Synthesis, structural characterization, antimicrobial and antifungal activity of substituted 6-fluorobenzo[d]thiazole amides

Article abstract of DOI:10.1007/s00044-015-1410-0

A series of novel 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3-substituted phenyl amides was synthesized by the condensation reaction of (1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethanamine with substituted benzoyl chlorides under mild conditions. Their structures were confirmed by ¹H NMR, ¹³C NMR and ¹⁹F NMR spectra, elemental analyses and in three cases also by single-crystal X-ray diffraction techniques. The optical activities were confirmed by optical rotation measurements. All the synthesized compounds were screened for antibacterial and antifungal activity against a variety of bacterial and fungal strains. Some of the compounds reveal antibacterial and antifungal activity comparable or slightly better to that of chloramphenicol, cefoperazone and amphotericin B used as medicinal standards.

Full text of DOI:10.1007/s00044-015-1410-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1410-0
ORIGINAL RESEARCH
Synthesis, structural characterization, antimicrobial
and antifungal activity of substituted 6-fluorobenzo[d]thiazole
amides
1
Vladimır Pejchal Marcela Pejchalova Zdenka Ruzickova
2
3
•
•
´
´
ˇ
˚ ˇ ˇ
´
Received: 27 August 2014 / Accepted: 9 July 2015
Ó Springer Science+Business Media New York 2015
Abstract A series of novel 1-[(1R)-1-(6-fluoro-1,3-ben-
zothiazol-2-yl)ethyl]-3-substituted phenyl amides was syn-
thesized by the condensation reaction of (1R)-1-(6-fluoro-
1,3-benzothiazol-2-yl)ethanamine with substituted benzoyl
chlorides under mild conditions. Their structures were
Introduction
Benzothiazoles are group of heterocyclic moieties found in
a plethora of natural compounds both of terrestrial or
marine origin and play an important role in living systems
(Gunawardana et al., 1988, 1992; Turan-Zitouni et al.,
2003). These compounds reveal interesting biocidal activ-
ities against a wide range of bacteria (Bondock et al.,
2010), viruses (Nagarajan et al., 2003), helminths (Sarkar
et al., 2008), fungi (Reuveni, 2003) and last but not least
some tumor cell lines (Lion et al., 2006; Sekar et al., 2010).
Molecular skeleton of these compounds can serve as a
unique and versatile playground for further synthetic
modification and thus also for an experimental drug design.
The studies of structure–activity relationships interestingly
reveal that a slight variation of the structure of substituent
group at C-2 position commonly results in significant
change of its biological activity (Pejchal et al., 2011a, b;
Imramovsky et al., 2013).
1
confirmed by H NMR, 13C NMR and 19F NMR spectra,
elemental analyses and in three cases also by single-crystal
X-ray diffraction techniques. The optical activities were
confirmed by optical rotation measurements. All the syn-
thesized compounds were screened for antibacterial and
antifungal activity against a variety of bacterial and fungal
strains. Some of the compounds reveal antibacterial and
antifungal activity comparable or slightly better to that of
chloramphenicol, cefoperazone and amphotericin B used as
medicinal standards.
Keywords Fluorinated benzothiazole derivates Á
Substituted benzoyl chloride Á Antimicrobial activity Á
Antifungal activity
(R)-1-(6-fluorobenzo[d]thiazol-2-yl)ethanamine, as
a
representative of above-mentioned group of compounds,
is the fundamental scaffold for antimicrobial treatment
(Patel and Rathod, 2006), herbicides, plant desiccants and
defoliants compounds (Hamprecht et al., 1999). Similar
compounds with adjacent substitution, such as iso-
propyl[(S)-1-[(R)-1-(6-flourobenzothiazolel-2-yl)ethylcar-
bamoyl]-2-methylpropyl] carbamate (Scheme 1), is
reported as commercially used fungicide (benthiavalicarb
isopropyl or KIF 230) highly effective for controlling the
oomycete fungal pathogen Plasmopara viticola, which
causes downy mildew in grapevines (Sarkar et al., 2008).
The aims of this study are the preparation and complete
characterization of novel amide derivates of compound 3
and an investigation of its fundamental biological activi-
ties (Schemes 2, 3).
´
& Vladimır Pejchal
vladimir.pejchal@upce.cz
1
Faculty of Chemical Technology, Institute of Organic
Chemistry and Technology, University of Pardubice,
´
Studentska 573, 532 10 Pardubice, Czech Republic
2
3
Department of Biological and Biochemical Sciences, Faculty
of Chemical Technology, University of Pardubice,
´
Studentska 573, 532 10 Pardubice, Czech Republic
Department of General and Inorganic Chemistry, Faculty of
´
Chemical Technology, University of Pardubice, Studentska
573, 532 10 Pardubice, Czech Republic
123

Med Chem Res
yl)ethanamine p-toluenesulfonic salt 2 were synthesized by
reported method (Hijikata, 2003; Pejchal et al., 2011a).
1
The structures of the intermediates were confirmed by H
NMR, 13C NMR and melting point.
Characterization of synthesized compound
(R)-4-methyloxazolidine-2,5-dione (1)
Scheme 1 Commercially available fungicide benthiavalicarb isopropyl
This compound was obtained by reaction of D-alanine with
phosgene. It was obtained as white solid; Yield: 83 %; m.p.
89–90 °C 1H NMR (DMSO-d6, 400.13 MHz): d = 9.01 (s,
1H, NH), 4.47 (q, 1H, 3J = 7.2 Hz, CH), 1.33 (d, 3H,
3J = 7.2 Hz, CH3); 13C NMR (DMSO-d6, 100.62 MHz)
d = 172.5 (COO), 151.8 (CONH), 52.9 (CH), 16.8 (CH3).
Scheme 2 Proton numbering for assignment of 1H NMR shifts
(compound 2)
Characterization of synthesized compound
(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethanamine
4-toluenesulfonate (2)
Scheme 3 Proton numbering
1
for assignment of H NMR
shifts (compounds 3a–m)
This compound was obtained by reaction of (R)-4-methy-
loxazolidine-2,5-dione with 2-amino-6-fluorobenzothia-
zole. It was obtained as white solid; Yield: 81 %; m.p.
1
241–242 °C H NMR (DMSO-d6, 400.13 MHz): d = 8.74
(s, 2H, NH2), 8.12 (dd, 1H, J = 2.4 Hz, JF-H = 8.4 Hz,
4
3
4
H-7), 8.09 (dd, 1H, 3J = 9.2 Hz, JF-H = 4.8 Hz, H-4),
Experimental
7.48 (d, 2H, 3J = 8.0 Hz, H-20), 7.37 (dt, 1H, 4J = 2.4 Hz,
3
3J = 9.2 Hz, JF-H = 9.2 Hz, H-5), 7.10 (d, 2H, 3J =
3
All reagents and solvents were purchased from commercial
sources (Sigma-Aldrich, Merck, Acros Organics). Phos-
gene was purchased from Synthesia (Pardubice, Czech
Republic). Reactions were monitored by thin-layer chro-
matography plates coated with 0.2-mm silica gel 60 F254
(Merck). TLC plates were visualized by the UV irradiation
(254 nm). All melting points were determined on Melting
Point B-545 apparatus (Buchi, Germany) and are uncor-
rected. Infrared spectra (ZnSe ATR experiments) were
recorded on a FT-IR spectrometer (PerkinElmer, USA) in
the range of 600–4000 cm-1. The NMR spectra were
measured in DMSO-d6 solutions at ambient temperature on
8.0 Hz, H-30), 5.01 (quint, 1H, J = 6.8 Hz, H-3), 2.28 (s,
3H, CH3), 1.66 (d, 3H, 3J = 6.8 Hz, H-2); 13C NMR
4
(DMSO-d6, 100.62 MHz): d = 169.1 (C, d, JF-C
=
1
3.4 Hz, C-9), 159.9 (C, d, JF-C = 243.5 Hz, C-6), 148.8
(C, C-3), 144.9 (C, C-40), 138.5 (C, C-10), 136.4 (C, d,
3JF-C = 11.9 Hz, C-8), 128.5 (CH, C-20), 125.7 (CH, C-30),
3
124.3 (CH, d, JF-C = 9.6 Hz, C-4), 115.5 (CH, d,
2
2JF-C = 24.9 Hz, C-5), 109.0 (CH, d, JF-C = 27.4 Hz,
C-7), 48.4 (CH, C-1), 20.9 (CH3), 19.9 (CH3, C-2); 19F
NMR (DMSO-d6, 376.46 MHz): d = -115.21. Anal.
