Synthesis of linezolid-like molecules and evaluation of their antimicrobial activities

Article abstract of DOI:10.3906/kim-1105-54

3-Fluoro-4-(morpholin-4-yl)aniline (2), prepared from 3,4- difluoronitrobenzene, was converted to the corresponding Schiff base (3) by treatment with indol-3-carbaldehyde. The treatment of thiourea 4 and carbothioamide derivatives 9 with ethyl bromoacetate or 4-substituted phenacyl bromides generated the corresponding thiazolidinone (5 and 13) and thiazoline (6 and 12) derivatives, respectively. The acidic or basic treatment of carbothioamide 9 produced 1,3,4-thiadiazole (11) or 1,2,4-triazole (10) compounds, respectively. The structural assignments of the new compounds were based on elemental analysis and spectral (IR, ¹H-NMR, ¹³C-NMR, and LC-MS) data. The antimicrobial activity study revealed that all compounds showed good antitubercular activities. TUeBITAK.

Full text of DOI:10.3906/kim-1105-54

Turk J Chem
36 (2012) , 37 – 53.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-1105-54
Synthesis of linezolid-like molecules and evaluation of
their antimicrobial activities
1
1
1
2
˘
˙
Serap BAS¸OGLU , Meltem YOLAL , Ahmet DEMIRBAS¸ , Hakan BEKTAS¸ ,
1
1,∗
˘
˙
Rza ABBASOGLU , Neslihan DEMIRBAS¸
1Department of Chemistry, Faculty of Sciences, Karadeniz Technical University,
61080 Trabzon-TURKEY
e-mail: neslihan@ktu.edu.tr
2Department of Chemistry, Faculty of Sciences, Giresun University,
28100 Giresun-TURKEY
Received: 26.05.2011
3-Fluoro-4-(morpholin-4-yl)aniline (2), prepared from 3,4-difluoronitrobenzene, was converted to the
corresponding Schiff base (3) by treatment with indol-3-carbaldehyde. The treatment of thiourea 4 and
carbothioamide derivatives 9 with ethyl bromoacetate or 4-substituted phenacyl bromides generated the
corresponding thiazolidinone (5 and 13) and thiazoline (6 and 12) derivatives, respectively. The acidic
or basic treatment of carbothioamide 9 produced 1,3,4-thiadiazole (11) or 1,2,4-triazole (10) compounds,
respectively. The structural assignments of the new compounds were based on elemental analysis and spectral
(IR, 1 H-NMR, 13 C-NMR, and LC-MS) data. The antimicrobial activity study revealed that all compounds
showed good antitubercular activities.
Key Words: 1,3-Thiazole, 1,3,4-thiadiazole, 1,2,4-triazole, linezolid, antimicrobial activity
Introduction
Despite the existence of a number of antibiotics that are used for the treatment of bacterial infections, the
mortality and morbidity caused by gram-positive bacteria have an alarming worldwide impact on the human
population due to the increasing number of multidrug-resistant microbial pathogens. Mycobacterium tuberculosis
is the etiological agent for tuberculosis (TB). The incidence of TB, which causes approximately 3 million deaths
worldwide every year, has steadily risen in the past years, and it is the world’s second most common cause of
∗Corresponding author
37

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Synthesis of linezolid-like molecules and evaluation of..., S. BAS¸OGLU, et al.
death from infectious disease, after acquired immunodeficiency syndrome (AIDS). Incidences of TB and AIDS
occurring together are common. According to the World Health Organization, about 30 million people will
be infected within the next 20 years. Thus, the exploration of a new class of antibacterial agents with novel
mechanisms is crucial to combat multidrug-resistant infections.1−5
Oxazolidinones are a relatively new class of synthetic antibacterial agents, having a new mechanism of
action that involves early inhibition of bacterial protein synthesis. This class of compounds is particularly
active against gram-positive organisms. Oxazolidinones are thought to not be cross-resistant with other types
of antibiotics due to their different action mechanism, which includes interaction with the bacterial ribosome to
inhibit bacteria.6−11 Important examples of this class are the morpholine derivative linezolid and the piperazine
derivative eperezolid (Scheme). The thiomorpholine analog of linezolid, PNU-100480, has also been reported to
exhibit antimicrobial activity. The compounds, including an azole moiety instead of the morpholine nucleus in
the linezolid structure, have also been reported as antimicrobial agents.12
O
HO
N
O
N
F
N
F
O
O
N
N
O
O
NHCOCH3
NHCOCH3
Eperezolid
Linezolid
S
N
F
O
N
O
NHCOCH3
PNU100480
Scheme.
Thiazolidinone derivatives have been further reported to possess diverse pharmacological properties, such
as antibacterial, antifungal, anticonvulsant, anticancer, antituberculosis, and anti-human immunodeficiency
virus type 1 (HIV-1) activities. Thiazolidinones are novel inhibitors of the bacterial enzyme MurB, a precursor
acting during the biosynthesis of peptidoglycan as an essential component of the cell wall of both gram-positive
and gram-negative bacteria.13−21
The identification and synthesis of combinational chemotherapeutic drugs with different mechanisms of
action and with few side effects is an important part of the efforts to overcome antimicrobial resistance.22
A
38

