Synthesis and antibacterial screening of novel 2-(4-(aryl) thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoisoindole-1,3(2H)-dione derivatives

Article abstract of DOI:10.1080/10426507.2017.1354209

A series of novel 2-(4-(aryl)thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoisoindole-1,3(2H)-dione derivatives were synthesized and evaluated for their antimicrobial activity. The structures of the synthesized derivatives (9a-j) were confirmed by means of IR, ¹H-NMR, ¹³C-NMR and elemental analyses. All the compounds 9a-j showed activity against all microorganisms. Compounds 9a, 9c-d, and 9j exhibit potent antibacterial activity against tested S. pyogenes. Compounds 9c showed higher activity than standards against C. perfringes. 9a-e, 9j and 9i possess good activity against A. tumefacen.

Full text of DOI:10.1080/10426507.2017.1354209

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis and antibacterial screening of novel 2-
(4-(aryl) thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-
ethanoisoindole-1,3(2H)-dione derivatives
Oguz Özbek, Necibe Canan Usta, Meliha Burcu Gürdere, Osman Nuri Aslan,
Yakup Budak & Mustafa Ceylan
To cite this article: Oguz Özbek, Necibe Canan Usta, Meliha Burcu Gürdere, Osman Nuri Aslan,
Yakup Budak & Mustafa Ceylan (2017): Synthesis and antibacterial screening of novel 2-(4-(aryl)
thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoisoindole-1,3(2H)-dione derivatives, Phosphorus,
Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2017.1354209
To link to this article: http://dx.doi.org/10.1080/10426507.2017.1354209
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Synthesis and antibacterial screening of novel 2-(4-(aryl) thiazol-2-yl)-3a,4,7,7a-tetrahydro-
1H-4,7-ethanoisoindole-1,3(2H)-dione derivatives
Oguz Özbeka, Necibe Canan Ustab,*, Meliha Burcu Gürderea,**, Osman Nuri Aslana, Yakup
Budaka, Mustafa Ceylana
aDepartment of Chemistry, Faculty of Arts and Sciences, Gaziosmanpasa University,
60250,Tokat, Turkey
bDepartment of Biology, Faculty of Arts and Sciences, Gaziosmanpasa University, 60250,Tokat,
Turkey
*Dr. Necibe Canan Usta Department of Biology, Faculty of Arts and Sciences, Gaziosmanpasa
University, 60250, Tokat, Turkey, E-mail: necibecanan.usta@gop.edu.tr
**Dr. Meliha Burcu Gürdere Department of Chemistry, Faculty of Arts and Sciences,
Gaziosmanpasa University, 60250, Tokat, Turkey, E-mail: burcu.gurdere@gop.edu.tr,
burcugurdere@gmail.com
ABSTRACT
A series of novel 2-(4-(aryl)thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoisoindole-1,3(2H)-
dione derivatives were synthesized and evaluated for their antimicrobial activity. The structures
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of the synthesized derivatives (9a-j) were confirmed by means of IR, H-NMR, C-NMR and
elemental analyses. All the compounds 9a-j showed activity against all microorganisms.
Compounds 9a, 9c-d and 9j exhibit potent antibacterial activity against tested S. pyogenes.
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Compounds 9c showed higher activity than standards against C. perfringes. 9a-e, 9j and 9i
possess good activity against A. tumefacen.
Keywords
Thiazole; 4,7-ethanoisoindole-1,3(2H)-dione; Antibacterial activity.
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Introduction
In general, naturally occurring, isoindole-1,3-dione, known as phthalimide, is essential for life.
Phthalimides have a -CO-N(R)-CO- unit, and their biological activity is attributed to an imide
ring.1 Phthalimides possess a wide range of biological activities and they are used for synthesis
of numerous of biologically active compounds.2-10
On the other hand, sulfur containing heterocycles such as thiazole and thiazepines are important
compounds in medicinal chemistry due to their wide range of biological properties.11,12 These
classes of compounds have been known to show antimicrobial,13-15 antioxidant,16 antitumor,17
antiinflammatory,18-19 anticancer,20-24 anti-angiogenic25 antitubercular26 and antidepressants27
properties.