Calcd. for C16H17FN2O3S2 (368.44): C, 52.16; H, 4.65; N,
7.60. Found: C, 52.00; H, 4.82; N, 17.51.
a
Bruker Advance III 400 (400.13 MHz for 1H,
100.62 MHz for 13C and 376.5 MHz for 19F). Coupling
constants are presented in Hz. Proton chemical shifts in
DMSO-d6 are related to the middle of the solvent multiplet
(d = 2.50). 13C NMR spectra were measured using APT
pulse sequence. Carbon chemical shifts are referenced to
the middle of the solvent’s multiplet (d = 39.5 in DMSO-
d6). The optical rotation was measured on a PerkinElmer
341 instrument, and concentration c is given in g/100 mL.
Elemental analysis (C, H, N) was performed on an auto-
matic microanalyzer CE Instruments EA 1110 CHN ele-
mental analyzer (Fisons Instruments).
General experimental procedure
and characterization data of prepared amides
compounds 3a–3m
To the mixture of toluene (70 mL) and water (30 mL) was
added sulfonate salt of (R)-1-(6-fluorobenzo[d]thiazol-2-
yl)ethanamine 2 (5.0 mmol) as a gray powder and substi-
tuted aroyl chloride (7.5 mmol). Solution of sodium
hydroxide was added dropwise to the reaction mixture to
change pH to 9–10 (approx. 4.5 g of 10 % solution).
Reaction mixture was stirred 5 h at room temperature. The
pH was maintained on 9–10 with addition of sodium
hydroxide solution. Reaction mixture was heated to 70 °C.
Desired compounds (4R)-4-methyl-1,3-oxazolidine-
2,5-dione
1
and (1R)-1-(6-fluoro-1,3-benzothiazol-2-
123

Med Chem Res
3
Toluene layer was separated and concentrated by vacuum
distillation. Distillation residue was cooled down to
0–5 °C. The precipitate was collected by filtration.
C-60), 127.2 (CH, C-50), 123.7 (CH, d, JF-C = 9.6 Hz,
2
C-4), 114.6 (CH, d, JF-C = 24.8 Hz, C-5), 108.6 (CH, d,
2JF-C = 27.2 Hz, C-7), 47.9 (CH, C-1), 19.9 (CH3, C-2);
19F NMR (DMSO-d6, 376.46 MHz): d = -116.5; Anal.
Calcd. for C16H12ClFN2OS (334.80): C, 57.40; H, 3.61; N,
8.37; S, 9.58. Found: C, 57.55; H, 3.67; N, 8.28; S, 9.38.
Characterization of synthesized compounds 3a–m
N-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]benzamide
(3a)
3-Chloro-N-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)
ethyl]benzamide (3c)
This compound was prepared by reaction of benzoyl
chloride with (1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)etha-
namine 4-toluenesulfonate. It was obtained as white solid;
Yield 84.0 %; m.p. 163–164 °C; [a]2D0 ?48.7 (c 1, ace-
tone); IR (ATR) mmax 3255, 1530 (NH of CONH), 1645
This compound was prepared by reaction of 3-chloroben-
zoyl chloride with (1R)-1-(6-fluoro-1,3-benzothiazol-2-
yl)ethanamine 4-toluenesulfonate. It was obtained as white
solid; Yield 88 %; m.p. 174–176 °C; [a]2D0 ?67.5 (c 1,
acetone); IR (ATR) mmax 3240, 1537 (NH of CONH), 1644
(CO of CONH), 1456, 1332, 824, 763, 708 cm-1; 1H NMR
(CO of CONH), 1455, 1348, 1329, 1198, 859, 821 cm-1
;
1H NMR (DMSO-d6, 400.13 MHz): d = 9.32 (1H, d,
4
3
3J = 7.5 Hz, NH), 7.99 (1H, dd, 3J = 8.8 Hz, JF-H
=
(DMSO-d6, 400.13 MHz): d = 9.44 (1H, d, J = 7.5 Hz,
5.2 Hz, H-4), 7.96 (3H, m, H-7, H-20), 7.60–7.50 (3H, m,
NH), 7.97 (3H, m, H-4, H-7, H-20), 7.89 (1H, d,
H-30, H-40), 7.36 (1H, dt, 4J = 2.6 Hz, 3J = 9.1 Hz,
3J = 7.8 Hz, H-60), 7.65 (1H, d, J = 7.6 Hz, H-40), 7.56
3
3
3
3JF-H = 9.1 Hz, H-5), 5.54 (1H, quint, J = 7.2 Hz, H-1),
(1H, t, J = 8.0 Hz, H-50), 7.37 (1H, dt, 4J = 2.6 Hz,
1.71 (3H, d, 3J = 7.2 Hz, H-2); 13C NMR (DMSO-d6,
3J = 9.1 Hz, JF-H = 9.1 Hz, H-5), 5.51 (1H, quint,
3
4
3
100.62 MHz): d = 176.1 (C, d, JF-C = 3.3 Hz, C-9),
166.4 (C=O), 159.5 (C, d, JF-C = 242.1 Hz, C-6), 149.7
3J = 7.2 Hz, H-1), 1.70 (3H, d, J = 7.2 Hz, H-2); 13C
1
4
NMR (DMSO-d6, 100.62 MHz): d = 175.6 (C, d, JF-C
=
5
(C, d, JF-C = 1.4 Hz, C-3), 135.8 (C, d, JF-C = 11.3 Hz,
3
3.2 Hz, C-9), 165.6 (C=O), 159.5 (C, d, 1JF-C = 243.0 Hz,
5
C-8), 133.8 (C, C-10), 131.7 (CH, C-40), 128.4 (CH, C-30,
C-6), 149.7 (C, d, JF-C = 1.3 Hz, C-3), 135.8 (C, d,
3
C-50), 127.5 (2CH, C-20, C-60), 123.7 (CH, d, JF-C
=
3JF-C = 12.1 Hz, C-8), 135.7 (C, C-10), 133.3 (C, C-30),
131.5 (CH, C-40), 130.5 (CH, C-50), 127.2 (CH, C-60),
126.4 (CH, C-20), 123.7 (CH, d, 3JF-C = 9.6 Hz, C-4), 114.6
2
9.7 Hz, C-4), 114.5 (CH, d, JF-C = 24.7 Hz, C-5), 108.5
(CH, d, 2JF-C = 27.1 Hz, C-7), 48.0 (CH, C-1), 19.8 (CH3,
C-2); 19F NMR (DMSO-d6, 376.46 MHz): d = -116.6;
Anal. Calcd. for C16H13FN2OS (300.35): C, 63.98; H, 4.36;
N, 9.33; S, 10.68. Found: C, 64.08; H, 4.28; N, 9.38; S,
10.58.
