatives was char-
acterized by single crystal X-ray diffraction studies. The
compounds showed antibacterial activity against Staphylo-
coccus aureus, Bacillus subtilis, Aeromonas hydrophila,
Escherichia. coli and Acinetobacter baumannii with mini-
mum inhibitory concentration values in the range of
62.5–1000 μg/mL against these bacterial strains. Anti-
mycobacterial activity of the compounds was investigated
against the M. tuberculosis H37Rv strain and all com-
pounds exhibited antimycobacterial activity with a mini-
mum inhibitory concentration value of 80 μg/mL.
Additionally, methyl 5,5-diphenylhexahydro-1-oxo-3-
thioxo-1H-pyrrolo[1,2-c]imidazole-6-carboxylate was syn-
thesized by cyclization reaction of the 5,5-diphenylpyrroli-
dine N-aroylthiourea derivatives in the presence of
hydrazine monohydrate and exhibited antibacterial activity
with a minimum inhibitory concentration value of 62.5 μg/
mL against the same bacterial strains and exhibited anti-
mycobacterial activity with a minimum inhibitory con-
centration value of 80 μg/mL against the M. tuberculosis
H37Rv strain.
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Keywords 5,5-Diphenylpyrrolidine Thiohydantoin
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Antibacterial activity Antimycobacterial activity
M. tuberculosis H37Rv
Introduction
Nitrogen and sulfur are among the most important elements,
which are present in the structure of biologically important
compounds. Many drug molecules, such as amoxicillin,
quetiapine, olanzapine, pioglitazone, and duloxetine contain
at least one nitrogen and sulfur atom in their structures
(Ilardi et al. 2014). Thiohydantoins, containing nitrogen and
sulfur atoms, represent an important class of compounds
within pharmaceutical chemistry and are present in a wide
range of pharmacologically active compounds exhibiting
antimicrobial (Khurana et al. 2014), antiviral (Khodair et al.
2001), anti-inflammatory (Blanc et al. 1992), antitumor (Al-
Obaid et al. 1996), and hypoglycemic (Yildiz and Bozdag-
Dundar 2010) activities. Thiohydantoins have also been
used as intermediates for the synthesis of biologically active
compounds (Abdelaziz et al. 2015; Metwally and Abdel-
Latif 2012).
* Yahya Nural
yahyanural@mersin.edu.tr
ynural1805@yahoo.com
1
Department of Chemistry, Faculty of Pharmacy, Mersin
University, Mersin, Turkey
2
Department of Pharmaceutical Microbiology, Faculty of
Pharmacy, Mersin University, Mersin, Turkey
N-Substituted-N’-aroyl(acyl)thiourea derivatives are
gaining significance in pharmaceutical, coordination and
analytical chemistry (Saeed et al. 2014b; Koch 2001). N-
Substituted-N′aroyl(acyl)thiourea derivatives are known to
show a wide range of biological properties, such as
3
Department of Sustainable Organic Chemistry and Technology,
Faculty of Bioscience Engineering, Ghent University, Ghent,
Belgium
4
Department of Chemistry, Faculty of Science, Atatürk University,
Erzurum, Turkey

Med Chem Res
15-lipoxygenase inhibitory activity (Mahdavi et al. 2014),
carbonic anhydrase inhibitor (Saeed et al. 2014a), anti-
microbial (Saeed et al. 2013; Döndaş et al. 2006), antitumor
(Saeed et al. 2010), and analgesic activity (Shoaib et al.
2014). In addition, some N-benzoyl-N′-ferrocenylthiourea
derivatives exhibited cytokinin and auxin activities (Zhang
et al. 2015). Furthermore, N-substituted-N′-aroyl(acyl)
thioureas are also useful compounds for the synthesis of
biologically important heterocyclic scaffolds, such as thio-
hydantoins (Nural et al. 2011) and thiazoles (Saeed et al.
2008). Ni(II) (Yang et al. 2012; Nural et al. 2009; Del
Campo et al. 2004), Pt(II) (Cîrcu et al. 2009; Del Campo
et al. 2004) and Co(III) (Tan et al. 2014; Del Campo et al.
2004) chelate complexes of N-Substituted-N′-aroyl(acyl)
thioureas have been synthesized. In addition, these types of
ligands are useful for analytical applications, such as
potentiometric sensors for heavy metals (Otazo-Sanchez
et al. 2002) or chemosensors for anions (Li et al. 2012; Hu
et al. 2009). Moreover, some N-aroyl(acyl)thioureas were
used for extraction, separation, and determination of heavy
metals (Alkherraz et al. 2014; Luckay et al. 2009).
Heterocycles containing one or more nitrogen atoms are
a priority area of drug research (Hernandez-Toribio et al.