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Synthesis of linezolid-like molecules and evaluation of..., S. BAS¸OGLU, et al.
recent survey of novel small-molecule therapeutics has revealed that the majority result from an analog-based
approach and that their market value represents two-thirds of all drug sales.23
Experimental
Chemistry
All chemicals were purchased from Fluka Chemie AG (Buchs, Switzerland) and were used without further
purification. Melting points of the synthesized compounds were determined in open capillaries on a Bu¨chi
B-540 melting point apparatus (Bu¨chi Labortechnik AG, Flawil, Switzerland) and are uncorrected. Reactions
were monitored by thin-layer chromatography (TLC) on silica gel 60 F254 aluminum sheets. The mobile phase
was ethanol and ethyl acetate (1:1), and detection was done with UV light. Infrared (IR) spectra were recorded
as potassium bromide pellets using a PerkinElmer 1600 series Fourier transform infrared (FTIR) spectrometer
(Waltham, MA, USA). 1 H-NMR and 13 C-NMR spectra were recorded on a Bruker AVANCE II 400-MHz NMR
spectrometer (Bruker Corporation, Billerica, MA, USA), with chemical shift in ppm downfield from TMS as an
internal reference. The elemental analysis was performed on a Costech Elemental Combustion System CHNS-O
elemental analyzer (Costech Analytical Technologies, Valencia, CA, USA). All compounds gave C, H, and N
analysis results within 0.4% of the theoretical values. The mass spectra were obtained on a Quattro liquid
chromatography-mass spectrometry (LC-MS) (70 eV) instrument (Waters Corporation, Milford, MA, USA).
Compounds 1 and 2 are commercially available.
4-(2-Fluoro-4-nitrophenyl)morpholine (1): 3,4-Difluoronitrobenzene (10 mmol) was refluxed with
an excess amount of morpholine (20 mL) for 8 h (TLC-controlled). The mixture was then poured into ice
water. The precipitated product was filtered off and recrystallized from ethanol (yield: 2.20 g, 97%). Mp 111
◦ C (yellow crystals); IR (KBr) cm−1 : 3074 (aromatic CH), 1345 and 1519 (-NO2); 1 H-NMR (DMSO-d6): δ
ppm 3.23 (brs, 4H, 2CH2), 3.70 (brs , 4H, 2CH2), 7.09 (t, 1H, arH, J = 9.2 Hz), 7.94 (d, 2H, arH, J = 7.8 Hz);
13 C-NMR (DMSO-d6): δ ppm 50.06-50.16 (2CH2), arC [112.61 (CH), 118.37 (CH), 121.92 (CH), 140.15 (C),
145.87 (C), 150.31 (C)]; MS m/z (%): 136.83 (77), 148.78 (24), 151.84 (18), 165.80 (20), 179.88 (42), 180.82
(48), 182.82 (100), 209.85 (62), 226.94 ([M]+ , 36); Anal. Calcd. (%) for C10 H11 FN2 O3 : 53.10, C; 4.90, H;
12.38, N. Found: 52.70, C; 4.60, H; 12.00, N.
3-Fluoro-4-(4-morpholin-4-yl)aniline (2): Pd/C catalyst (5 mmol) was added to a solution of
compound 1 (10 mmol) in butanol, and the mixture was allowed to reflux in the presence of hydrazine hydrate
(50 mmol) for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the
catalyst was removed by filtration, and the reaction solvent was removed under reduced pressure. The obtained
white solid was recrystallized from ethanol to afford the desired compound (yield: 1.66 g, 85%). Mp 119 ◦ C
(white crystals); IR (KBr) cm−1 : 3419 and 3338 (NH2); 1 H-NMR (DMSO-d6): δ ppm 2.77 (brs, 4H, 2CH2),
3.65 (brs, 4H, 2CH2), 4.98 (s, 2H, NH2 , D2 O exchange), 6.26-6.36 (m, 2H, arH), 6.68-6.78 (m, 1H, arH);
13 C-NMR (DMSO-d6): δ ppm 51.73 (2CH2), 66.50 (2CH2), arC [101.90 (CH), 109.84 (CH), 120.63 (CH),
129.17 (C), 145.58 (C), 153.98 (C)]; MS m/z (%): 196.84 ([M+ ], 100), 197.90 ([M+1]+ , 11); Anal. Calcd. (%)
for C10 H13 FN2 O: 61.21, C; 6.68, H; 14.28, N. Found: 61.46, C; 6.43, H; 14.18, N.
3-Fluoro-N -[(1H -indol-3-yl)methylidene]-4-(morpholin-4-yl)aniline (3): A solution of com-
39

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Synthesis of linezolid-like molecules and evaluation of..., S. BAS¸OGLU, et al.
pound 2 (10 mmol) in absolute ethanol was refluxed with indol-3-carbaldehyde (10 mmol) for 6 h. The reaction
content was allowed to reach room temperature, and a solid appeared. This crude product was filtered off and
recrystallized from acetone to obtain the desired compound (yield: 3.07 g, 95%). Mp 180 ◦ C; IR (KBr) cm−1
:
3092 (aromatic CH), 1443 (C=N); 1 H-NMR (DMSO-d6): δ ppm 2.91 (s, 4H, 2CH2), 3.71 (s, 4H, 2CH2), 6.70-
6.80 (brs, 5H, arH), 6.91-7.00 (t, 3H, arH, J = 9.1 Hz), 9.11 (s, 1H, N=CH); 13 C-NMR (DMSO-d6): δ ppm
51.64 (2CH2), 66.84 (2CH2), 107.04 (N=CH), arC [107.51 (CH), 115.22 (2CH), 120.80 (2CH), 120.88 (2CH),
130.33 (CH), 134.54 (C), 136.43 (C), 136.64 (C), 146.95 (C), 153.51 (C), 158.38 (C)]; MS m/z (%): 298.19
(91), 298.38 (86), 298.51 (54), 300.2 (36), 301.13 (26), 324.29 ([M+1]+ , 40), 336.17 (60), 364.14 ([M+2+K]+
,
61); Anal. Calcd. (%) for C19 H18 FN3 O: 70.57, C; 5.61, H; 12.99, N. Found: 70.20, C; 5.75, H; 12.65, N.
1-[3-Fluoro-4-(morpholin-4-yl)phenyl]-3-(4-fluorophenyl)thiourea (4): A solution of compound
2 (10 mmol) in absolute ethanol was stirred under reflux in the presence of 4- fluorophenyl isothiocyanate (10
mmol) for 7 h. The progress of the reaction was monitored by TLC. After the reaction mixture cooled to room
temperature, a solid formed. This crude product was separated by filtration and recrystallized from ethanol
to give the target compound (yield: 1.56 g, 67%). Mp 160 ◦ C; IR (KBr) cm−1 : 3202 (2NH), 3022 (aromatic
CH), 1219 (C=S); 1 H-NMR (DMSO-d6): δ ppm 2.95 (s, 4H, 2CH2), 3.72 (s, 4H, 2CH2), 6.93-7.19 (m, 4H,
arH), 7.33-7.40 (m, 3H, arH), 9.73 (s, 2H, 2NH, D2 O exchange); 13 C-NMR (DMSO-d6): δ ppm 51.31 (CH2),
51.36 (CH2), 66.86 (2CH2), arC [112.61 (CH), 115.51 (CH), 119.23 (2CH), 120.72 (2CH), 126.92 (CH), 134.66
(2C), 137.08 (2C), 152.34 (C)], 180.10 (C=S); MS m/z (%): 101.85 (46), 103.10 (37), 105.73 (33), 109.80 (26),
121.25 (18), 152.91 (50), 196.02 (25), 196.96 (50), 228.99 (36), 264.97 (38), 300.07 (91), 301.07 (23), 316.09
(100), 317.09 (21), 350.06 ([M]+ , 40); Anal. Calcd. (%) for C17 H17 F2 N3 OS: 58.44, C; 4.90, H; 12.03, N.
Found: 58.10, C; 5.23, H; 11.81, N.
1-[3-Fluoro-4-(morpholin-4-yl)phenyl]-3-[3-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-2-ylidene]
thiourea (5): A mixture of compound 4 (10 mmol) and ethyl bromoacetate in absolute ethanol was allowed
to reflux in the presence of dried sodium acetate (50 mmol) for 5 h; the progress of the reaction was monitored
by TLC. The reaction mixture was then cooled to room temperature and the salt was separated by filtration.
After the solvent was removed under reduced pressure, a solid appeared. This crude product was recrystallized
from dimethyl sulfoxide to afford the desired product (yield: 2.44 g, 63%). Mp 206 ◦ C; IR (KBr) cm−1 : 1725
(C=O), 1449 (C=N); 1 H-NMR (DMSO-d6): δ ppm 2.99-2.95 (brs, 4H, 2CH2), 3.72 (s, 4H, 2CH2), 4.12 (s,
2H, thiazole C4), 6.68-6.74 (m, 3H, arH), 6.98-7.29 (m, 4H, arH); MS m/z (%): 117.87 (76), 117.99 (86), 148.71
(58), 148.84 (79), 152.91 (73), 153.09 (58), 154.72 (43), 155.10 (32), 214.79 (38), 214.91 (48), 229.05 (100),
229.24 (72), 230.87 (55), 270.16 (37), 271.16 (50), 273.10 (58), 284.18 (56), 300.20 (35), 370.27 (33), 371.34 (75),
383.29 (78), 384.36 (46), 413.39 ([M+1+Na]+ , 60); Anal. Calcd. (%) for C19 H17 F2 N3 O2 S: 58.60, C; 4.40, H;
10.79, N. Found: 58.77, C; 4.80, H; 11.08, N.
1-[5-(4-Nitrophenyl)-3-(4-fluorophenyl)-1,3-thiazol-2(3H)-ylidene]-3-[3-fluoro-4-(morpholin-
4-yl)phenyl]thiourea (6): A mixture of compound 4 (10 mmol) and 4-nitrophenacylbromide (10 mmol) in
absolute ethanol was refluxed in the presence of dried sodium acetate (50 mmol) for 8 h. The reaction content
was then cooled to room temperature and the salt was separated by filtration. After the solvent was evaporated
under reduced pressure, an oily product appeared. Upon treating that product with water, a solid was obtained.
This crude product was recrystallized from benzene and petroleum ether (1:2) to afford the desired compound
(yield: 4.31 g, 87%). Mp 136 ◦ C; IR (KBr) cm−1 : 1450 (C=N), 1348 and 1527 (NO2); 1 H-NMR (DMSO-d6):
40