2
2
(CH, d, JF-C = 24.7 Hz, C-5), 108.6 (CH, d, JF-C
=
27.1 Hz, C-7), 48.2 (CH, C-1), 19.8 (CH3, C-2); 19F
NMR (DMSO-d6, 376.46 MHz): d = -116.5; Anal. Calcd.
C16H12ClFN2OS (334.80): C, 57.40; H, 3.61; N, 8.37; S,
9.58. Found: C, 57.52; H, 3.72; N, 8.28; S, 9.42.
2-Chloro-N-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)
ethyl]benzamide (3b)
4-Chloro-N-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)
ethyl]benzamide (3d)
This compound was prepared by reaction of 2-chloro
benzoylchloride with (1R)-1-(6-fluoro-1,3-benzothiazol-2-
yl)ethanamine 4-toluenesulfonate. It was obtained as white
solid; Yield 86 %; m.p. 168–170 °C; [a]2D0 ?66.7 (c 1,
acetone); IR (ATR)mmax 3237, 1534 (NH of CONH), 1628
(CO of CONH), 1453, 1330, 1329, 866, 810, 730 cm-1; 1H
NMR (DMSO-d6, 400.13 MHz): d = (1H, d, 3J = 7.7 Hz,
This compound was prepared by reaction of 4-chloroben-
zoyl chloride with (1R)-1-(6-fluoro-1,3-benzothiazol-2-
yl)ethanamine 4-toluenesulfonate. It was obtained as white
solid; Yield 87 %; m.p. 193–194 °C; [a]2D0 ?64.2 (c 1,
acetone); IR (ATR) mmax 3265, 1534 (NH of CONH), 1641
(CO of CONH), 1456, 1333, 1252, 1196, 1015, 843, 704,
3
1
NH), 8.03 (1H, dd, 4J = 2.6 Hz, JF-H = 8.9 Hz, H-7);
680 cm-1; H NMR (DMSO-d6, 400.13 MHz): d = 9.39
4
3
(1H, d, J = 7.3 Hz, NH), 8.01 – 7.94 (4H, m, H-4, H-7,
8.00 (1H, dd, 3J = 8.9 Hz, JF-H = 5.1 Hz, H-4),
4
3
7.56–7.43 (4H, m, H-30–H-60), 7.38 (1H, dt, J = 2.7 Hz,
H-20, H-60), 7.59 (2H, d, J = 8.6 Hz, H-30, H-50), 7.36
3
4
3
3
3J(1H, 1H) = 9.1 Hz, JF-H = 9.1 Hz, H-5), 5.47 (1H,
(1H, dt, J = 2.6 Hz, J = 9.1 Hz, JF-H = 9.1 Hz, H-5),
5.52 (1H, quint, 3J = 7.2 Hz, H-1), 1.70 (3H, d,
3J = 7.2 Hz, H-2); 13C NMR (DMSO-d6, 100.62 MHz):
d = 175.7 (C, d, 4JF-C = 3.2 Hz, C-9), 165.3 (C=O), 159.5
(C, d, 1JF-C = 240.8 Hz, C-6), 149.7 (C, d, 5JF-C = 1.6 Hz,
3
3
quint, J = 7.2 Hz, H-1); 1.66 (3H, d, J = 7.2 Hz, H-2);
13C NMR (DMSO-d6, 100.62 MHz): d = 175.4 (C, d,
1
4JF-C = 3.0 Hz, C-9), 166.3 (C=O), 159.6 (C, d, JF-C
=
5
241.0 Hz, C-6), 149.7 (C, d, JF-C = 1.4 Hz, C-3), 136.2
(C, C-20), 135.8 (C, d, JF-C = 12.0 Hz, C-8), 131.1 (CH,
3
3
C-3), 136.6 (C, C-4), 135.7 (C, d, JF-C = 11.7 Hz, C-8),
132.5 (C, C-10), 129.5 (2CH, C-20, C-60), 128.5 (2CH, C-30,
C-40), 130.0 (CH, C-10), 129.7 (CH, C-30), 128.9 (CH,
123

Med Chem Res
3
3
C-50), 123.7 (CH, d, JF-C = 9.5 Hz, C-4), 114.5 (CH, d,
3JF-H = 9.2 Hz, H-5), 7.17 (1H, d, J = 8.2 Hz, H-30),
2JF-C = 24.7 Hz, C-5), 108.6 (CH, d, JF-C = 27.1 Hz,
7.01 (1H, m, H-50), 5.51 (1H, quint, J = 7,2 Hz, H-1),
2
3
C-7), 48.1 (CH, C-1), 19.8 (CH3, C-2); 19F NMR (DMSO-
d6, 376.46 MHz): d = -116.5; Anal. Calcd. C16H12
ClFN2OS (334.80): C, 57.40; H, 3.61; N, 8.37; S, 9.58.
Found: C, 57.51; H, 3.78; N, 8.25; S, 9.44.
3.93 (3H, s, O-CH3), 1.68 (3H, d, J = 7.2 Hz, H-2); 13C
3
4
NMR (DMSO-d6, 100.62 MHz): d 175.9 (C, d, JF-C
=
3.1 Hz, C-9), 165.3 (C=O), 159.5 (C, d, 1JF-C = 242.2 Hz,
5
C-6), 157.0 (C, C-20), 149.7 (C, d, JF-C = 1.6 Hz, C-3),
135.9 (C, d, JF-C = 11.5 Hz, C-8), 132.5 (CH, C-40),
130.2 (CH, C-60), 123.7 (CH, d, JF-C = 9.5 Hz, C-4),
123.1 (C, C-10), 120.5 (CH, C-50), 114.5 (CH, d, JF-C
3
3
3-Fluoro-N-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)
2
ethyl]benzamide (3e)
=
=
2
24.9 Hz, C-5), 112.1 (CH, C-30), 108.6 (CH, d, JF-C
This compound was prepared by reaction of 3-fluoroben-
zoyl chloride with (1R)-1-(6-fluoro-1,3-benzothiazol-2-
yl)ethanamine 4-toluenesulfonate. It was obtained as white
solid; Yield 85 %; m.p. 157–159 °C; [a]2D0 ?58.4 (c 1,
acetone); IR (ATR) mmax 3258, 1533 (NH of CONH), 1640
27.1 Hz, C-7), 56.0 (OCH3), 47.9 (CH, C-1), 20.3 (CH3,
C-2); 19F NMR (DMSO-d6, 376.46 MHz): d = -116.6;
Anal. Calcd. C17H15FN2O2S (330.38): C, 61.80; H,
4.58; N, 8.48; S, 9.71. Found: C, 61.66; H, 4.68; N, 8.29; S,
9.64.