2012). Pyrrolidines incorporate one of the most important
scaffolds, possessing various pharmacological activities,
such as antimicrobial (Schwartz et al. 1998), antiviral
(Martín-Rodríguez et al. 2011; Nájera and Sansano 2009)
andantitumor (Fujimoto et al. 1987) activity. Furthermore,
the pyrrolidine ring is present in many synthetic or natural
bioactive molecules, such as procyclidine (Ettinger et al.
2003),bepridil (Fujiki et al. 2003), elacomine (Pellegrini
et al. 1996), anisomycin (Stocker et al. 2010), and hygrine
(Rubioa et al. 2013). Although pyrrolidine derivatives have
been intensively studied in the literature (Verma et al. 2016;
Chen et al. 2013; Pandey et al. 2006; Dondas et al. 1996
2004 Döndaş et al. 2003), there are only a limited number
of studies about their 5,5-diphenylpyrrolidine derivatives
(Hut’ka et al. 2013; Kim et al. 2011; Tsubogo et al. 2008;
Xue et al. 2008; Wang et al. 2008, Khlebnikov et al. 1997,
2001). Noteworthy, the gem-diphenyl group is present in
various physiologically active nitrogen-containing com-
pounds, such as methadone (Hassan et al. 2009), diphen-
hydramine (Ahmadi et al. 2012), clotrimazole (Prasanna
et al. 2014), loperamide (Geyer et al. 2015), cinnarizine
(Sassene et al. 2015), dextromoramide (Bye 1976), benza-
tropine (Othman et al. 2008), darifenacin (Pramanik et al.
2012), doxapram (Krasikovs 2015), modafinil (Okunola-
Bakare et al. 2014), and phenytoin (Soman et al. 2014).
In this study, we designed and synthesized five novel
5,5-diphenylpyrrolidine N-aroylthioureas as precursors of a
compound with a thiohydantoin moiety fused to a pyrroli-
dine and investigated their antibacterial and anti-
mycobacterial activities.
Material and methods
Chemicals and general technical data
All chemicals used were high-grade commercial products
purchased from Merck or Aldrich and all solvents provided
from commercial suppliers as having reagent grade quality,
and used without further purification.
IR spectra were recorded in the range of 4000–600 cm−1
by a Varian Scimitar Series 1000 FT-IR spectrophotometer,
using horizontal Attenuated Total Reflectance. Nuclear
magnetic resonance spectra and decoupling experiments
were determined at 400 MHz on a Bruker Ultrashield Plus
Biospin GmbH. Chemical shifts are given in parts per
million (δ) downfield from tetramethylsilane as internal
standard. Spectra were determined in deuterochloroform.
The following abbreviations are used; s = singlet, d =
doublet, m = multiplet and brs = broad singlet. Flash col-
umn chromatography was performed using silica gel 60
(230–400 mesh). Kieselgel columns were packed with silica
gel GF254. Melting points were determined on Stuart
SMP3 hot stage apparatus and are uncorrected. Mass
spectra were recorded by an Agilent 6460 Triple Quad LC/
MS/MS mass spectrometer. High resolution mass spectra
were recorded by an LC-MS TOF electrospray ionization
technique. The X-ray crystal structure data were collected
by a Rigaku R-Axis Rapid-S model X-ray diffractometer.
Synthesis of cis-dimethyl 5,5-diphenylpyrrolidine-2,4-
dicarboxylate (3)
The compound 3 was prepared by modification of literature
methods (Dondas et al. 1996, 2004, Döndaş et al. 2003). To
a stirred solution of methyl 2-(diphenylmethyleneamino)
acetate 1 prepared according to the literature (De Bra-
bandere et al. 2014) (0.25 g, 1 mmol) in dry toluene (10 mL)
was added a solution of Et3N (0.17 g, 1.7 mmol) in dry
toluene (10 mL) and Ag2O (0.06 g, 0.25 mmol). After 5
min, methyl acrylate 2 (0.17 g, 2 mmol) in dry toluene (20
mL) was added. The mixture was stirred at room tempera-
ture for 18 h. After completion of the reaction, the mixture
was quenched sequentially with saturated aqueous sodium
chloride and aqueous ammonium chloride, and extracted
with ethyl acetate. The crude mixture was purified by col-
umn chromatography (Et2O:hexane/1:8) to give 3 (0.3 g,
89%) as colorless crystals. m.p.: 127–129 °C. IR (cm−1):
1
υmax 3296, 3060, 2950, 1743, 1724. H NMR (400 MHz,
CDCl3): δ 7.67–7.11 (m, 10H, Ar-H), 4.00 (dd, 1H, J = 6.7
Hz, 3.2 Hz, 2-H), 3.84 (dd, 1H, J = 9.0 Hz, 6.6 Hz, 4-H),
3.78 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 2.30–2.28 (m, 2H,
3-H, 3-H′). 13C NMR (100 MHz, CDCl3): δ 174.5 (C=O),
173.5 (C=O), 144.6, 143.8, 128.6 (2 × C), 128.2 (2 × C),
127.0, 126.9, 126.1 (2 × C), 126.0 (2 × C), 76.2, 58.4, 52.3

Med Chem Res
(2 × C), 51.5, 34.3. MS (ESI, M + H+): m/z 340.2 (M +
H+, 100). HRMS (ESI-TOF-MS): calcd. for C20H21NO4
[MH]+ 340.1549; found 340.1548.