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Synthesis of linezolid-like molecules and evaluation of..., S. BAS¸OGLU, et al.
δ ppm 2.94 (brs, 4H, 2CH2), 3.72 (brs, 4H, 2CH2), 5.48 (brs, 1H, thiazole C4), 6.69-7.14 (m, 6H, arH), 7.15-
7.60 (m, 1H, arH), 7.69 (s, 1H, arH), 7.82-7.86 (m, 1H, arH), 8.13-8.17 (m, 2H, arH); 13 C-NMR (DMSO-d6):
δ ppm 50.88-51.50 (2CH2), 66.78-66.94 (2CH2), arC [110.19 (CH), 117.13 (CH), 118.25 (CH), 120.58 (2CH),
123.94 (CH), 125.79 (CH), 129.07 (2CH), 129.85 (2CH), 131.48 (C), 132.25 (C), 137.73 (C), 137.92 (C), 147.57
(C), 147.80 (C), 157.19 (C)], 120.58 (thiadiazole C4), 138.49 (thiazole C5), 149.63 (thiazole C2); MS m/z (%):
284.17 (24), 316.20 (21), 330.05 (29), 335.14 (22), 371.39 (21), 383.28 (100), 399.33 (39), 401.28 (22), 415.38
(39), 431.36 (20), 459.43 (27), 474.41 (40), 495.30 ([M+1]+ , 24), 513.23 (53), 519.40 ([M+2+Na]+ , 43), 580.31
(93); Anal. Calcd. (%) for C25 H20 F2 N4 O3 S: 60.72, C; 4.08, H; 11.33, N. Found: 60.33, C; 4.48, H; 11.30, N.
Ethyl {[3-fluoro-4-(morpholin-4-yl)phenyl]amino}acetate (7): Ethyl bromoacetate (10 mmol)
was added to a mixture of compound 2 (10 mmol) and triethylamine (10 mmol) dropwise in dry tetrahydrofuran
at 0-5 ◦ C. The reaction content was allowed to reach room temperature and was stirred for 11 h; the progress
of the reaction was monitored by TLC. The precipitated triethylammonium salt was removed by filtration.
After the solvent was evaporated under reduced pressure, a yellow solid appeared. This crude product was
recrystallized from ethyl acetate and petroleum ether (1:2) to afford the desired product (yield: 1.94 g, 69%).
Mp 85 ◦ C; IR (KBr) cm−1 : 3384 (NH), 1729 (C=O), 1117 (C-O); 1 H-NMR (DMSO-d6): δ ppm 1.16 (t, 3H,
CH3 , J = 6.6 Hz), 2.79 (brs, 4H, 2CH2), 3.66 (brs, 4H, 2CH2), 3.82 (s, 2H, NCH2), 4.07 (q, 2H, OCH2 , J =
6.6 Hz), 5.93 (brs, 1H, NH, D2 O exchange), 6.25-6.40 (m, 2H, arH), 6.81 (t, 1H, arH, J = 9.0 Hz); 13 C-NMR
(DMSO-d6): δ ppm 14.68 (CH3), 45.48 (CH2), 52.14 (2CH2), 61.18 (CH2), 66.90 (2CH2), arC [100.94 (CH),
108.45 (CH), 121.10 (CH), 130.04 (C), 145.54 (C), 154.49 (C)], 172.10 (C=O); MS m/z (%): 124.80 (43), 130.80
(100), 152.83 (64), 162.84 (42), 190.94 (37), 195.88 (68), 196.89 (54), 208.90 (38), 210.90 (23), 283.05 ([M+1]+ ,
19), 383.24 (48); Anal. Calcd. (%) for C14 H19 FN2 O3 : 59.56, C; 6.78, H; 9.92, N. Found: 59.16, C; 6.97, H;
10.32, N.
2-{[3-Fluoro-4-(morpholin-4-yl)phenyl]amino}acetohydrazide (8): Hydrazide hydrate (25 mmol)
was added to a solution of compound 7 (10 mmol) in absolute ethanol, and the mixture was allowed to reflux
for 7 h. When the reaction mixture cooled to room temperature, a white solid appeared. The crude product
was filtered off and recrystallized from ethanol to give the desired compound (yield: 1.87 g, 70%). Mp 182 ◦ C;
IR (KBr) cm−1 : 3339-3293 (NH2), 3339 (NH), 1653 (C=O); 1 H-NMR (DMSO-d6): δ ppm 2.75 (brs, 4H,
2CH2), 3.56 (brs, 4H, 2CH2), 3.88 (s, 2H, CH2), 4.25 (brs, 2H, NH2 , D2 O exchange), 5.87 (brs, 1H, NH, D2 O
exchange), 6.26-6.46 (m, 2H, arH), 6.81 (t, 1H, arH, J = 9.2 Hz), 9.11 (brs, 1H, NH, D2 O exchange); 13 C-NMR
(DMSO-d6): δ ppm 46.06 (CH2), 52.23 (2CH2), 67.04 (2CH2), arC [101.01 (CH), 108.56 (CH), 121.03 (CH),
130.13 (C), 145.82 (C), 154.06 (C)], 170.01 (C=O); MS m/z (%): 137.94 (28), 150.83 (21), 162.97 (39), 164.97
(23), 195.88 (71), 208.90 (95), 309.15 (75), 331.18 (100); Anal. Calcd. (%) for C12 H17 FN4 O2 : 53.72, C; 6.39,
H; 20.88, N. Found: 54.12, C; 6.20, H; 20.71, N.
N -(4-Fluorophenyl)-2-({[3-fluoro-4-(morpholin-4-yl)phenyl]amino}acetyl) hydrazinecarboth-
ioamide (9): A mixture of compound 8 (10 mmol) and 4-fluorophenyl isothiocyanate (10 mmol) in absolute
ethanol was refluxed for 7 h. When the reaction content cooled to room temperature, a white solid formed.
This crude product was filtered off and recrystallized from ethyl acetate to afford the desired compound (yield:
3.02 g, 61%). Mp 160 ˚C; IR (KBr) cm−1 : 3331 (2NH), 3164 (2NH), 1690 (C=O), 1226 (C=S). 1 H-NMR
(DMSO-d6): δ ppm 2.79 (brs, 4H, 2CH2), 3.41 (brs, 4H, 2CH2), 3.76 (d, 2H, CH2 , J = 5.2 Hz), 5.88 (s,
1H, NH, D2 O exchange), 6.34-6.48 (m, 2H, arH), 6.82 (t, 1H, arH, J = 9.8 Hz), 7.16 (t, 2H, arH, J = 9.0
41