1
(CO of CONH), 1456, 1335, 1014, 825 cm-1; H NMR
3
(DMSO-d6, 400.13 MHz): d = 9.40 (1H, d, J = 7.5 Hz,
2-Methyl-N-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)
4
NH), 8.00 (1H, dd, 3J = 8.9 Hz, JF-H = 4.9 Hz, H-4),
ethyl]benzamide (3g)
7.96 (1H, dd, 4J = 2.6 Hz, 3JF-H = 8.8 Hz, H-7), 7.80 (1H,
3
dd, 4J = 2.5 Hz, JF-H = 8.8 Hz, H-20), 7.74 (1H, m,
This compound was prepared by reaction of 2-methyl-
benzoyl chloride with (1R)-1-(6-fluoro-1,3-benzothiazol-2-
yl)ethanamine 4-toluenesulfonate. It was obtained as white
solid; Yield 86 %; m.p. 161–163 °C; [a]2D0 ?78.1 (c 1,
acetone); IR (ATR) mmax 3243, 1532 (NH of CONH), 1640
H-60), 7.58 (1H, m, H-50), 7.44 (1H, dt, 4J = 2.5 Hz,
3
3J = 9.1 Hz, JF-H = 9.1 Hz, H-40), 7.37 (1H, dt,
4J = 2.6 Hz, 3J = 9.2 Hz, 3JF-H = 9.2 Hz, H-5), 5.52 (1H,
3
3
quint, J = 7.2 Hz, H-1), 1.70 (3H, d, J = 7.2 Hz, H-2);
13C NMR (DMSO-d6, 100.62 MHz): d 175.7 (C, d,
(CO of CONH), 1456, 1329, 1200, 1012, 810, 725 cm-1
;
4
4JF-C = 3.2 Hz, C-9), 165.0 (C, d, JF-C = 2.5 Hz,
1H NMR (DMSO-d6, 400.13 MHz): d = 9.22 (1H, d,
C = O), 162.0 (C, d, 1JF-C = 244.6 Hz, C-30), 159.5 (C, d,
3J = 7.6 Hz, NH), 8.00 (2H, m, H-4, H-7), 7.44 – 7.27
1JF-C = 242.1 Hz, C-6), 149.7 (C, d, 5JF-C = 1.4 Hz, C-3),
(5H, m, H-5, H-30–H-60), 5.47 (1H, quint, J = 7.2 Hz,
3
3
3
3
H-1), 3.40 (3H, s, CH3); 1.66 (3H, d, J = 7.2 Hz, H-2);
136.0 (C, d, JF-C = 6.7 Hz, C-10), 135.7 (C, d, JF-C
=
3
11.8 Hz, C-8), 130.6 (CH, d, JF-C = 8.0 Hz, C-50), 123.8
13C NMR (DMSO-d6, 100.62 MHz): d = 176.0 (C, d,
3
(CH, d, JF-C = 9.6 Hz, C-4), 123.7 (CH, d, JF-C
4
1
=
4JF-C = 3.1 Hz, C-9), 169.0 (C=O), 159.5 (C, d, JF-C
=
2.9 Hz, C-60), 118.6 (CH, d, 2JF-C = 21.1 Hz, C-40), 114.6
242.1 Hz, C-6), 149.7 (C, d, JF-C = 1.4 Hz, C-3), 136.3
3
5
2
2
(CH, d, JF-C = 24.7 Hz, C-5), 114.3 (CH, d, JF-C
=
(C, C-20), 135.8 (C, d, JF-C = 11.7 Hz, C-8), 135.5 (C,
2
22.8 Hz, C-20), 108.6 (CH, d, JF-C = 27.1 Hz, C-7), 48.1
(CH, C-1), 19.8 (CH3, C-2); 19F NMR (DMSO-d6,
376.46 MHz): d = -112.6, -116.5; Anal. Calcd. C16H12
F2N2OS (318.34): C, 60.37; H, 3.80; N, 8.80; S, 10.07.
Found: C, 60.45; H, 3.68; N, 8.92; S, 10.18.
C-10), 130.5 (CH, C-40), 129.7 (CH, C-30), 127.2 (CH,
3
C-50), 125.6 (CH, C-60), 123.7 (CH, d, JF-C = 9.5 Hz,
2
C-4), 114.5 (CH, d, JF-C = 24.7 Hz, C-5), 108.6 (CH, d,
2JF-C = 27.2 Hz, C-7), 47.8 (CH, C-1), 19.9 (CH3, C-2),
19.5 (CH3); 19F NMR (DMSO-d6, 376.46 MHz):
d = -116.5; Anal. Calcd. C17H15FN2OS (314.38): C,
64.95; H, 4.81; N, 8.91; S, 10.20. Found: C, 65.06; H, 4.78;
N, 8.79; S, 10.28.
2-Methoxy-N-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)
ethyl]benzamide (3f)
This compound was prepared by reaction of 2-methoxy-
benzoyl chloride with (1R)-1-(6-fluoro-1,3-benzothiazol-2-
yl)ethanamine 4-toluenesulfonate. It was obtained as white
solid; Yield 85 %; m.p. 91–92 °C; [a]2D0 ?52.5 (c 1, ace-
tone); IR (ATR) mmax 3257, 1527 (NH of CONH), 1640
4-Methyl-3-nitro-N-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)
ethyl]benzamide (3h)
This compound was prepared by reaction of 3-nitro-4-
methylbenzoyl chloride with (1R)-1-(6-fluoro-1,3-benzoth-
iazol-2-yl)ethanamine 4-toluenesulfonate. It was obtained as
white solid; Yield 87 %; m.p. 162–163 °C; [a]2D0 ?38.5 (c 1,
acetone); IR (ATR) mmax 3256, 1525 (NH of CONH), 1638
(CO of CONH), 1458, 1248, 1012, 821, 754 cm-1
;
1H
NMR (DMSO-d6, 400.13 MHz): d = 9.00 (1H, d, 3J =
7.7 Hz, NH), 8.00 (1H, dd, J = 8.9 Hz, JF-H = 4.9 Hz,
3
4
3
1
H-4), 7.98 (1H, dd, 4J = 2.6 Hz, JF-H = 8.9 Hz, H-7),
(CO of CONH), 1456, 1335, 1198, 1020, 818 cm-1; H
4
7.71 (1H, dd, 3J = 7.5 Hz, J = 1.8 Hz H-50), 7.51
NMR (DMSO-d6, 400.13 MHz): d = 9.58 (1H, d,
(1H, m, H-40), 7.37 (1H, dt, 4J = 2.6 Hz, 3J = 9.2 Hz,
3J = 7.6 Hz, NH), 8.57 (1H, d, J = 1.7 Hz, H-20), 8.17
4
123

Med Chem Res
3
4
(1H, dd, J = 7.9 Hz, J = 1.5 Hz, H-50), 8.00 (1H, dd,
1644 (CO of CONH), 1456, 1343, 1306, 1092, 816 cm-1
;
3J = 9.0 Hz, JF-H = 4.9 Hz, H-4), 7.95 (1H, dd,
1H NMR (DMSO-d6, 400.13 MHz): d = 10.01 (1H, d,
4
4J = 2.3 Hz, 3JF-H = 8.8 Hz, H-7), 7.65 (1H, d,
3J = 8.1 Hz, H-60), 7.36 (1H, dt, 4J = 2.6 Hz, 3J = 9.2 Hz,
3J = 7.3 Hz, NH), 9.14 (2H, d, J = 2.1 Hz, H-20, H-60),
4
8.99 (1H, t, 4J = 2.1 Hz, H-40), 8.00 (1H, dd, 3J = 9.0 Hz,
3JF-H = 9.2 Hz, H-5), 5.54 (1H, quint, J = 7.2 Hz, H-1),
4JF-H = 4.9 Hz, H-4), 7.96 (1H, dd, J = 2.7 Hz, JF-H
=
3
4
3
2.58 (3H, s, CH3), 1.71 (3H, d, 3J = 7.2 Hz, H-2); 13C NMR
(DMSO-d6, 100.62 MHz): d = 175.4 (C, d, 4JF-C = 3.1 Hz,
C-9), 164.2 (C=O), 159.5 (C, d, JF-C = 242.3 Hz, C-6),
8.8 Hz, H-7), 7.36 (1H, dt, 4J = 2.7 Hz, 3J = 9.0 Hz,
3JF-H = 9.0 Hz, H-5), 5.59 (1H, quint, J = 7.2 Hz, H-1),
3
1
1.74 (3H, d, 3J = 7.2 Hz, H-2); 13C NMR (DMSO-d6,
149.7 (C, d, 5JF-C = 1.3 Hz, C3), 148.8 (C, C-30), 136.6 (C,
C-40), 135.7 (C, d, 3JF-C = 11.5 Hz, C-8), 133.2 (CH, C-60),
132.6 (C, C-10), 132.1 (CH, C-50), 123.7 (CH, d, JF-C
9.6 Hz, C-4), 123.4 (CH, C-20), 114.6 (CH, d, JF-C
100.62 MHz): d = 175.4 (C, d, JF-C = 3.1 Hz, C-9),
4
1
162.2 (C=O), 159.5 (C, d, JF-C = 242.1 Hz, C-6), 149.5
3
5
=
=
(C, d, JF-C = 1.4 Hz, C-3), 148.3 (2C, C-30, C-50), 136.1
2
(C, C-10), 135.7 (C, d, 3JF-C = 11.7 Hz, C-8), 127.8 (2CH,
2
24.8 Hz, C-5), 108.6 (CH, d, JF-C = 27.2 Hz, C-7), 48.2
(CH, C-1), 19.8 (CH3, C-2), 19.7 (CH3); 19F NMR (DMSO-
d6, 376.46 MHz): d = -116.4; Anal. Calcd. C17H14FN3O3S
(359.37): C, 56.82; H, 3.93; N, 11.69; S, 8.92. Found: C,
56.68; H, 4.05; N, 11.52; S, 8.84.