Furthermore, thiazole especially 2-aminothiazole structures are important in nature. The 2-
aminothiazole derivatives are a useful structural element for drug development for the treatment
of many diseases.28-31 A lot of compounds used as drug such as Famotidine, Cefdinir, Meloxcam
contain 2-aminothiazole unit.32
We aim to synthesize a series of new hybrid compounds containing both isoindole-1,3-
dione and thiazole ring and evaluation for their antibacterial activity.
Results and discussion
Chemistry
Firstly, 2-aminothiazole derivatives were synthesized according to the previously published
method. Treatment of the corresponding ketone with thiourea in the presence of I2 in EtOH under
reflux conditions gave 2-aminothiazole derivatives in good yields (Scheme 1). All synthesized
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compounds are known and their structures were explained on the basis of spectral data and
comparision with their authentic samples.33-38
Then, ethanoisobenzofuran-1,3-dione (8) was obtained by the addition of maleic
anhydride to cyclopentadiene in EtOAC/n-hexane (1:1) at r.t. for 1 h. in a yield of 90%
according to published procedure.39 Finally, the reaction of 2-aminothiazole with
ethanoisobenzofuran-1,3-dione (8) gave the target compounds in toluene in the presence of NEt3
for 48 h. under reflux conditions. The reaction was followed by TLC. After the completion of the
reaction, the toluene was removed under reduced pressure and the residue was extracted with
CHCl3. The crude solid product was crystallized with CHCl3/n-Hexane (3/7) (Scheme 2).
Spectroscopy
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The chemical structures of the compounds 9a-j were elucidated by H and C NMR, IR and
elemental analysis. There are two strong absorptions between 1725-1790 cm1 of the imide
carbonyl functions. The aromatic protons of this compounds resonated at δ 7.92-7.84 ppm, CH
at δ 6.30-6.29 (dd, J = 4.4 Hz; 3.2 Hz, 2H) and bridge protons CH at 1.47-1.45 (dd, J = 7.6 Hz;
13
1.2 Hz, 2H). The C NMR spectra of 9a-j showed the characteristic carbon atom of the amide
(O = C-N) with a chemical shift at 175.5 ppm. All spectral data were in agreement the proposed
structures.
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Biological activity
Antibacterial activity
The synthesized compounds (9a-j) were tested for their antibacterial activity against fourteen
different types of pathogenic bacterial strains. The microorganisms used were: Staphylococcus
aureus (ATCC® 25923), Staphylococcus epidermidis (ATCC® 12228), Streptococcus pyogenes
(ATCC® 19615), Listeria monocytogenes (ATCC® 19115), Bacillus cereus and Clostridium
perfringes (ATCC® 12124) which are Gram-positive bacteria and Proteus vulgaris (ATCC®
13315), Klebsiella pneumoniae (ATCC® 13883), Escherichia coli (ATCC® 25922),
Pseudomonas aeruginosa (ATCC® 27853), Agrobacterium tumefaciens (ATCC® 2334),
Salmonella typhimurium (ATCC® 14028), Enterobacter cloacae (ATCC® 23355) and Serratia
marcescens (ATCC® 8100) which are Gram-negative bacteria. In these tests, P (Penicillin) and
C (Chloramphenicol) were used as standard.
Both the gram-positive and gram-negative bacteria commonly seem to be more
susceptible to the inhibitory effects of the synthesized compounds (9a-j).40 Their susceptibility
may come from their metabolic, nucleic acid toxicity properties. In addition, the possibility that
there are more direct effects of the compounds (9a-j) on the machinery of protein synthesis due
to the 3 or more membered rings which undergoes an acylation reaction with the enzymes as
transpeptidase, that cross-link the polymers in protein synthesis, must not be excluded.41
The results of the antibacterial screening of the compounds indicate that almost all the
compounds 9a-j showed activity against all microorganisms (Tables S 1 and S 2, Supplemental
Materials). The standards (Penicillin and Chloramphenicol) had the 17-21 mm of inhibition zone.