Cis-dimethyl
1-((4-methoxybenzoyl)carbamothioyl)-5,5-
diphenylpyrrolidine-2,4-dicarboxylate
(5c) Amorphous
yellow solid. Yield, 0.3 g, 71%. m.p.: 85–87 °C. IR (cm−1):
1
υmax 3348, 3057, 2955, 1736, 1688, 1354, 1253, 1207. H
General procedure for the synthesis of cis-5,5-
diphenylpyrrolidine N-aroylthiourea derivatives (5a–e)
NMR (400 MHz, CDCl3): δ 8.07 (s, 1H, NH), 7.94–6.60
(m, 14H, Ar-H), 5.40 (dd, 1H, J = 8.2 Hz, 8.2 Hz, 2-H),
4.04 (dd, 1H, J = 7.9 Hz, 7.9 Hz, 4-H), 3.88 (s, 3H, OCH3),
3.77 (s, 3H, OCH3), 3.39 (s, 3H, OCH3), 2.43 (dd, 2H, J =
8.1 Hz, 8.1 Hz, 3-H, 3-H′). 13C NMR (100 MHz, CDCl3): δ
178.2 (C=S), 170.7 (C=O), 169.4 (C=O), 163.1 (C=O),
162.8, 140.09, 135.9, 129.4 (2 × C), 129.1 (2 × C), 129.0
(2 × C), 128.9 (2 × C), 128.6 (2 × C), 127.8 (2 × C), 125.7,
113.5 (2 × C), 79.7, 64.9, 61.1, 55.4, 52.6, 52.0, 28.7. MS
(ESI, M − H+): m/z 531.2 (M − H+, 100). HRMS (ESI-
TOF-MS): calcd. for C29H28N2O6S [MH]+ 533.1746;
found 533.1745.
The novel 5,5-diphenylpyrrolidine N-aroylthiourea deriva-
tives 5a–e were synthesized by modification of the literature
methods (Nural et al. 2011, 2009; Döndaş et al. 2006;
Arslan and Külcü 2003) from reaction of 3 and corre-
sponding aroylisothiocyanates 4 in acetonitrile for 36 h. The
solvent was evaporated under reduced pressure and the
crude mixture was purified by column chromatography
(Et2O:hexane/1:6). The requisite aroylisothiocyanates 4
were synthesized by modification of the literature method
(Arslan and Külcü 2003) via reaction of potassium thio-
cyanate and corresponding acyl chloride in acetone at reflux
temperature for 2 h. Upon reaction completion, the solvent
was removed and used without any further purification.
Cis-dimethyl
1-((4-chlorobenzoyl)carbamothioyl)-5,5-
diphenylpyrrolidine-2,4-dicarboxylate (5d) Amorphous
yellow solid. Yield, 0.5 g, 72%. m.p.: 90–92 °C. IR (cm−1):
1
Cis-dimethyl 1-((benzoyl)carbamothioyl)-5,5-diphenylpyr-
rolidine-2,4-dicarboxylate (5a) Yellow crystals. Yield,
0.8 g, 95%. m.p.: 178–180 °C. IR (cm−1): υmax 3366, 3057,
υmax 3340, 3060, 2950, 1736, 1684, 1344, 1267, 1206. H
NMR (400 MHz, CDCl3): δ 8.05 (brs, 1H, NH), 7.93–6.77
(m, 14H, Ar-H), 5.38 (dd, 1H, J = 8.2 Hz, 8.2 Hz, 2-H),
4.04 (dd, 1H, J = 8.0 Hz, 8.0 Hz, 4-H), 3.88 (s, 3H, OCH3),
3.39 (s, 3H, OCH3), 2.44 (dd, 2H, J = 8.0 Hz, 8.0 Hz, 3-H,
3-H′). 13C NMR (100 MHz, CDCl3): δ 177.8 (C=S), 170.5
(C=O), 169.3 (C=O), 163.0 (C=O), 140.1, 138.6, 135.7,
131.8, 129.5 (2 × C), 129.4, 129.0 (2 × C), 128.8, 128.7,
128.6 (2 × C), 128.5 (2 × C), 128.2, 127.8 (2 × C), 79.8,
65.0, 61.1, 52.6, 52.1, 28.7. MS (ESI, M − H+): m/z 535.5
(M − H+, 100), 537.5 (M − H+, 35). HRMS (ESI-TOF-
MS): calcd. for C28H25ClN2O5S [MH]+ 537.1251; found
537.1257.