C-20, C-60), 123.7 (CH, d, 3JF-C = 9.5 Hz, C-4), 121.3 (CH,
2
C-40), 114.7 (CH, d, JF-C = 24.8 Hz, C-5), 108.6 (CH, d,
2JF-C = 27.2 Hz, C-7), 48.5 (CH, C-1), 19.8 (CH3, C-2);
19F NMR (DMSO-d6, 376.46 MHz): d = -116.3; Anal.
Calcd. C16H11FN4O5S (390.35): C, 49.23; H, 2.84; N,
14.35; S, 8.21. Found: C, 49.20; H, 2.75; N, 14.52; S, 8.12.
N-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]furan-2-
carboxamide (3i)
4-Nitro-N-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)
ethyl]benzamide (3k)
This compound was prepared by reaction of 3-nitro-4-
methylbenzoyl chloride with (1R)-1-(6-fluoro-1,3-ben-
zothiazol-2-yl)ethanamine 4-toluenesulfonate. It was
obtained as white solid; Yield 85 %; m.p. 136–137 °C;
[a]2D0 ?28.7 (c 1, acetone); IR (ATR) mmax 3266, 1532 (NH
of CONH), 1633 (CO of CONH), 1456, 1348, 1012,
This compound was prepared by reaction of 4-nitrobenzoyl
chloride with (1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)etha-
namine 4-toluenesulfonate. It was obtained as white solid;
Yield 86 %; m.p. 217–218 °C; [a]2D0 ?48.7 (c 1, acetone);
IR (ATR) mmax 3284, 1529 (NH of CONH), 1641 (CO of
1
1
815 cm-1; H NMR (DMSO-d6, 400.13 MHz): d = 9.23
CONH), 1456, 1342, 1310, 825 cm-1; H NMR (DMSO-
(1H, d, 3J = 7.7 Hz, NH), 7.99 (1H, dd, 3J = 8.9 Hz,
d6, 400.13 MHz): d = 9.65 (1H, d, 3J = 7.4 Hz, NH), 8.36
4
3
3
3
4JF-H = 4.9 Hz, H-4), 7.95 (1H, dd, J = 2.6 Hz, JF-H
=
(2H, d, J = 8.8 Hz, H-30, H50), 8.16 (2H, d, J = 8.8 Hz,
8.8 Hz, H-7), 7.90 (1H, m, H-30), 7.36 (1H, dt, 4J =
3
2.6 Hz, J = 9.1 Hz, JF-H = 9.1 Hz, H-5), 7.25 (1H, m,
H-20, H-60), 8.00 (1H, dd, J = 9.0 Hz, JF-H = 5.0 Hz,
H-4), 7.96 (1H, dd, 4J = 2.7 Hz, JF-H = 8.8 Hz, H-7),
3
4
3
3
3
4
3
3
H-50), 6.67 (1H, m, H-40), 5,47 (1H, quint, J = 7.2 Hz,
7.36 (1H, dt, J = 2.7 Hz, J = 9.0 Hz, JF-H = 9.0 Hz,
H-5), 5.54 (1H, quint, 3J = 7.2 Hz, H-1), 1.71 (3H, d,
3J = 7.2 Hz, H-2); 13C NMR (DMSO-d6, 100.62 MHz):
d = 175.3 (C, d, 4JF-C = 3.1 Hz, C-9), 164.8 (C=O), 159.5
(C, d, 1JF-C = 242.4 Hz, C-6), 149.6 (C, d, 5JF-C = 1.3 Hz,
H-1), 1,68 (3H, d, J = 7.2 Hz, H-2); 13C NMR (DMSO-
3
4
d6, 100.62 MHz): d = 175.6 (C, d, JF-C = 3.2 Hz, C-9),
159.5 (C, d, JF-C = 242.4 Hz, C-6), 157.6 (C=O), 149.7
1
5
(C, d, JF-C = 1.7 Hz C-3), 147.3 (C, C-10), 145.6 (CH,
C-30), 135.8 (C, d, JF-C = 11.3 Hz, C-8), 123.8 (CH, d,
3JF-C = 9.5 Hz, C-4), 114.6 (CH, d, JF-C = 24.8 Hz,
3
C-3), 149.3 (C, C-40), 139.3 (C, C-10), 135.7 (C, d, 3JF-C
=
2
11.8 Hz, C-8), 129.1 (2CH, C-20, C-60), 123.7 (CH, d,
C-5), 114.4 (CH, C-50), 112.0 (CH, C-40), 108.6 (CH, d,
2JF-C = 27.2 Hz, C-7), 47.3 (CH, C-1), 19.8 (CH3, C-2);
19F NMR (DMSO-d6, 376.46 MHz): d = -116.6; Anal.
Calcd. C14H11FN2O2S (290.31): C, 57.92; H, 3.82; N, 9.65;
S, 11.04. Found: C, 58.08; H, 3.88; N, 9.75; S, 10.95.
3JF-C = 9.5 Hz, C-4), 123.7 (CH, C-30, C-50), 114.7 (CH,
2
2
d, JF-C = 24.5 Hz, C-5), 108.6 (CH, d, JF-C = 27.2 Hz,
C-7), 48.3 (CH, C-1), 19.8 (CH3, C-2); 19F NMR (DMSO-
d6, 376.46 MHz): d = -116.4; Anal. Calcd. C16H12FN3
O3S (345.35): C, 55.65; H, 3.50; N, 12.17; S, 9.28. Found:
C, 55.78; H, 3.55; N, 12.12; S, 9.18.