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All compounds exhibited low to moderate activity against S. epidermitis, S. typhimurium, P.
vulgaris, L. monocytogenes and E. bacteriaceae. Compounds 9d and 9e demonstrated moderate
activity with 15 mm of inhibition zone against S. aureus compared with other compounds (10-12
mm of inhibition zone). Compounds 9a, 9c-d and 9j displayed high activity (with 16-18 mm
inhib. zone) against S. pyogenes, the others compounds displayed low activity. Compound 9i
demonstrated high activity (with 17 mm of inhib. zone) against B. cereus. While compounds 9a
and 9h exhibited high activity (with 16 and 18 mm of inhib. zone, respectively) against C.
perfringes, compound 9c showed higher activity than standards with 22 mm of inhibition zone
and the others compounds showed very low activity against C. perfringes. However though
majority of the compounds showed low to moderate activity against S. marcescens, K.
pneumoniae and E. Coli, the compounds 9d and 9e showed high activity with 17-18 mm of
inhibition zone. Only one compound 9h exhibited high activity (with 17 mm of inhib. zone)
against P. aeruginosa. The compounds 9a-e, 9j and 9i (with 17-19 mm of inhib. zone) had
approximately the same activity with standards (with 17-19 mm of inhib. zone) against A.
tumefacens.
The active compounds were subjected to MIC (minimum inhibitory concentrations)
studies and the results are given in Table S 2. Compounds 9d and 9e demonstrated lower activity
(MIC: 0.625 g/mL) than P. (Penicillin) and C. (Chloramphenicol) (MIC: 0.039 and 0.078
g/mL, respectively) against S. aureus. The most active compound is 9c with 0.156 g/mL MIC
value against S. pyogenes, the compounds 9a, 9d,e (MIC: 0.312 g/mL), 9i (MIC: 1.250 g/mL)
and 9j (MIC: 0.625 g/mL) showed low activity. Compound 9i showed remarkable activity
(MIC: 1.250 g/mL), 9j showed very low activity (MIC: 0.625 g/mL) against B. cereus.
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Compounds 9c showed the same activity with P. (MIC: 0,039g/mL) and 9a showed
significantly activity (MIC: 0.156 g/mL), compound 9h (MIC: 0.625 g/mL) showed low
activity against C. perfringes. Compounds 9d and 9e (MIC: 0.156 g/mL) showed significantly
activity against K. Pneumonia. Compounds 9d and 9e (MIC: 0.312 g/mL) showed remarkable
activity against E. coli. Compounds 9h (MIC: 0.312 g/mL) showed remarkable activity against
P. Aeruginosa. Compound 9a showed the same activity with P. (MIC: 0.078 g/mL) and 9i
showed the same activity with C. (MIC: 0.156 g/mL) against A. tumefacens, while other
compounds 9b-e and 9j showed lower activity (MIC: 0.312 g/mL) than positive controls.
Compounds 9h and 9j (MIC: 1.250 and 0.625 g/mL, respectively) demonstrated very lower
activity than positive controls against S. typhimurium. Compounds 9b and 9i (MIC: 1.250
g/mL), 9c (MIC: 0.625 g/mL) showed low activity, 9d and 9e (MIC: 0.312 g/mL) showed
remarkable activity against S. marcescens. Summary, according to MIC values, the most active
compounds are 9c (MIC: 0.039 g/mL) against C. perfringes and 9a (MIC: 0.078 g/mL)
against A. tumefacens.
Concerning SAR, compound 9d containing 4-Br group and 9e containig 4-Cl group
found to be the most active compounds according to the inhibition zone. They showed extremely
high activity against most microorganisms.
Conclusions
In summary,
a
series of novel 2-(4-(aryl)thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-
ethanoisoindole-1,3(2H)-dione derivatives (9a-j) were designed, synthesized and evaluated for
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their antibacterial activity against fourteen different types of pathogenic bacterial strains. All the
compounds 9a-j showed activity against all microorganisms. Some of the compounds inhibited
same activity with standards. The active compounds were subjected to MIC (minimum inhibitory
concentrations) studies. Compound 9a and 9c found to be the most active compounds according
to the inhibition zone and MIC values. They showed high activity against most microorganisms.
Experimental
General Methods
IR spectra were recorded on a Jasco FTIR-430 spectrophotometer with KBr optics. Melting
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points were measured on Electrothermal 9100 apparatus and are uncorrected. H and C NMR
spectra were recorded on a Bruker Avance DPX-400 instrument. As internal standards served
TMS ( 0.00) for 1H NMR and CDCl3 ( 77.0) for 13C NMR spectroscopy J values are given in
Hz. Elemental analyses were obtained from a LECO CHNS 932 Elemental Analyzer. All the
chemicals and solvents employed in the synthesis were supplied by Merck (Germany) and Fluka
(Germany) and used without purification. The Supplemental Materials contains 1H and 13C
NMR spectra for products 9 (Figures S 3 -- S 22).