1
2982, 1746, 1735, 1710, 1349, 1225, 1210. H NMR (400
MHz, CDCl3): δ 8.15 (brs, 1H, NH), 7.93–6.86 (m, 15H,
Ar-H), 5.39 (dd, 1H, J = 8.3 Hz, 8.3 Hz, 2-H), 4.04 (dd, 1H,
J = 8.4 Hz, 8.4 Hz, 4-H), 3.88 (s, 3H, OCH3), 3.38 (s, 3H,
OCH3), 2.44 (dd, 2H, J = 8.0 Hz, 8.0 Hz, 3-H, 3-H′). 13C
NMR (100 MHz, CDCl3): δ 177.9 (C=S), 170.6 (C=O),
169.3 (C=O), 163.6 (C=O), 140.1, 135.7, 135.1, 133.4,
132.2, 130.5, 129.4 (2 × C), 129.0 (3 × C), 128.9 (2 × C),
128.7, 128.3, 127.8, 127.0 (2 × C), 79.8, 64.9, 61.1, 52.7,
52.1, 28.8. MS (ESI, M − H+): m/z 501.4 (M − H+, 100).
HRMS (ESI-TOF-MS): calcd. for C28H26N2O5S [MH]+
503.1641; found 503.1657.
Cis-dimethyl
1-((4-phenylbenzoyl)carbamothioyl)-5,5-
Cis-dimethyl 1-((4-tert-butylbenzoyl)carbamothioyl)-5,5-
diphenylpyrrolidine-2,4-dicarboxylate (5b) Amorphous
yellow solid. Yield, 0.5 g, 79%. m.p.: 87–89 °C. IR (cm−1):
diphenylpyrrolidine-2,4-dicarboxylate (5e) Yellow crys-
tals. Yield, 0.3 g, 80%. m.p.: 108–110 °C. IR (cm−1): υmax
3304, 3035, 2986, 1730, 1696, 1368, 1252, 1211. 1H NMR
(400 MHz, CDCl3): δ 8.19 (brs, 1H, NH), 7.96–6.92 (m,
19H, Ar-H), 5.41 (dd, 1H, J = 8.2 Hz, 8.2 Hz, 2-H), 4.04
(dd, 1H, J = 8.0 Hz, 8.0 Hz, 4-H), 3.89 (s, 3H, OCH3), 3.39
(s, 3H, OCH3), 2.45 (dd, 2H, J = 8.1 Hz, 8.1 Hz, 3-H, 3-H′).
13C NMR (100 MHz, CDCl3): δ 178.0 (C=S), 170.6
(C=O), 169.4 (C=O), 163.4 (C=O), 145.0, 140.1, 139.6,
135.8, 132.0, 129.4 (2 × C), 129.1, 129.0, 128.9 (4 × C),
128.7, 128.2, 127.8, 127.6 (2 × C), 127.2 (4 × C), 126.9
(2 × C), 79.8, 65.0, 61.1, 52.6, 52.1, 28.7. MS (ESI,
M − H+): m/z 577.5 (M − H+, 100). HRMS (ESI-TOF-
MS): calcd. for C34H30N2O5S [MH]+ 579.1954; found
579.1975.
1
υmax 3385, 3062, 2952, 1736, 1685, 1346, 1267, 1195. H
NMR (400 MHz, CDCl3): δ 8.14 (brs, 1H, NH), 7.95–6.78
(m, 14H, Ar-H), 5.41(dd, 1H, J = 8.1 Hz, 8.1 Hz, 2-H), 4.03
(dd, 1H, J = 7.8 Hz, 7.8 Hz, 4-H), 3.88 (s, 3H, OCH3), 3.39
(s, 3H, OCH3), 2.43 (dd, 2H, J = 8.4 Hz, 8.1 Hz, 3-H, 3-H′),
1.25 (s, 9H, C(CH3)3). 13C NMR (100 MHz, CDCl3): δ
178.0 (C=S), 170.7 (C=O), 169.4 (C=O), 163.4 (C=O),
156.0, 140.0, 135.9, 130.4, 129.4 (2 × C), 129.0 (2 × C),
128.9 (2 × C), 128.6, 127.8 (2 × C), 126.9 (2 × C), 126.0,
125.2 (2 × C), 79.8, 65.0, 61.2, 52.6, 52.0, 34.9, 31.0 (3 ×
C), 28.7. MS (ESI, M − H+): m/z 557.2 (M − H+, 100).