3,5-Dinitro-N-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)
ethyl]benzamide (3j)
2-Chloro-4-nitro-N-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)
ethyl]benzamide (3l)
This compound was prepared by reaction of 3,5-dini-
trobenzoyl chloride with (1R)-1-(6-fluoro-1,3-benzothiazol-
2-yl)ethanamine 4-toluenesulfonate. It was obtained as
white solid; Yield 85 %; m.p. 224–225 °C; [a]2D0 ?34.7
(c 1, acetone); IR (ATR) mmax 3283, 1527 (NH of CONH),
This compound was prepared by reaction of 2-chloro-4-
nitrobenzoyl chloride with (1R)-1-(6-fluoro-1,3-benzothia-
zol-2-yl)ethanamine 4-toluenesulfonate. It was obtained as
white solid; Yield 88 %; m.p. 156–158 °C; [a]2D0 ?41.7
123

Med Chem Res
(c 1, acetone); IR (ATR) mmax 3282, 1539 (NH of CONH),
low-temperature device on a Nonius Kappa CCD diffrac-
1644 (CO of CONH), 1456, 1373, 857, 822 cm-1; 1H NMR
tometer with MoKa radiation (k = 0.71073 A), a graphite
˚
3
(DMSO-d6, 400.13 MHz): d = 9.68 (1H, d, J = 7.7 Hz,
monochromator and the u and v scan mode. Data reduc-
tions were performed with DENZO-SMN (Otwinowski and
Minor, 1997). The absorption was corrected by integration
methods (Ahmed et al., 1970). Structures were solved by
direct methods (Sir92) (Altomare et al., 1993) and refined
by full matrix least square based on F2 (SHELXL97)
(Sheldrick, 1997). Hydrogen atoms were mostly localized
on a difference Fourier map; however, to ensure uniformity
of the treatment of the crystal, all hydrogen atoms were
recalculated into idealized positions (riding model) and
assigned temperature factors Hiso(H) = 1.2 Ueq (pivot
atom) or of 1.5 Ueq for the methyl moiety with C–
4
NH), 8.39 (1H, d, J = 2.2 Hz, H-30), 8.30 (1H, dd,
4
3J = 8.4 Hz, J = 2.2 Hz, H-50), 8.02 (2H, m, H-4, H-7),
7.78 (1H, d, 3J = 8.4 Hz, H-60), 7.39 (1H, dt, 4J = 2.6 Hz,
3
3J = 9.1 Hz, JF-H = 9.1 Hz, H-5), 5.50 (1H, quint,
3
3J = 7.2 Hz, H-1), 1.67 (3H, d, J = 7.2 Hz, H-2); 13C
4
NMR (DMSO-d6, 100.62 MHz): d = 174.6 (C, d, JF-C
=
3.0 Hz, C-9), 164.8 (C=O), 159.5 (C, d, 1JF-C = 242.0 Hz,
C-6), 149.6 (C, d, JF-C = 1.3 Hz, C-3), 148.4 (C, C-40),
141.8 (C, C10), 135.8 (C, d, JF-C = 11.8 Hz, C-8), 131.2
5
3
(C, C-20), 130.0 (CH, C-60), 124.7 (CH, C-30), 123.9 (CH,
3
d, JF-C = 9.4 Hz, C-4), 122.5 (CH, C-50), 114.7 (CH, d,
2
2JF-C = 25.1 Hz, C-5), 108.6 (CH, d, JF-C = 27.2 Hz,
H = 0.96, 0.98 and 0.93 A for methyl, methine and
˚
C-7), 48.0 (CH, C-1), 19.9 (CH3, C-2); 19F NMR (DMSO-
d6, 376.46 MHz): d = -116.3; Anal. Calcd. C16H11
ClFN3O3S (379.79): C, 50.60; H, 2.92; N, 11.06; S, 8.44.
Found: C, 50.78; H, 2.85; N, 11.12; S, 8.38.
hydrogen atoms in the aromatic rings, respectively.
Selected crystallographic data for compounds 3b, 3f and 3i
are presented in Table 3. Crystallographic data for struc-
tural analysis have been deposited with the Cambridge
Crystallographic Data Centre (deposition number CCDC
1018178, CCDC 1018179, CCDC 1018180). Copies of this
information may be obtained free of charge from the
Director, CCDC, 12 Union Road, Cambridge CB2 1EY, UK
(fax: ?44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk or
http://www.ccdc.cam.ac.uk).
4-Chloro-3-nitro-N-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)
ethyl]benzamide (3m)
This compound was prepared by reaction of 4-chloro-3-
nitrobenzoyl chloride with (1R)-1-(6-fluoro-1,3-benzothia-
zol-2-yl)ethanamine 4-toluenesulfonate. It was obtained as
white solid; Yield 86 %; m.p. 161–162 °C; [a]2D0 ?44.3 (c
1, acetone); IR (ATR) mmax 3263, 1527 (NH of CONH),
Evaluation of antimicrobial activity
The newly synthesized compounds were screened for their
antibacterial activity against a range of gram-positive
bacterial strains S. aureus (CCM 422), S. aureus (CCM
4223), S. epidermidis (CCM 4418) and E. faecalis (CCM
4224), and gram-negative bacterial strains E. coli (CCM
3954), E. cloacae (CCM 1903), P. mirabilis (CCM 7188)
and P. aeruginosa (CCM 3955). Nutrient broth was pre-
pared using 9 mL of Muller–Hinton agar (70191 Fluka)
and 1 mL of each dilution tested compounds prepared in
sterile dry test tubes. The mixture was immediately poured
into a sterile Petri dish with a diameter of 10 cm. A twofold
serial dilution of the compounds and the reference drug
were dissolved in DMSO. Tested compounds were taken at
different concentrations (200, 100, 50, 25, 12.5 and
6.25 lg/mL) for minimum inhibitory concentration (MIC).
Hundred-microliter microbial suspension of 3 9 106 cfu/
mL density was streaked on the nutrient agar medium after
solidification. The Petri dishes were incubated at 37 °C for
48 h. The MIC was the lowest concentration of the tested
compound that resulted in no visible growth of the
organisms. To ensure that the solvent had no effect on
bacterial growth, a control test was also performed with
test medium supplemented with DMSO at same dilutions
as used in the experiment. Antifungal activity was evalu-
ated against C. albicans (CCM 8311), C. glabrata (CCM
1636 (CO of CONH), 1456, 1341, 1010, 843, 693 cm-1
;
1H NMR (DMSO-d6, 400.13 MHz): d = 9.67 (1H, d,
4
3J = 7.5 Hz, NH), 8.62 (1H, d, J = 2.1 Hz, H-20), 8.23
3
4
(1H, dd, J = 8.4 Hz, J = 2.1 Hz, H-60), 8.00 (1H, dd,
3J = 8.9 Hz, JF-H = 4.9 Hz, H-4), 8.02 (2H, m, H-7,
H-50), 7.37 (1H, dt, 4J = 2.7 Hz, 3J = 9.1 Hz, JF-H
4
3
=
9.1 Hz, H-5), 5.53 (1H, quint, 3J = 7.2 Hz, H-1), 1.70 (3H,
d, 3J = 7.2 Hz, H-2); 13C NMR (DMSO-d6, 100.62 MHz):
d = 175.0 (C, d, 4JF-C = 3.1 Hz, C-9), 163.3 (C=O), 159.5
(C, d, 1JF-C = 242.4 Hz, C-6), 149.6 (C, d, 5JF-C = 1.7 Hz,
3
C-3), 147.3 (C, C-30), 135.7 (C, d, JF-C = 11.7 Hz, C-8),
133.6 (C, C-10), 132.7 (CH, C-60), 132.2 (CH, C-50), 128.4
(C, C-40), 124.7 (CH, C-20), 123.8 (CH, d, 3JF-C = 9.6 Hz,
2
C-4), 114.7 (CH, d, JF-C = 24.9 Hz, C-5), 108.7 (CH, d,
2JF-C = 27.2 Hz, C-7), 48.3 (CH, C-1, 19.8 (CH3, C-2);
19F NMR (DMSO-d6, 376.46 MHz): d = -116.4;
Anal. Calcd. C16H11ClFN3O3S (379.79) C, 50.60; H, 2.92;
N, 11.06; S, 8.44. Found: C, 50.74; H, 2.88; N, 11.15; S,
8.35.