Thiazole derivatives (3a-h and 5a,b)33-38 and compound 839 were synthesized by the
literature procedures and their structures were determined on the basis of their spectral data.
General procedure for synthesis of (4R,7S)-2-(4-phenylthiazol-2-yl)-3a,4,7,7a-tetrahydro-
1H-4,7-ethanoisoindole-1,3(2H)-dione derivatives (9a-j)
Thiazole derivative (3a-h and 5a,b) (1 mmol) was dissolved in toluene (7.5 mL) and NEt3
(1 mL) and stirred for about 10 min. Then, dicarboxylicanhydride (8) (1 mmol) in toluene (7.5
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mL) was added drop wise into the reaction mixture. The reaction mixture was refluxed for 48 h.
Toluene was removed by a rotovap. The residue was extracted with chloroform, the organic layer
was dried over Na2SO4 and solvent was removed by rotovap. The crude product was crystallized
in chloroform/hexane (3/7) mixture.
(4R,7S)-2-(4-phenylthiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoisoindole-1,3(2H)-dione
(9a)
Solid, yield: 60%, m.p.: 178-181°C. IR (KBr, cm1): 3099, 3054, 2969, 2879, 1799, 1725,
1
1599, 1505, 1470, 1443, 1403, 1351, 1272, 1187, 1078, 1043, 1024; H NMR (400 MHz,
CDCl3): δ 7.92-7.90 (dd, J = 8.0 Hz; 0.8 Hz, 2H), 7.46 (s, 1H), 7.42 (t, J = 7.4, 2H), 7.36-7.32
(m, 1H), 6.30-6.29 (dd, J = 4.4 Hz; 3.2 Hz, 2H), 3.31 (bs, 2H), 3.09 (s, 2H), 1.67 (d, J = 8.4 Hz;
13
2H), 1.45 (d, J = 7.6 Hz; 2H); C NMR (100 MHz, CDCl3, ppm): δ 175.5 (2C), 152.5, 151.4,
133.9, 132.6 (2C), 128,7 (2C), 128.3, 126.3 (2C), 111.8, 44.2 (2C), 32.02 (2C), 23.5 (2C);
Elemental analysis (%), Calcd for C19H16N2O2S: C, 67.84; H, 4.79; N, 8.33; S, 9.53; Found: C,
67.72; H, 4.71; N, 8.26; S, 9.47.
(4R,7S)-2-(4-(p-tolyl)thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoisoindole-1,3(2H)-
dione (9b)
Solid, yield: 70%, m.p.: 193-196°C. IR (KBr, cm1): 3106, 3043, 2957, 2869, 1790, 1726,
1500, 1348, 1321, 1182, 1159, 1046; 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.0 Hz, 2H),
7.41 (s, 1H), 7.23(d, J = 8.0 Hz, 2H), 6.31-6.29 (dd, J = 4.6 Hz; 3.2 Hz, 2H), 3.32-3.31 (m, 2H),
3.09 (t, J = 1.6 Hz; 2H), 2.39 (s, 3H), 1.70-1.67 (dd, J = 7.6 Hz; 1.2 Hz, 2H), 1.47-1.45 (dd, J =
7.6 Hz; 1.2 Hz, 2H); 13C NMR (100 MHz, CDCl3, ppm): δ 175.5 (2C), 152.7, 151.2, 138.1, 132.6
(2C), 131.2, 129.3 (2C), 126.2 (2C), 111.1, 44.2 (2C), 32.0 (2C), 23.5 (2C), 21.3; Elemental
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analysis (%), Calcd for C20H18N2O2S: C, 68.55; H, 5.18; N, 7.99; S, 9.15; Found: C, 68.42; H,
5.06; N, 7.86; S, 9.07.