HRMS (ESI-TOF-MS): calcd. for C32H34N2O5S [MH]+
559.2267; found 559.2280.

Med Chem Res
The synthesis of cis-methyl 5,5-diphenylhexahydro-1-oxo-3-
thioxo-1H-pyrrolo[1,2-c]imidazole-6-carboxylate (6)
final R-indices [I > 2σ(I)]: R1 = 0.068, wR2 = 0.088; largest
diff. peak and hole: 0.179 and −0.203 e/Å3.
Crystallographic data that were deposited in the Cam-
bridge Structural Database under CCDC-1476027 registra-
tion number contain the supplementary crystallographic
data for this Letter. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre
(CCDC) via www.ccdc.cam.ac.uk/data_request/cif and are
available free of charge upon request to CCDC, 12 Union
Road, Cambridge, UK (fax: +441223 336033, e-mail:
deposit@ccdc.cam.ac.uk).
To a stirred solution of 5a (0.502 g, 1 mmol) in dry MeOH
(20 mL) was added a solution of hydrazine monohydrate
(0.055 g, 1.1 mmol) in dry MeOH (10 mL) and the mixture
was stirred at reflux temperature for 12 h. After completion
of the reaction, the solvent was evaporated under reduced
pressure, quenched with saturated aqueous sodium chloride
and extracted with ethyl acetate. The crude mixture was
purified by column chromatography (ethyl acetate:hexane/
1:4) to afford compound 6. Amorphous white solid. Yield,
0.28 g, 84%. m.p.: 172–174 °C. IR (cm−1): υmax 3202, 3069,
2921, 1746, 1716,1463, 1345, 1271, 1225.1H NMR (400
MHz, CDCl3): δ 8.56 (bs, 1H, NH), 8.01–7.98 (m, 2H, Ar-
H), 7.51–6.86 (m, 8H, Ar-H), 4.60 (dd, 1H, J = 12.4 Hz, 6.1
Hz, 7a-H), 4.24 (dd, 1H, J = 12.3 Hz, 7.3 Hz, 6-H), 3.25 (s,
3H, OCH3), 2.90 (dt, 1H, J = 12.6 Hz, 12.3 Hz, 7-H),2.60
(ddd, 1H, J = 13.1 Hz, 7.0 Hz, 6.0 Hz, 7-H′). 13C NMR
(100 MHz, CDCl3): δ 178.5 (C=S), 171.2 (C=O), 169.7
(C=O), 142.6, 137.3, 128.7 (3 × C), 128.5 (3 × C), 128.2,
128.1, 127.6 (2 × C), 76.1, 66.1, 62.6, 52.2, 29.4. MS (ESI,
M+H+): m/z 367.1 (M+H+, 100). HRMS (ESI-TOF-MS):
calcd. for C20H18N2O3S [MH]+ 367.1116; found 367.1130.
Antibacterial activity
Stock solutions of 5a–e, 6 were prepared by dissolving the
compounds in dimethyl sulfoxide (DMSO) and then dilut-
ing in Mueller–Hinton broth and Triptic soy broth to give
an initial concentration of 2000 μg/mL. Further dilutions of
the compounds and ampicillin, which was used as control
drug in the test medium were prepared at the concentrations
of 2000, 1000, 500, 250, 125, 62.5, 31.25, 15.62, 7.8, 3.9,
and 1.9 μg/mL. To ensure that the solvents had no effect on
microbial growth, a control test was performed containing
inoculated broth supplemented with DMSO at the same
dilutions used for the test compounds, and was determined
to be inactive. MIC values for each compound were
determined in duplicate against Staphylococcus aureus
(ATCC 25925) and Bacillus subtilis (ATCC 6633) as Gram
(+) bacterial strains and Aeromonas hydrophila (ATCC
95080), Escherichia coli (ATCC 25923) and A. baumannii
(ATCC 02026) as Gram (−) bacterial strains obtained from
the Refik Saydam Hıfzıssıhha Institute, Ankara, Turkey.
The observed data on the antibacterial activity of 5a–e, 6
and ampicillin are reported in Table 1.