Crystallographic details
The X-ray data for colorless crystals of compounds 3b, 3f
and 3i were obtained at 150 K using Oxford Cryostream
123

Med Chem Res
8270) and C. tropicalis (CCM 8268) in Sabouraud’s dex-
trose agar medium (S3306 Fluka). Preparation of nutrient
broth, dilution and application were carried out using the
some procedure as for antimicrobial testing. The Petri
dishes were incubated at 30 °C for 48 h.
were confirmed by optical rotation measurements. The
structures of compounds 3b, 3f and 3i were determined by
single-crystal X-ray diffraction. The IR spectral peaks of
compounds 3a–m were recognized for C=O of CONH from
1628 to 1645 and NH of CONH from 1525 to 1539 and from
3237 to 3284 cm-1.1H NMR spectra of compounds 3a–
m showed the presence CONH amide proton peaks as dou-
blets due to coupling to CH group. The signal for CH group
bound to amide function appears as a quintet due to the
interaction with CH3 group and CONH protons. The assign-
Result and discussion
Chemistry
1
ment and numbering of H NMR shifts are illustrated in
Schemes 4 and 5 and given in experimental section. The 13
C
The starting compound (R)-1-(6-fluorobenzo[d]thiazol-2-
yl)ethanamine 2 was prepared as the corresponding p-tolue-
nesulfonate salt (PTS) according to Scheme 4 (Hijikata,
2003; Pejchal et al., 2011a). (4R)-4-Methyl-1,3-oxazolidine-
2,5-dione 1 was prepared by reaction of D-alanine with
phosgene in THF according reported method (Blacklock
et al., 1988); (1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethana-
mine p-toluenesulfonic salt 2 was prepared by three-step
process (Scheme 4). Compound 1 reacted with water solution
of potassium hydroxide in the first step to give 2-aminoben-
zothiol potassium salt, which reacted with compound 1 in the
second step to give hydrochloride of 2. Product 2 p-toluene-
sulfonic salt was prepared by reaction of hydrochloride of 2
with p-toluenesulfonic acid in water. The synthesis of sub-
stituted 6-fluorobenzo[d]thiazole amides 3a–m was carried
out according to Scheme 5. The desired compounds 3a–
m were synthesized in mixture toluene–water, where the
starting (R)-1-(6-fluorobenzo[d]thiazol-2-yl)ethanamine lib-
erated from its p-toluene sulfonate salt subsequently reacts
with corresponding aroyl chlorides in reaction mixture using
an aqueous solution of sodium hydroxide. Reaction of sub-
stituted aroyl chlorides with in situ liberated amine (from 2)
form target molecules 3a–m (Scheme 5). Toluene layer was
warmed to 70 °C in order to dissolve product formed. Prod-
ucts were precipitated by cooling of the separated and con-
centrated toluene solution. Products were isolated by filtration
in high yields 80 %–90 %. Compounds 3a–m were charac-
terized by melting points, IR, 1H NMR, 13C NMR, 19F NMR
spectra and elemental analyses (CHN). The optical activities
NMR spectra display two peaks in the alkyl region indicating
the presence of the CH3–CH– group. Other seven peaks
appearing as doublets (split by coupling with 19F nuclei) were
found in the aromatic part of spectra and assigned to substi-
tuted benzothiazole group. The rest of signals in the aromatic
part are due to substituted phenyl groups. The optical rotation
measurements were performed in acetone (c = 1).
Crystallography
The benzothiazole motif is also quite popular from the
point of view of high number of crystal structures
(* 1500) determined up to now, while the number of
related structures to that particular work is limited to a
couple of tens (Kello et al., 1986; Brandenburg et al.,
1987). Taking into the account the substitution of carbon
atom in the position 2 of the benzothiazole ring by a
methine group or an ipso carbon directly connected to an
aliphatic amine, only four crystal structures is selected for a
direct comparison (Pindinelli et al., 2007; Zhang and Zhao,
2009; Pejchal et al., 2011; Karagiannidis et al., 2011). All
three compounds under crystallographic investigation, 3b,
3f and 3i, crystallize in the chiral P21 or P212121 space
groups in monoclinic or orthorhombic crystal systems as
R-isomers with the central chirality at C2 atoms. In all
structures, the intermolecular H-bond between the carbonyl
and N–H groups form the supramolecular 2D linear wires.
Moreover, in the structure of 3f, relatively strong
Scheme 4 Synthetic route to
compound 2
123

Med Chem Res
Scheme 5 Synthetic route to
compound 3
intramolecular contact from N–H group to the methoxy
substituent of the phenyl ring delimits the orientation of
whole benzothiazole substituent and is most probably
responsible for the short contact of sulfur atom and the
˚
oxygen of the carbonyl group being 3.179 (4) A. All
compounds reveal a high degree of p-electron cloud
delocalization (Figs. 1, 2, 3), including the amido groups
where the interatomic distances and angles are comparable
to the literature parameters found for amides and peptides
¨
(Pyykko and Atsumi, 2009a, b). In particular, in the case of
the substitution pattern and interatomic distances and
angles within the pendant, aminomethine group seems to
be almost identical (Pejchal et al., 2011b).
Fig. 2 Molecular structure (ORTEP 50 % probability level) of
compound 3f, only one of two independent molecules is shown.
Selected interatomic distances (A) and bond angles (°): N1 C1 1.348
˚
(2), N1 C2 1.464 (2), O1 C1 1.232 (2), C11 C1 1.498 (3), C3 C2 1.519
(2), C10 C2 1.518 (2), N2 C3 1.284 (2), S1 C3 1.7618 (18), N2 C4
1.400 (2), S1 C5 1.7317 (19).C1 N1 C2 120.72 (14), O1 C1 N1 122.26
(16), N1 C1 C11 117.19 (15), O1 C1 C11 120.37 (16), C16 C11 C12
118.68 (17), C12 C11 C1 125.32 (16), N1 C2 C3 108.83 (14), N1 C2
C10 111.11 (14), C2 C3 S1 118.61 (12), N2 C3 C2 125.23 (16), C2 C3
S1 118.61 (12), N2 C3 S1 116.12 (14), C5 S1 C3 88.67 (9)
Antimicrobial activities
All the compounds have been screened for antibacterial
and antifungal activities using twofold serial dilution
method (for results, see Tables 1, 2). Chloramphenicol,
Fig. 3 Molecular structure (ORTEP 50 % probability level) of
compound 3i, only one of two independent molecules is shown.
Selected interatomic distances (A) and bond angles (°): N1 C1 1.340
Fig. 1 Molecular structure (ORTEP 50 % probability level) of
compound 3b, only one of two independent molecules is shown.