(4R,7S)-2-(4-(4-methoxyphenyl)thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoisoindole-
1,3(2H)-dione (9c)
Solid, yield: 70%, m.p.: 158-161°C; IR (KBr, cm1):3108, 3054, 3025, 2954, 2934, 2869,
2832, 1784, 1769, 1714, 1602, 1589, 1521, 1486, 1465, 1428, 1342, 1321, 1258, 1223, 1148,
1
1116, 1034; H NMR (400 MHz, CDCl3): δ = 7.84-7.82 (dd, J = 6.6Hz; 2.4 Hz, 2H), 7.30 (s,
1H), 6.95-6.93 (dd, J = 6.8 Hz; 2.0 Hz, 2H), 6.31-6.28 (dd, J = 4.4 Hz; 3.2 Hz, 2H), 3.85 (s, 3H),
13
3.31 (bs, 2H), 3.09 (t, J = 1.6 Hz; 2H), 1.71-1.66 (m, 2H), 1.48-1.44 (m, 2H); C NMR (100
MHz, CDCl3, ppm): δ = 175.5 (2C), 159.7, 152.4, 151.2, 132.6 (2C), 127.7 (2C), 126.9, 114.0
(2C), 110.1, 55.3, 44.2 (2C), 32.0 (2C), 23.5 (2C); Elemental analysis (%), Calcd for
C20H18N2O3S: C, 65.55; H, 4.95; N, 7.64; S, 8.75; Found: C, 65.42; H, 4.91; N, 7.58; S, 8.67.
(4R,7S)-2-(4-(4-bromophenyl)thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoisoindole-
1,3(2H)-dione (9d)
Solid, yield: 70%, m.p.: 158-161°C. IR (KBr, cm1):3190, 3108, 3055, 2949, 2869, 2534,
1
1720, 1698, 1566, 1480, 1397, 1373, 1349, 1318, 1281, 1250, 1178, 1164, 1076, 1051, 1008; H
NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.4 Hz; 2H), 7.55 (d, J = 8.8 Hz; 2H), 7.46 (s, 1H),
6.31-6.28 (dd, J = 7.6 Hz; 3.2 Hz, 2H), 3.33 (bs, 2H), 3.11 (s, 2H), 1.72-1.68 (dd, J = 12.4 Hz;
5.2 Hz, 2H), 1.48-1.46 (dd, J = 7.8 Hz; 1.2 Hz, 2H); 13C NMR (100 MHz, CDCl3, ppm): δ 175.4
(2C), 151.6, 151.3, 132.8 (2C), 132.6 (2C), 131.8 (2C), 127.9, 122.3, 111.9, 44.2 (2C), 32.0 (2C),
23.5 (2C); Elemental analysis (%), Calcd for C19H15BrN2O2S: C, 54.95; H, 3.64; N, 6.75; S,
7.72; Found: C, 54.85; H, 3.61; N, 6.66; S, 7.68.
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(4R,7S)-2-(4-(4-chlorophenyl)thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoisoindole-
1,3(2H)-dione (9e)
Solid, yield: 60%, m.p.: 133-136°C. IR (KBr, cm1): 3109, 3050, 2980, 2952, 2931, 2864,
1
1782, 1718, 1495, 1469, 1339, 1319, 1237, 1219, 1189, 1151, 1126, 1066, 1006; H NMR (400
MHz, CDCl3): δ 7.86-7.84 (dd, J = 6.8 Hz; 2.0 Hz, 2H), 7.45 (s, 1H), 7.40-7.38 (dd, J = 6.6 Hz;
1.8 Hz, 2H), 6.31-6.30 (dd, J = 4.4 Hz; 3.2 Hz, 2H), 3.33 (bs, 2H), 3.11 (d, J = 1.2 Hz; 2H),
1.72-1.68 (dd, J = 12.4 Hz; 4.8 Hz, 2H), 1.49-1.46 (dd, J = 7.6 Hz; 1.2 Hz, 2H); 13C NMR (100
MHz, CDCl3, ppm): δ 175.4 (2C), 151.3, 134.1, 132.6 (2C), 132.4, 128.9 (2C), 128.7, 127.6
(2C), 111.9, 44.2 (2C), 32.0 (2C), 23.5 (2C); Elemental analysis (%), Calcd for C19H15 ClN2O2S:
C, 61.53; H, 4.08; N, 7.55; S, 8.65; Found: C, 61.32; H, 4.00; N, 7.49; S, 8.56.