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Synthesis of linezolid-like molecules and evaluation of..., S. BAS¸OGLU, et al.
Hz), 7.37 (brs, 2H, arH), 9.57 (brs, 1H, NH, D2 O exchange), 9.69 (brs, 1H, NH, D2 O exchange), 10.10 (brs,
1H, NH, D2 O exchange); 13 C-NMR (DMSO-d6): δ ppm 45.38 (CH2), 51.61 (2CH2), 66.40 (2CH2), arC
[100.57 (CH), 114.67 (2CH), 115.48 (2CH), 116.15 (CH), 120.40 (CH), 135.33 (C), 145.11 (C), 153.97-157.24
(C), 158.40-158.79 (C), 160.04-162.06 (C)], 170.20 (C=O), 181.27 (C=S); MS (ESI) m/z (%): 104.73 (26),
122.73 (24), 137.77 (46), 150.75 (34), 164.80 (23), 190.81 (36), 195.83 (45), 208.87 (100), 268.94 (32), 403.11
(25), 421.10 ([M+ ], 32), 422.17 ([M+1]+ , 82), 423.17 ([M+Na]+ , 20), 460.10 ([M+K]+ , 61); Anal. Calcd. (%)
for C19 H21 F2 N5 O2 S: 54.15, C; 5.02, H; 16.62, N. Found: 54.55, C; 5.22, H; 16.23, N.
4-(4-Fluorophenyl)-5-({[3-fluoro-4-(morpholin-4-yl)phenyl]amino}methyl)-4H-1,2,4-triazole-
3-thiol (10): A solution of compound 9 (10 mmol) in ethanol and water (1:1) was refluxed in the presence of
2 N NaOH for 3 h, and then the resulting solution was cooled to room temperature and acidified to pH 4 with
37% HCl. The precipitate that formed was filtered off, washed with water, and recrystallized from ethyl acetate
to afford the desired compound (yield: 2.47 g, 61%). Mp 211 ◦ C; IR (KBr) cm−1 : 3412 (NH), 3064 (arH), 2850
(SH); 1 H-NMR (DMSO-d6): δ ppm 2.74 (s, 4H, 2CH2), 3.67 (s, 4H, 2CH2), 4.06 (s, 2H, CH2), 5.82 (brs, 1H,
NH, D2 O exchange), 6.17-6.31 (m, 2H, arH), 6.72 (t, 1H, arH, J = 8.8 Hz), 7.24-7.42 (m, 4H, arH), 13.80 (s,
1H, SH, D2 O exchange); 13 C-NMR (DMSO-d6): δ ppm 38.82-41.35 (DMSO-d6 +CH2), 52.08 (2CH2), 67.00
(2CH2), arC [101.02 (CH), 108.56 (CH), 116.7 (CH), 117.18 (CH), 120.88 (CH), 120.97 (CH), 131.04 (CH),
130.40 (C), 145.13 (C), 151.00 (C), 159.18-160.41 (C), 165.31-168.95 (C)], 144.92 (triazole C3), 154.36 (triazole
C5); MS m/z (%): 237.00 (31), 404.19 ([M+1]+ , 100), 405.19 (25); Anal. Calcd. (%) for C19 H19 F2 N5 OS:
56.56, C; 4.75, H; 17.36, N. Found: 56.96, C; 4.68, H; 17.13, N.
5-({[3-Fluoro-4-(morpholin-4-yl)phenyl]amino}methyl)-N-(4-fluorophenyl)-1,3,4-thiadiazol-
2-amine (11): Concentrated sulfuric acid (64 mmol) was added to compound 9 (10 mmol) dropwise while
stirring, and the reaction content was stirred in an ice bath for 15 min. The mixture was allowed to reach
room temperature and was stirred for an additional 3 h. The resulting solution was then poured into ice-cold
water and made alkaline (pH 8) with ammonia. The precipitated product was filtered, washed with water, and
recrystallized from ethanol to afford the desired product (yield: 3.83 g, 95%). Mp 177 ◦ C; IR (KBr) cm−1
:
3412 (NH), 3064 (aromatic CH); 1 H-NMR (DMSO-d6): δ ppm 2.80 (s, 4H, 2CH2), 3.67 (s, 4H, 2CH2), 4.48
(s, 2H, CH2), 6.42 (brs, 3H, NH + 2arH, partial D2 O exchange), 6.83 (t, 1H, arH, J = 8.95 Hz), 7.11-7.19 (m,
2H, arH), 7.59 (brs, 2H, arH), 10.24 (s, 1H, NH, D2 O exchange); 13 C-NMR (DMSO-d6): δ ppm 43.18 (CH2),
52.11 (2CH2), 67.00 (2CH2), arC [101.45 (CH), 101.92 (CH), 109.02 (CH), 116.05 (CH), 116.50 (CH), 119.51
(CH), 121.21 (CH), 130.83 (C), 144.96 (C), 154.50 (C), 159.33 (C), 161.74 (C)], 155.43 (thiadiazole C5), 165.20
(thiadiazole C3); MS m/z (%): 100.85 (70), 105.92 (21), 128.82 (20), 144.78 (27), 160.79 (50), 162.73 (25),
300.08 (21), 358.21 (39), 404.20 ([M+1]+ , 100), 405.20 (21); Anal. Calcd. (%) for C19 H19 F2 N5 OS: 56.56, C;
4.75, H; 17.36, N. Found: 56.66, C; 4.45, H; 17.16, N.
N ꢀ -[(2Z)-3-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-2-ylidene]-2-{[3-fluoro-4-(morpholin-4-yl)
phenyl]amino}acetohydrazide (12): Ethyl bromoacetate was added to a solution of compound 9 in absolute
ethanol (10 mmol) and the mixture was refluxed in the presence of dried sodium acetate (16.4 g, 200 mmol)
for 9 h. The mixture was then cooled to room temperature, poured into ice-cold water while stirring, and left
overnight in the cold. The formed solid was filtered, washed with water 3 times, and recrystallized from benzene
and petroleum ether (1:2) to afford the pure desired compound (yield: 2.42 g, 52.5%). Mp 152 ◦ C; IR (KBr)
cm−1 : 3361 (NH), 3065 (aromatic CH), 1747 and 1709 (2C=O), 1450 (C=N); 1 H-NMR (DMSO-d6): δ ppm
42