Crystallography
For the crystal structure determination, single-crystal of 5a,
obtained from Et2O:hexane 1:6 as crystallization solvent
was used for data collection on a four-circle Rigaku R-
AXIS RAPID-S diffractometer (equipped with a two-
dimensional area IP detector). Graphite-monochromated
Mo-Kα radiation (λ = 0.71073 Å) and oscillation scans
technique with Δw = 5° for one image were used for data
collection. The lattice parameters were determined by the
least-squares methods on the basis of all reflections with F2
> 2σ(F2). Integration of the intensities, correction for Lor-
entz and polarization effects and cell refinement was per-
formed using CrystalClear (2005) software. The structures
were solved by direct methods using SHELXS-97and
refined by a full-matrix least-squares procedure using the
program SHELXL-97 (Sheldrick 1997). All non-hydrogen
atoms were refined anisotropically and H atoms were
positioned geometrically and refined using a riding model.
The final difference Fourier maps showed no peaks of
chemical significance. Crystal data for 5a: C28H26N2O5S,
crystal system, space group: triclinic, P-1; (no:2); unit cell
dimensions: a = 14.190(2), b = 13.043(2), c = 14.261(2) Å,
α = 90, β = 103.451(4), γ = 90°; volume: 2567.0(6) Å3; Z
= 2; calculated density: 1.30 g/cm3; absorption coefficient:
0.167 mm−1; F(000): 1056; θ-range for data collection
3.1–25.9°; refinement method: full matrix least-square on
F2; data/parameters: 5040/328; goodness-of-fit on F2: 0.95;
Antimycobacterial activity
Agar proportion method
MIC values of synthesized compounds 5a–e, 6 were
determined by agar dilution in duplicate as recommended
by the Clinical Laboratory Standards Institute (CLSI)
(NCCLS -M24-A 2003; NCCLS -M24-T 2002). Positive
and negative growth controls were run in each assay. Iso-
niazid (INH) (Sigma I3377) and ethambutol (EMB) (Sigma
E4630) were used as control agents. M. tuberculosis H37Rv
was used as the standard strain and was provided by the
Refik Saydam National Public Health Agency, National
Tuberculosis Reference Laboratory, Ankara, Turkey. Stock
solutions of 5a–e, 6 and reference compounds were pre-
pared in DMSO at a concentration of 1000 μg/mL. These
solutions were then filtered through a 0.22-μm membrane
filter (Millipore, USA). Middlebrook 7H10 agar medium

Med Chem Res
Table 1 The MIC values (μg/
mL) of the tested compounds
against the (myco)bacterial
strains
Compound S. aureus B. subtilis A. hydrophila E. coli
A. baumanii M. tuberculosis H37Rv
5a
125
62.5
250
500
125
500
62.5
0.9
125
125
62.5
500
125
62.5
500
62.5
125
80
80
80
80
80
80
5b
1000
125
500
1000
125
5c
250
5d
125
62.5
500
125
5e
500
500
6
62.5
31.25
62.5
31.25
62.5
15.62
Ampicillin
Isoniazid
Ethambutol
0.2
5
MIC the minimal inhibitory concentrations determined in duplicate with deviations within one two-fold
dilution
(BBL, Becton Dickinson and Company, Sparks, MD, USA)
was supplemented with oleic acid-albumin-dextrose-
catalase (OADC, BBL, Becton Dickinson and Company,
Sparks, MD, USA). Compounds 5a–e, 6 and control agents
were added to obtain an appropriate final concentration in
the medium. The final concentrations of INH and EMB
were 0.2–1 and 5–10 μg/mL, respectively. Compounds 5a–
e, 6 were prepared at final concentrations of 5, 10, 20, 40,
80, and 160 μg/mL.Three milliliters of prepared medium
without any references and synthesized compounds 5a–e, 6
were dispensed into a sterile tube and it was used as a
growth control. The DMSO concentration in the final
solutions was not above 1% for antimycobacterial activity.
diphenylpyrrolidine-2,4-dicarboxylate 3, which was ste-
reoselectively prepared as the sole and pure diastereomer by
1,3‐dipolar endo-cycloaddition reaction of methyl 2-
(diphenylmethyleneamino)acetate 1 (De Brabandere et al.
2014) and methyl acrylate 2, and 4-substituted-benzoyl
isothiocyanate 4, prepared by reaction of potassium thio-
cyanate and the corresponding acyl chloride by modifica-
tion of the literature method (Arslan and Külcü 2003), in
good to excellent yields (Scheme 1). In the cycloaddition
reaction, the formation of the trans-isomer of 5,5-diphe-
nylpyrrolidine-2,4-dicarboxylate 3 was not observed.