(4R,7S)-2-(4-(3-methoxyphenyl)thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoisoindole-
1,3(2H)-dione (9f)
Solid, yield: 65%, m.p.: 133-136°C. IR (KBr, cm1): 3108, 3054, 3025, 2954, 2869, 2832,
1
1784, 1714, 1602, 1486, 1465, 1428, 1342, 1321, 1258, 1222, 1148, 1116, 1034; H NMR (400
MHz, CDCl3): δ 7.50 (d, J = 0.8 Hz; 1H), 7.47-7.46 (m, 2H), 7.33 (t, J = 8.0 Hz, 1H), 6.91-6.89
(dd, J = 8.0 Hz; 2.4 Hz, 1H), 6.31-6.29 (dd, J = 5.4 Hz; 2.8 Hz, 2H), 3.88 (s, 3H), 3.32 (bs, 2H),
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3.10 (d, J = 1.2 Hz, 2H), 1.69 (d, J = 7.2 Hz, 2H), 1.46 (d, J = 7.6 Hz, 2H); C NMR (100
MHz, CDCl3, ppm): δ 175.5 (2C), 159.9, 152.4, 151.3, 135.2, 132.6 (2C), 129.7, 118.8, 114.2,
112.1, 111.7, 55.3, 44.2 (2C), 32.0 (2C), 23.5 (2C); Elemental analysis (%), Calcd for
C20H18N2O3S: C, 65.55; H, 4.95; N, 7.64; S, 8.75; Found: C, 65.48; H, 4.85; N, 7.57; S, 8.60.
(4R,7S)-2-(4-(3-bromophenyl)thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoisoindole-
1,3(2H)-dione (9g)
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Solid, yield: 60%, m.p.: 155-158C. IR (KBr, cm1): 3105, 3059, 2942, 2868, 1796, 1725,
1
1591, 1563, 1512, 1497, 1421, 1356, 1292, 1186, 1152, 1135, 1074, 1047; H NMR (400 MHz,
CDCl3): δ 8.06 (t, J = 1.8 Hz; 1H), 7.85-7.82 (ddd, J = 7.8 Hz; 1.6 Hz, 1.2 Hz, 1H), 7.48 (s, 1H),
7.47-7.46 (dd, J = 2.0 Hz; 1.2 Hz, 1H), 7.31-7.27 (m, 1H), 6.32-6.30 (dd, J = 4.6 Hz; 3.0 Hz,
2H), 3.33 (t, J = 1.2 Hz, 2H), 3.11 (t, J = 1.6 Hz, 2H), 1.73-1.68 (m, 2H), 1.50-1.45 (m, 2H); 13C
NMR (100 MHz, CDCl3, ppm): δ 175.4 (2C), 151.6, 150.9, 135.8, 132.6 (2C), 131.2, 130.2,
129.3, 124.9, 122.9, 112.6, 44.2 (2C), 32.0 (2C), 23.5 (2C); Elemental analysis (%), Calcd for
C19H15BrN2O2S: C, 54.95; H, 3.64; N, 6.75; S, 7.72; Found: C, 54.82; H, 3.58; N, 6.66; S, 7.63.
(4R,7S)-2-(4,5-diphenylthiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoisoindole-1,3(2H)-
dione (9h)
Solid, yield: 72%, m.p.: 164-167°C. IR (KBr, cm1): 3056, 2935, 2867, 1778, 1715, 1600,
1
1579, 1539, 1490, 1444, 1336, 1240, 1213, 1155, 1130, 1073, 1054, 1027; H NMR (400 MHz,
CDCl3): δ 7.54-7.52 (m, 2H), 7.38-7.34 (m, 5H), 7.28-7.27 (m, 3H), 3.22 (t, J = 3.2 Hz, 2H),
13
3.33 (bs, 2H), 3.11 (d, J = 1.2 Hz, 2H), 1.69 (d, J = 7.6 Hz, 2H), 1.47 (d, J = 7.6 Hz, 2H); C
NMR (100 MHz, CDCl3, ppm): δ 175.6 (2C), 149.1, 147.1, 134.1, 132.6 (2C), 132.5, 131.2,
129.7 (2C), 129.1 (2C), 128.8 (2C), 128.4, 128.2 (2C), 127.9, 44.2 (2C), 32.0 (2C), 23.5 (2C);
Elemental analysis (%), Calcd for C25H20N2O2S: C, 72.79; H, 4.89; N, 6.79; S, 7.77; Found: C,
72.71; H, 4.79; N, 6.75; S, 7.65.