˘
Synthesis of linezolid-like molecules and evaluation of..., S. BAS¸OGLU, et al.
2.80 (s, 4H, 2CH2), 3.68 (s, 4H, 2CH2), 4.14 (s, 2H, thiazole C4), 4.37 (s, 2H, CH2), 6.12 (brs, 1H, NH, D2 O
exchange), 6.39-6.47 (m, 2H, arH), 6.78-6.91 (brs, 2H, arH), 7.18-7.34 (brs, 3H, arH), 10.82 (brs, 1H, NH, D2 O
exchange); 13 C-NMR (DMSO-d6): δ ppm 29.90 (thiazole C4), 51.41 (2CH2), 45.45 (NCH2), 66.28 (2CH2),
arC [101.05 (CH), 108.29 (CH), 116.18 (CH), 120.12 (CH), 120.20 (CH), 122.24 (CH), 122.40 (CH), 143.62 (C),
143.67 (C), 145.10 (C), 152.28 (C), 156.68 (C)], 153.75 (thiazole C2), 168.33 (exocyclic C=O), 169.22 (thiazole
C5); MS m/z (%): 100.79 (84), 102.73 (72), 103.10 (68), 110.86 (31), 196.96 (43), 208.91 (43), 229.00 (44),
368.16 (45), 388.25 (20), 462.27 ([M+1]+ , 100), 463.21 (25), 484.17 ([M+Na]+ , 38), 500.13 ([M+K]+ , 13);
Anal. Calcd. (%) for C21 H21 F2 N5 O3 S: 54.66, C; 4.59, H; 15.18, N. Found: 54.26, C; 4.25, H; 15.58, N.
N ’-[(2Z)-5-(4-Chlorophenyl)-3-(4-fluorophenyl)-1,3-thiazol-2(3H)-ylidene]-2-{[3-fluoro-4-
(morpholin-4-yl)phenyl]amino}acetohydrazide (13): 4-Chlorophenacylbromide (10 mmol) and dried
sodium acetate (16.4 g, 200 mmol) were added to a solution of compound 9 in absolute ethanol, and the
reaction mixture was refluxed for 11 h. The mixture was cooled to room temperature, poured into ice-cold
water while stirring, and left overnight in the cold. The formed solid was filtered, washed with water 3 times,
and recrystallized from ethanol to afford the desired compound (yield: 1.37 g, 25.3%). Mp 156 ◦ C; IR (KBr)
cm−1 : 3373-3290 (2NH), 3076 (aromatic CH), 1698 (C=O); 1 H-NMR (DMSO-d6): δ ppm 2.80 (s, 4H, 2CH2),
3.67 (s, 6H, 3CH2), 4.18 (brs, 1H, NH, D2 O exchange), 4.84 (brs, 1H, NH, D2 O exchange), 5.86 (brs, 1H,
thiazole C4), 6.29-6.36 (m, 2H, arH ), 6.75 (brs, 1H, arH), 7.39-7.63 (m, 6H, arH), 7.97-8.01 (m, 2H, arH); 13 C-
NMR (DMSO-d6): δ ppm 38.77-41.28 (DMSO-d6 +CH2), 52.14 (2CH2), 67.01 (2CH2), arC [100.95 (CH),
101.44 (CH), 108.63 (CH), 116.75 (CH), 117.26 (CH), 117.72 (CH), 120.93 (CH), 129.62 (CH), 130.13 (CH),
130.48 (CH), 130.31 (CH), 134.56 (C), 139.38 (C), 145.19 (C), 145.40 (C), 151.08 (C), 154.37 (C), 154.65 (C)],
131.06 (thiazole C4), 159.19 (thiazole C5), 160.70 (thiazole C2), 165.62 (C=O); MS m/z (%): 555.33 (27),
556.27 ([M]+ , 100), 557.22 ([M+1]+ , 43), 563.57 (24), 578.24 ([M-1+Na]+ , 84), 582.26 (69), 584.15 (26),
594.28 ([M-1+K]+ , 76), 596.23 ([M+1+K]+ , 42); Anal. Calcd. (%) for C27 H24 ClF2 N5 O2 S: 58.32, C; 4.35,
H; 12.60, N. Found: 58.72, C; 4.75, H; 12.20, N.
Antimicrobial activity assessment
All test microorganisms were obtained from the Refik Saydam Hıfzıssıhha Institute (Ankara, Turkey) and were
as follows: E. coli ATCC35218, E. aerogenes ATCC13048, Y. pseudotuberculosis ATCC911, P. aeruginosa
ATCC43288, S. aureus ATCC25923, E. faecalis ATCC29212, B. cereus 709 Roma, M. smegmatis ATCC607,
C. albicans ATCC60193, C. tropicalis ATCC 13803, A. niger RSKK 4017, and S. cerevisiae RSKK 251. All
of the newly synthesized compounds were weighed and dissolved in dimethyl sulfoxide to prepare extract stock
solutions of 5.000 mg mL−1 . A screening test using the agar-well diffusion method,24 as adapted earlier,25
was used for all newly synthesized compounds. Each microorganism was suspended in Mueller-Hinton (MH)
broth (Difco, Detroit, MI, USA) and the solutions were diluted to approximately 106 cfu mL−1 . They were
flood-inoculated onto the surface of MH agar and Sabouraud dextrose agar (SDA; Difco) and then dried. For
C. albicans and C. tropicalis, SDA was used. Wells 5 mL in diameter were cut from the agar using a sterile cork
borer, and 50 mL of the extracted substances was delivered into the wells. The plates were incubated for 18 h
at 35 ◦ C. Antimicrobial activity was evaluated by measuring the zone of inhibition against the test organism.
Ampicillin (10 mg), streptomycin (10 mg), and fluconazole (5 mg) were the standard drugs. Dimethyl sulfoxide
and ethanol were used as solvent controls. The antimicrobial activity results are summarized in Table 1.
43