The cis-methyl 5,5-diphenylhexahydro-1-oxo-3-thioxo-
1H-pyrrolo[1,2-c]imidazole-6-carboxylate 6 was synthe-
sized by cyclization reaction of the cis-5,5-diphenylpyrroli-
dine N-aroylthioureas 5a–e with concomitant cleavage of the
N-acyl group in the presence of hydrazine monohydrate in
refluxing dry MeOH for 12 h (Scheme 1). The highest yield
(84%) was obtained from the cyclization reaction of 5a and
the lowest yield (30%) was obtained from the cyclization
reaction of 5c in the presence of hydrazine monohydrate
(Table 2). After all of these cyclization reactions, starting
pyrrolidine 3 was found in the reaction mixture and could be
recovered. The most recovery of pyrrolidine 3 (55%) was
observed in the cyclization reaction of 5c. Therefore, the
decreasing yield can be explained by cleavage of the 4-
substituted-N-thioformylbenzamide group. Structures of 3,
Inoculum preparation
H37Rv was maintained in Lowenstein–Jensen medium. A
culture suspension was prepared by subculturing in Mid-
dlebrook 7H9 broth (BBL, Becton Dickinson and Company,
Sparks, MD, USA) supplemented with 10% OADC at 37 °C
for 7–10 days, until a density corresponding to 10−2 dilution
was obtained from McFarland standard No. 1. Then 0.1 mL of
the diluted suspension was inoculated onto the control and the
other tubes with compounds 5a–e, 6 in different concentra-
tions. The tubes were incubated at 37 °C in an atmosphere of
5% CO2 for 3 weeks. The MIC values were defined as the
lowest concentration that inhibited more than 90% of the
bacterial growth, and the results of INH and EMB were
interpreted according to the CLSI. The MIC was considered
the lowest concentration that showed no visible colonies in all
dilutions. In case duplicates did not give an identical result and
indicated different MIC values within one two-fold dilution,
the highest of the different values was defined as the MIC.
1
5a–e and 6 were fully characterized by H and 13C NMR,
FT-IR, MS and HRMS studies. The stereochemistry was
unambiguously determined for 5a by single crystal X-ray
diffraction studies (Fig. 1). Additionally, analogous 1H
NMR chemical shifts (2-H: δ = 5.39–5.41 ppm, 3-H and 3′-
H: δ = 2.43–2.45 ppm, 4-H: δ = 4.03–4.04 ppm) and the
corresponding coupling constants (Table 3) of all derivatives
5 pointed out the cis-stereochemistry.
The structure of 5a was fully characterized by single
crystal X-ray diffraction study. Compound 5a crystallized
as yellow prisms and the structure was solved in the triclinic
centrosymmetric space group P1 with one molecule in the
asymmetric unit (Fig. 1). There are two stereogenic carbon
Results and discussion
Cis-5,5-diphenylpyrrolidine N-aroylthiourea derivatives
5a–e were synthesized from reaction of cis-5,5-

Med Chem Res
Scheme 1 Synthesis of the 5,5-
diphenylpyrrolidine
N-aroylthiourea derivatives 5
and hexahydro-1H-pyrrolo[1,2-
c]imidazole 6
COOMe
NH
COOMe
N
Ag2O,
Et3N
MeOOC
toluene,
rt, 18h
MeOOC
Ph
Ph
Ph
Ph
1
2
3
89%
O
X
CH3CN
rt, 36h
NCS
4
X = H, CMe3,
OMe, Cl, Ph
X
O
COOMe
N2H4.H2O
H
N
NH
MeOOC
N
MeOH, reflux,
12h
N
MeOOC
Ph
Ph
O
S
Ph
S
Ph
6 (30-84%)
5a-e
a. X = H
95%
79%
71%
72%
80%
b. X = CMe3
c. X = OMe
d. X = Cl
e. X = Ph
Table 2 Synthesis of hexahydro-1H-pyrrolo[1,2-c]imidazole 6
inhibitory concentrations (MIC) of 62.5 to 1000 μg/mL
(Table 1). 5a, 5c, and 5d, containing H, OMe and Cl as
substituent at the 4-position of the aromatic ring, respectively,
exhibited antibacterial activity against the S. aureus strain with
a MIC value of 125 μg/mL. For the same bacterial strain, 5b
containing CMe3 and 5e containing Ph as substituent at the 4-
position of the aromatic ring exhibited antibacterial activity
with a MIC value of 1000 and 500 μg/mL, respectively.