(4R,7S)-2-(8H-indeno[1,2-d]thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoisoindole-
1,3(2H)-dione) (9i)
Solid, yield: 80%, m.p.: 184-187C. IR (KBr, cm1):2932, 1790, 1724, 1499, 1484, 1455,
1397, 1319, 1052; 1H NMR (400 MHz, CDCl3): δ 7,82 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 7.6 Hz,
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1H), 7.36 (t, J = 7.6 Hz, 1H), 7.24-7.22 (dd, J = 7.6 Hz; 0.8 Hz, 1H), 6,31-6.30 (dd, J = 4.4 Hz;
3.2 Hz, 2H), 3.85(s, 2H), 3.29 (bs, 2H), 3.08 (s, 2H), 1.66 (d, J = 7.2 Hz, 2H), 1.43 (d, J = 7.6
13
Hz, 2H); C NMR (100 MHz, CDCl3, ppm): δ 175.8 (2C), 158.4, 154.0, 145.0, 136.7, 135.4,
132.6 (2C), 127.1, 125.6, 124.8, 119.6, 44.2 (2C), 32.7, 32.0 (2C), 23.5 (2C); Elemental analysis
(%), Calcd for C20H16N2O2S: C, 68.94; H, 4.63; N, 8.04; S, 9.20; Found: C, 68.72; H, 4.57; N,
7.98; S, 9.17.
(4R,7S)-2-(4,5-dihydronaphtho[1,2-d]thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-
ethanoisoindole-1,3(2H)-dione (9j)
Solid, yield: 75%, m.p.: 237-240°C. IR (KBr, cm1):3042, 2947, 1781, 1716, 1497, 1473,
1339, 1213, 1145, 1125; 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 7.2 Hz, 1H), 7.31-7.28 (m,
1H), 7.21-7.20 (m, 2H), 6.32-6.30 (dd, J = 4.4 Hz; 3.2 Hz, 2H), 3.30 (bs, 2H), 3.08 (t, J = 1.4
Hz, 2H), 3.06-3.04 (m, 4H), 1.69-1.67 (dd, J = 7.6 Hz; 1.2 Hz, 2H), 1.47-1.44 (dd, J = 7.81 Hz;
13
1.4 Hz, 2H); C NMR (100 MHz, CDCl3, ppm): δ 175.8 (2C), 148.9, 147.3, 134.2, 132.6 (2C),
130.8, 129.8, 127.7, 127.5, 127.1, 123.6, 44.2 (2C), 32.0 (2C), 28.6, 23.5 (2C), 21.8; Elemental
analysis (%), Calcd for C21H18N2O2S: C, 69.59; H, 5.01; N, 7.73; S, 8.85; Found: C, 69.42; H,
4.89; N, 7.71; S, 8.78.
Microbiology
Preparation of microorganisms
Preparation of microorganisms and antibacterial tests were performed according to previously
described methods.42-45
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MIC determination for the most efficient polymers against tested microorganisms
The MIC was defined as the lowest concentration of the newly synthesized compounds where no
growth was observed after 48 h. Negative controls included DMSO in amounts corresponding to
the highest quantity present in the agar dilution assay. Inoculated agar plates without added the
test compound served as positive controls. Agar dilution method was applied for minimal
inhibitory concentration (MIC. µg/ mL) values assessment of the selected compounds (9a-j).
Fifteen milliliters of MHA containing definite concentration of the compounds was poured onto
6 cm diameter petri dish. The range of the 9a-j concentration was 0.082 to 20 mg/mL. The
bacterial suspensions 0.1 mL with 0.5 McFarland) were inoculated on MHA containing 0.1mL of
serial different 9a-j concentrations. Control media with 5% DMSO served as negative controls.
The plates were incubated at 37°C for 48 hours before reading the results.
Acknowledgments
The authors are indebted to the Gaziosmanpasa University, Scientific Research Projects
Commission (Project No: BAP2015/90) for financial supports.
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Scheme 1.Synthesis of 2-aminothiazole derivatives38
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Scheme 2. Synthesis of 9a-j
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