˘
Synthesis of linezolid-like molecules and evaluation of..., S. BAS¸OGLU, et al.
Table 1. Screening for antimicrobial activity of new compounds (mm).
Microorganisms and inhibition zones (mm)
Comp. no.
Ec Ea Yp Pa Sa Ef Bc Ms Ca
Sc
10
-
3
4
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
15
-
8
-
-
-
-
-
-
-
-
-
-
8
-
-
-
-
-
-
-
-
-
-
8
8
-
-
-
12
10
10
10
14
12
22
20
12
20
-
5
-
6
-
8
-
6
10
-
-
7
-
-
-
8
-
-
-
-
9
-
-
-
-
10
11
12
13
Amp.
Strep.
Flu.
-
-
-
-
-
-
-
-
-
-
6
-
7
-
-
-
10 10 10 18 35 10 15
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
35
-
-
-
25 < 25
Ec: Escherichia coli ATCC 25922, Ea: Enterobacter aeruginosa ATCC 13048, Yp: Yersinia pseudotuberculosis ATCC
911, Pa: Pseudomonas aeruginosa ATCC 43288, Sa: Staphylococcus aureus ATCC 25923, Ef: Enterococcus faecalis
ATCC 29212, Bc: Bacillus cereus 702 Roma, Ms: Mycobacterium smegmatis ATCC607, Ca: Candida albicans ATCC
60193, Sa: Saccharomyces cerevisiae RSKK 251, Amp.: ampicillin, Strep.: streptomycin, Flu.: fluconazole, (-): no
activity.
Results and discussion
The main aim of the present study was to synthesize and investigate the antimicrobial activities of linezolid-
like molecules. Synthesis of the intermediate and target compounds was performed according to the reactions
outlined in Figures 1 and 2.
The IR and 1 H-NMR spectra of compound 3, obtained from the condensation of 2 with indol-3-
carbaldehyde, contained no signals corresponding to an amine group. Instead, new signals due to indole-3-yl
moiety were recorded at the related chemical shift values. Moreover, the IR spectrum of compound 3 showed
an absorption band at 1443 cm−1 , indicating the presence of a CH=N bond in the ring. In addition, a singlet
corresponding to 1 proton characteristic of the N=CH group was observed at 9.11 ppm in the 1 H-NMR spectrum
of compound 3. This group was recorded at 107.01 ppm in the 13 C-NMR spectrum.
It has been reported that compounds with imine bonds may exist as E/Z geometrical isomers about
the N=CH double bond.26−36 A literature survey revealed that the compounds containing imine bonds are
present in higher percentages in DMSO-d6 solution in the form of the geometrical E isomer about the N=CH
double bond.31 The Z isomer can be stabilized in less polar solvents by an intramolecular hydrogen bond. The
1 H-NMR and 13 C-NMR spectra (in DMSO-d6) of compound 3 confirmed its existence as an E geometrical
44

˘
Synthesis of linezolid-like molecules and evaluation of..., S. BAS¸OGLU, et al.
O
NH + O2N
F
O2N
N
O
F
F
1
Pd/C
H2NNH2
CHO
N
H
N
N
O
H2N
N
O
N
H
F
F
3
2
O
N
F
S
N
FC6H4NCS
N
O
BrCH2CO2Et
5
F
S
HN
N
F
O
HN
O
O2N
N
S
N
N
4
F
F
NO2C6H4COCH2Br
F
6
Figure 1. Synthetic pathway for the preparation of compounds 1-6.
isomer, which exhibited NMR data consistent with the literature findings for analogous compounds containing
the imine functionality.31−36
The synthesis of 1-[3-fluoro-4-(morpholin-4-yl)phenyl]-3-(4-fluorophenyl)thiourea (4) was performed from
the reaction of compound 2 with 4-fluorophenyl isothiocyanate, and the structure was confirmed based on
spectroscopic methods. Thiourea derivative 4 was then converted to (Z)-2-(3-fluoro-4-morpholinophenylimino)-
3-(4-fluorophenyl)thiazolidin-4-one (5) by cyclocondensation with ethyl bromoacetate, while the condensation
45