Ampicillin exhibited activity with a MIC value of 31.25 μg/
mL against the S. aureus strain. Compared to ampicillin, 5a–e
showed moderate antibacterial activity against the B. subtilis
strain. Compared to the other compounds, 5d showed the best
activity against the A. hydrophila strain with a MIC value of
62.5 μg/mL, while MIC values of the other compounds were
observed in the range of 125–500 μg/mL. Compounds 5a, 5c,
and 5d exhibited antibacterial activity against the E. coli strain
with a MIC value of 125 μg/mL, whereas the other com-
pounds 5b and 5e exhibited bioactivity with a MIC value of
1000 and 500 μg/mL, respectively. The compounds 5a, 5d
showed higher activity than the control against the A. bau-
manii strain, with a MIC value of 62.5 μg/mL. Compound 5c
showed activity with a MIC value of 125 μg/mL similar to
ampicillin. Finally, derivatives 5b and 5e showed activity with
a MIC value of 500 μg/mL against the A. baumanii strain.
Compound 6 exhibited antibacterial activity against the
tested ATCC strains with a MIC value of 62.5 μg/mL. Thus,
Entry
X
Yield (%)
5a
5b
5c
5d
5e
H
84
42
30
82
46
CMe3
OMe
Cl
Ph
atoms and both have S-configuration (C14 and C16). The
bond length of N1-C21 = 1.351(5) Å, N2-C21 = 1.393(5)
Å and N2-C22 = 1.387(5) Å are shorter than typical N–C
single bond values. Whereas, the bond S–C(21) = 1.640(4)
Å and O(1)–C(22) = 1.203(5) Å are considerably longer
than C=S and C=O double bonds, respectively. The bond
values are consistent with the literature and these results
show us the existence of a partial electron delocalization in
the N–C(S)–NH–C(O) structural fragment (Saeed et al.
2010; Döndaş et al. 2006; Del Campo et al. 2004).
Antibacterial and antimycobacterial activities
Antibacterial activity studies of the compounds 5a–e, 6 were
performed against five standard bacterial strains. The com-
pounds 5a–e inhibited the growth of bacteria at minimum

Med Chem Res
Fig. 1 Crystal structure of 5a.
Selected bond lengths (Å) and
angles: S–C21 1.640(4), O(1)–C
(22) = 1.203(5), N1–C7 1.511
(5), N1–C16 1.458(5), N1–C21
1.351(5), N2–C21 1.393(5),
N2–C22 1.387(5), S–C21–N1
123.6(3), S–C21–N2 123.1(3),
C22–N2–C21 128.4(3),
N1–C7–C14 99.1(5)
1
cyclization reaction of the 5,5-diphenylpyrrolidine N-
aroylthiourea derivatives in the presence of hydrazine
monohydrate. These type of structures are very useful in
pharmaceutical studies because the different functional
groups of the synthesized hexahydro-1H-pyrrolo[1,2-c]
imidazole compound can be easily modified. Although all
compounds 5a–e and 6 showed antibacterial activity, the
final compound 6 exhibited better activity and its anti-
bacterial activity is promising for future studies. Further-
more, the synthesized novel 5,5-diphenylpyrrolidine, N-
aroylthioureas and the hexahydro-1H-pyrrolo[1,2-c]imida-
zole compounds showed a considerable antimycobacterial
activity against the M. tuberculosis H37Rv strain.
Table 3 Selected H NMR chemical shifts and coupling constants of
pyrrolidines 5
Compound 2-H
3-H, 3′-H
4-H
δ (ppm) J (Hz) δ (ppm) J (Hz) δ (ppm) J (Hz)
5a
5b
5c
5d
5e
5.39
5.41
5.40
5.38
5.41
8.3
8.1
8.2
8.2
8.2
2.44
2.43
2.43
2.44
2.45
8.0
4.04
8.4
7.8
7.9
8.0
8.0
8.4, 8.1 4.03
8.1
8.0
8.1
4.04
4.04
4.04
the 5,5-diphenylpyrrolidine N-aroylthiourea derivatives
possessed a broad spectrum of antibacterial activity, and it
can be said that 5a and 5d showed a better pharmacological
activity than the other derivatives. The pyrrolidine-fused
thiohydantoin 6 showed better antibacterial activity than the
Acknowledgements This work is a part of Duygu Erşen master
thesis and we are thankful to Mersin University (project grant BAP-
SBE TEB (DE) 2014-4 YL) and the Scientific and Technological
Research Council of Turkey (TÜBİTAK, project grant 214Z289) for
financial support.
5,5-diphenylpyrrolidine N-aroylthiourea derivatives
against the tested ATCC strains.
5
Antimycobacterial activity studies of the compounds 5a–
e, 6 were performed against the M. tuberculosis H37Rv
strain, and all compounds exhibited activity with a MIC
value of 80 μg/mL against the M. tuberculosis H37Rv strain
(Table 1). It can be said that the presence of the tert-butyl,
chloro, methoxy, and phenyl substituent on para position of
the phenyl ring of the benzoyl group has no effect on
bioactivity.
Compliance with ethical standards
Conflict of interest The authors declare that they have no competing
interests.
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