˘
Synthesis of linezolid-like molecules and evaluation of..., S. BAS¸OGLU, et al.
BrCH2CO2Et
O
2
Et
N
H
N
O
O
F
7
H2NNH2
H
N
H2N
N
N
F
O
H
O
8
FC6H4NCS
F
S
H
N
N
N
N
H
N
O
H
H
O
9
F
H2SO4
NaOH
F
N
N
H
N
N
N
H
N
N
O
N
O
HS
N
H
N
S
F
F
10
11
F
BrCH2CO2Et
ClC6H4COCH2Br
O
Cl
O
H
H
N
N
O
N
N
O
HN
NH
S
N
N
S
N
F
F
N
O
13
12
F
F
Figure 2. Synthetic of compounds 7-13.
46

˘
Synthesis of linezolid-like molecules and evaluation of..., S. BAS¸OGLU, et al.
of the same intermediate (4) with 4-nitrophenacylbromide afforded (Z)-3-fluoro-N -(3-(4-fluorophenyl)-5-(4-
nitrophenyl)thiazol-2(3H)-ylidene)-4-morpholinobenzen amine (6). In the 1 H-NMR spectra of compounds 5
and 6, no signal pointing toward thiourea moiety was observed. Instead, a new signal due to the C4 proton
(for 6) or C5 protons (for 5) of the 1,3-thiazole scaffold was recorded at 4.12 ppm (for 5) and 5.48 ppm (for 6),
integrating for 2 protons and 1 proton, respectively. A satisfactory 13 C-NMR spectrum for compound 5 was
not obtained due to the slight solubility of 5 in all NMR solvents.
The treatment of compound 2 with ethyl bromoacetate in basic media produced ethyl {[3-fluoro-4-
(morpholin-4-yl)phenyl]amino}acetate (7). Ester 7 was then converted to the corresponding hydrazide deriva-
tive, 2-{[3-fluoro-4-(morpholin-4-yl)phenyl]amino}acetohydrazide (8), via the substitution of the ethoxy group
by hydrazine hydrate.
Compound 7 was characterized by the presence of additional signals derived from the ester group, which
were observed in the 1 H-NMR spectrum of compound 7 at 1.16 ppm (-OCH2 CH3) and 3.82 (-OCH2 CH3)
ppm, integrating for 3 and 2 protons, respectively. This group appeared at 14.68 and 61.18 ppm in the 13 C-NMR
spectrum. When compound 7 was converted to hydrazide 8, the signals that originated from ester functionality
disappeared; instead, new signals due to the hydrazide structure were recorded at 4.25 and 9.11 ppm, integrating
2 protons and 1 proton, respectively, and controlled by D2 O exchange. Further support for the formation of
the hydrazide structure is the appearance of strong absorption vibrations pointing toward NHNH2 at 3339 and
3293 cm−1 in the FTIR spectrum.
The treatment of 8 with 4-fluorophenyl isothiocyanate afforded corresponding carbothioamide derivative
9 under reflux conditions. In contrast to those of compound 8, the 1 H- and 13 C-NMR spectra of compound
9 exhibited additional signals due to carbothioamide moiety at the related chemical shift values. In addition,
+
compound 9 had relatively stable [M+ ] and [M+1]
ion peaks in its mass spectrum.
The treatment of compound 9 with 2 N NaOH caused the conversion of the carbothioamide side chain
into a 1,2,4-triazole ring; thus, 5-({[3-fluoro-4-(morpholin-4-yl)phenyl]amino}methyl)-4-(4-fluorophenyl)-4H-
1,2,4-triazole-3-thiol (10) was obtained. The cyclization of the same intermediate (9) in the presence of cold
concentrated sulfuric acid produced 5-((3-fluoro-4-morpholinophenylamino)methyl)-N-(4-fluorophenyl)-1,3,4-
thiadiazol-2-amine (11). In the FTIR spectrum of compound 10, the –NH- stretching band appeared at 3412
cm−1 . The –NH- proton resonated at 5.82 ppm in the 1 H-NMR spectrum of compound 10 as a broad singlet.
Moreover, the IR spectrum of compound 10 displayed a -SH stretching band at 2850 cm−1
. This group
resonated at 13.80 ppm in the 1 H-NMR spectrum of compound 10, controlled by D2 O exchange. In the FTIR
and 1 H-NMR spectra of compound 11, no signal derived from the –SH function was recorded, while 2 signals
pointing toward the presence of 2 –NH- groups were observed in the related frequencies and the chemical shift
values were consistent with the literature. Furthermore, the mass spectra of these compounds exhibited stable
[M+1] ion peaks.
The synthesis of compounds 12 and 13 was carried out by the reaction of compound 9 with 4-
chlorophenacylbromide (for 13) or ethyl bromoacetate (for 12) in ethanolic solution in the presence of dried
sodium acetate under reflux conditions.
The FTIR spectra of compounds 12 and 13 displayed a signal at 1698 (for 13) and 1702 (for 12) cm−1
pointing toward the presence of the carbonyl function. Moreover, in the 1 H-NMR spectra of compounds 12 and
13, no signal derived from the -SH group was observed; instead, new signals due to 2 –NH- groups were detected
47

˘
Synthesis of linezolid-like molecules and evaluation of..., S. BAS¸OGLU, et al.
at 6.12 or 10.82 ppm (for 12) and 4.18 ppm or 9.37 ppm (for 13), exchangeable with D2 O. Furthermore, the
C-4 proton(s) of the 1,3-thiazole scaffold appeared at 4.14 (for 12) and 5.86 ppm (for 13), integrating 2 protons
and 1 proton, respectively.
All of the newly synthesized compounds had elemental analysis results consistent with the assigned
structures.
Additional support for the formation of the targeted compounds was obtained from the appearance of
[M]+ or [M+1]+ ion peaks at corresponding m/z values, confirming their molecular masses.
Hantzsch synthesis, involving the reaction of α-halocarbonyl compounds with thioamides, is the most
commonly applied method,37,38 although several other methods have been developed for the preparation of
1,3-thiazoles. The Hantzsch reaction starts with the attack of the sulfur atom of thioamide, which is present in
its enethiol form, on the halogen-containing atom of phenacyl bromide, and then the elimination of HBr and
H2 O leads to the 1,3-thiazole ring.38
Because compound 9 possess more than 1 nucleophilic center and phenacyl bromide has 2 positions for
nucleophilic attacks, there are at least 4 different possibilities leading to the formation of 4 different structural
isomers; each of them can exist as their individual E and Z geometrical isomers (Figure 3).
To identify the exact structure of compound 13, full geometric optimization of possible products 13-16
was obtained by the DFT/B3LYP39,40 method with the 6-31G(d,p) basis set, and the structure of the molecules
was also investigated in detail. The solvent effect was evaluated using the conducting polarized continuum model
(CPCM).41,42 Using the optimized geometries of the molecules at the B3LYP/6-31G(d,p) level, their single-
point energies were computed using the CPCM-B3LYP/6-31G(d,p) method. The calculated relative energies
are given in Table 2.
Table 2. The calculated relative energies of possible isomer molecules.
Comp. no.
Relative energy (kcal mol−1
B3LYP/6-31G(d,p) CPCM-B3LYP/6-31G(d,p)//B3LYP/6-31G(d,p)
)
Z-13
E-13
Z-14
0.0
0.0
13.884
14.833
0.339
0.328
E-14 Z-15 E-15 12.353 4.204 10.949
16.464 2.416 8.077
4.243
Z-16
E-16
5.543
10.421
8.921
According to the obtained results, the most stable product is the Z geometrical isomer of structure 13,
with a calculated relative energy of 0.000 kcal mol−1 . Therefore, thermodynamically, the formation of the Z
isomers of 13 is more favorable. Although a type of 16 isomers has been reported in the literature as reaction
products between thioamides and phenacyl bromides,43,44 the calculated relative energy for the Z geometrical
isomer of 16, in the range of 4.243 to 5.543 kcal mol−1 , indicates that this isomer is less favorable than 13.
Although the stability of the Z geometrical isomer of 14, with the calculated relative energy of 0.339 and
0.328 kcal mol−1 , is close to the Z geometrical isomer of 13, the existence of only 1 spot in the TLC plate of
compound 13 strongly supports the formation of the Z geometrical isomer of 13 as the unique reaction product.
48

˘
Synthesis of linezolid-like molecules and evaluation of..., S. BAS¸OGLU, et al.
Cl
Cl
O
O
S
H
N
H
N
H
N
N
N
O
N
O
S
N
H
N
N
F
F
N
F
F
(Z)13
(E)13
F
F
N
N
O
O
H
N
H
N
S
N
O
S
N
O
N N
N N
H
H
F
F
Cl
Cl
(Z)14
(E)14
F
F
N
N
O
O
H
N
H
N
S
N
O
S
N
O
N N
N N
H
H
F
F
Cl
Cl
(Z)15
(E)15
S
O
O
H
N
H
N
H
N
N
O
N
N
O
N
H
S
N
N
F
F
N
Cl
F
Cl
F
(E)16
(Z)16
Figure 3. Possible structural and geometrical isomers for compounds 13.
49

˘
Synthesis of linezolid-like molecules and evaluation of..., S. BAS¸OGLU, et al.
a
F
F
S
O
SH
NH
Br
NH
R
NH
R
N
4 or 9
Cl
b
-HBr
b
a
O
Cl
HO
S
S
R
N
C
Br
R
N
NH
NH
Cl
F
F
A
-H2O
-HBr
-H2O
S
R
Cl
N
N
S
Cl
N
R
N
R
S
Cl
S
N
F
N
N
R
N
(Z) 16
F
(E) 6 or 13
Cl
F
F
(Z) 6 or 13
(E) 16
N
O
4 and 6 : R=
HNCOCH2NH
N
O
9 and 13:
F
F
Figure 4. Mechanism leading to the formation of compounds 6 and 13.
50

˘
Synthesis of linezolid-like molecules and evaluation of..., S. BAS¸OGLU, et al.
Moreover, the melting point and NMR spectral data point to the formation of only one product. Contrary to
the description in the literature,43,44 the reaction between carbothioamide 9 and phenacyl bromide began with
the attack of the sulfur atom on the carbonyl carbon of phenacyl bromide instead of the halogen-bearing carbon
atom of the acyl component, because the latter attack leads to the formation of 16, which is a less favorable
isomer due to its higher energy content (Figure 4).
It has been speculated that in 16 the bulky groups are positioned too close to each other, causing a less
stable structure, as seen in Table 2. The Z rearrangement of the groups in compound 13 is likely due to the
steric hindrance of the bulky R group and the fluorophenyl moiety in isothiocyanate intermediate A. Based on
the same idea, it can be concluded that compounds 5, 6, and 12 exist as their individualZ isomers. In the
reaction media, the presence of dried sodium acetate is necessary to accelerate the reaction by catching the
H2 O and HBr furnished during the reaction. In the same manner, compound 6 can be considered to exist as its
Z isomer. Similarly, due to the hindrance between the fluorophenyl ring and other bulky groups incorporating
morphlin-4-ylphenyl moiety, compounds 5 and 12 exist as their Z geometrical isomers.
All of the newly synthesized compounds were tested for their antimicrobial activities and the obtained
results are presented in Table 1. The substitution of the 1,3-oxazol-2-one scaffold in the structure of linezolid
by the 1,3-thiazole nucleus caused the loss of antimicrobial activity against gram-positive bacteria, whereas
linezolid has been used as an antibiotic for infectious diseases caused by gram-positive pathogens. As seen in
Table 1, only moderate activity against Pseudomonas aeruginosa (Pa), a gram-negative bacillus, was detected
for compound 6 with an inhibition zone of 10 mm. In addition, slight activities against yeast like Candida
albicans (Ca) and Saccharomyces cerevisiae (Sc) were observed for compounds 3, 5, and 12, with inhibition
zones between 6 and 10 mm. Moreover, compound 3 displayed moderate activities against Staphylococcus
aureus (Sa) and Enterococcus faecalis (Ef), which are gram-positive cocci, and Bacillus cereus (Bc), a gram-
positive spore bacillus, with inhibition zones of 15, 8, and 8 mm, respectively. On the other hand, this structural
modification of the linezolid molecule resulted in the emergence of activity against Mycobacterium smegmatis
(Ms), a nonpigmented, rapidly growing mycobacterium and an atypical tuberculosis factor leading to morbidity
and mortality. The highest activities, with inhibition zones of 20 mm, were observed for compounds 11 and 13,
which contain a 4-oxo-1,3-thiazolidine nucleus or 5-(4-fluorophenyl)-1,3,4-thiadiazole, respectively, in the core
structure of linezolid.
Acknowledgment
¨
˙
Support was provided by the Scientific and Technological Research Council of Turkey (TUBITAK, Project No.
107T333) and Karadeniz Technical University (BAP, Ref. No. 2007.111.002.5). The authors thank S¸engu¨l
Alpay Karaog˘lu for performing the antimicrobial screening studies.
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