Selected interatomic distances (A) and bond angles (°): N1 C1 1.325
˚
˚
(3), N1 C2 1.457 (3), O1 C1 1.231 (3), C1 C11 1.467 (4), C3 C2 1.504
(4), C2 C10 1.521 (4), N2 C3 1.301 (3), S1 C3 1.751 (3), N2 C4 1.399
(3), S1 C5 1.724 (3), C1 N1 C2 122.7 (2), O1 C1 N1 123.5 (2), N1 C1
C11 114.7 (2), O1 C1 C11 121.8 (2), C14 C11 O2 113.9 (3), C14 C11
C1 129.2 (3), O2 C11 C1 116.7 (2), N1 C2 C3 108.4 (2), N1 C2 C10
112.1 (2), C2 C3 S1 119.44 (19), N2 C3 C2 124.2 (2), C2 C3 S1
119.44 (19), N2 C3 S1 116.4 (2), C5 S1 C3 88.98 (13)
(3), N1 C2 1.460 (3), C1 O1 1.227 (3), C1 C11 1.498 (4), C2 C3 1.508
(4), C2 C10 1.515 (4), N2 C3 1.296 (4), S1 C3 1.753 (3), N2 C4 1.388
(4), S1 C5 1.731 (3), C1 N1 C2 124.0 (2), O1 C1 N1 122.6 (3), N1 C1
C11 115.3 (2), O1 C1 C11 122.0 (3), C12 C11 C16 117.1 (3), C12
C11 C1 123.5 (2), N1 C2 C3 108.0 (2), N1 C2 C10 111.6 (2), C2 C3
S1 118.6 (2), N2 C3 C2 125.4 (3), C2 C3 S1 118.6 (2), N2 C3 S1
116.0 (2), C5 S1 C3 88.71 (13)
123

Med Chem Res
Table 1 Antimicrobial activities of the compounds 3a–m (bacterial strains)
Compounds
Minimum inhibitory concentration (lg/ml)
Enterobacter Escherichia Proteus Pseudomonas Enterococcus Staphylococcus Staphylococcus Stahylococcus
cloacae
CCM 1903
coli CCM
3954
mirabilis aeruginosa
CCM
7188
faecalis CCM aureus CCM
4224
aureus CCM
4223
epidermidis
CCM 4418
CCM 3955
4222
Gram-negative
Gram-positive
3a
3b
3c
3d
3e
3f
50.00
[200
[200
[200
[200
100.00
[200
[200
[200
[200
[200
[200
[200
[200
50.00
[200
[200
[200
[200
[200
100.00
[200
[200
[200
[200
50.00
6.25
50.00
[200
[200
[200
[200
50.00
[200
[200
[200
100.00
[200
[200
50.00
50.00
12.50
[200
[200
[200
[200
[200
[200
100.00
[200
[200
[200
[200
[200
50.00
[200
[200
[200
[200
[200
[200
[200
[200
[200
[200
[200
[200
[200
[200
[200
[200
6.25
[200
50.00
[200
[200
[200
[200
[200
[200
[200
[200
[200
[200
50.00
6.25
[200
50.00
[200
[200
[200
12.50
50.00
[200
[200
[200
[200
[200
50.00
[200
6.25
50.00
[200
[200
[200
[200
[200
50.00
50.00
[200
[200
50.00
[200
6.25
3g
3h
3i
3j
3k
3l
3m
Chloramphenicol [200
Cefoperazone 6.25
50.00
50.00
12.50
12.50
Table 2 Antimicrobial activities of the compounds 3a–m (fungal strains)
Compounds
Minimum inhibitory concentration (lg/ml)
Candida albicans
CCM 8311
Candida glabrata
CCM 8270
Candida tropicalis
CCM 8268
3a
[200
[200
[200
[200
25.00
[200
50.00
50.00
50.00
25.00
[200
[200
50.00
50
[200
[200
[200
50.00
50.00
[200
25.00
[200
50.00
[200
100.00
[200
[200
100
[200
[200
[200
[200
100
3b
3c
3d
3e
3f
[200
50.00
[200
[200
[200
50.00
[200
50.00
50
3g
3h
3i
3j
3k
3l
3m
Amphotericin B
cefoperazone and amphotericin B were used as compara-
tive standard drugs under the same protocol. All com-
pounds were screened for antibacterial activity against
gram-positive bacterial strains S. aureus (CCM 4222), S.
aureus (CCM 4223), S. epidermidis (CCM 4418) and E.
faecalis (CCM 4224), and gram-negative bacterial strains
E. coli (CCM 3954), E. cloacae (CCM 1903), P. mirabilis
(CCM 7188) and P. aeruginosa (CCM 3955) in Mueller–
Hinton agar medium and for antifungal activity against C.
albicans (CCM 8311), C. glabrata (CCM 8270) and C.
tropicalis (CCM 8268) in Sabouraud’s dextrose agar
medium. Compound 3m exhibited antibacterial activity
123

Med Chem Res
Table 3 Selected crystallographic data for compounds 3b, 3f and 3i
Compounds
3b
3f
3i
Empirical formula
Crystal system
Space group
C16H12Cl FN2OS
Monoclinic
P21
C17H15 FN2O2S
C14H11 FN2O2S
Monoclinic
Orthorhombic
P21
P212121
˚
a (A)
4.8960 (2)
10.7881 (7)
14.2110 (8)
90
5.1820 (3)
4.9400 (4)
˚
b (A)
11.1301 (4)
11.0531 (11)
˚
c (A)
13.4580 (7)
24.3780 (11)
a (°)
b (°)
c (°)
Z
90
90
95.909 (5)
90
100.482 (5)
90
90
90
2
2
4
3
˚
V (A )
746.62 (7)
1.489
763.25 (7)
1331.10 (18)
Dc (g cm-3
)
1.438
1.449
Crystal size (mm)
0.35 9 0.24 9 0.10
Block
0.58 9 018 9 0.16
0.59 9 0.27 9 0.14
Crystal shape
l (mm-1
F (000)
Block
Block
)
0.408
0.234
0.257
344
344
600
h; k; l range
h range (°)
Reflections measured
-6, 5; -14, 12; -18, 17
2.37–27.49
6227
-6, 6; -14, 14; -17, 14
-5, 6; -14, 13; -31, 29
2.39–27.50
6577
2.02–27.00
9993
a
Independent (Rint
)
2870 (0.0399)
2625
3350 (0.0305)
3184
2935 (0.0332)
2531
Observed [I [ 2r(I)]
Parameters refined
-3
199
208
181
˚
Max/min s (eA
)
0.228/-0.260
1.111
0.198/0.198
1.153
0.572/-0.313
1.110
GOFb
Rc/wRc
ꢀ
0.0373/0.0824
0.0294/0.0644
i
0.0464/0.1072
h
ꢀ
ꢀ
ꢀ
.
h
ꢁ
ꢂ.
1=2
À
Á
À
Á
À
Á
P
P
P
ꢀ
2
2
a
b
c
Rint
¼
F2 À F2
Fo2,
S ¼
w Fo2 À Fo2
Ndiffrs À Nparams
,
and weighting scheme: w ¼ r2 Fo2 þ ðw1PÞ þ
ꢀ
o
o;mean
Â
h ꢁ
ꢂ.ꢁ
ꢂi
1=2
À
Á
Ã
À
Á
À
Á
2
2
w2PŠÀ1, where P ¼ max Fc2 þ 2Fc2 , RðFÞ ¼ RjjFoj À jFcjj=jFoj, and wRðF2Þ ¼ R w Fo2 À Fc2
Rw Fo2
against all bacterial strains except of E. cloacae (CCM
1903) and E. faecalis (CCM 4224). Exceptionally, high
antibacterial activity has been observed for 3m against S.
epidermidis (CCM 4418) when compared with cefopera-
zone and chloramphenicol as currently used drugs. Com-
pounds 3a and 3f exhibited satisfactory antibacterial
activity against three strains of bacteria: E. cloacae (CCM
1903), P. aeruginosa (CCM 3955) and S. epidermidis
(CCM 4418). On the other hand, the activity of 3b covers
another three strains: E. coli (CCM 3954), S. aureus (CCM
4222) and S. aureus (CCM 4223). Compounds 3h and 3k
reveal selective and similarly high activity parameters,
when compared to the standards, against S. epidermidis
(CCM 4418) strain only. The bacterial strain E. faecalis
(CCM 4224) seems to be resistant against all compounds
tested.
opportunistic pathogen representing a serious threat to
immunocompromised individuals deserves a special focus
along with other fungal strains under investigation. As the
number of immunologically weakened patients increase,
opportunistic infections have become a widely recognized
public health problem (Diekema et al., 2012). In that
respect, 3m exhibited comparable antifungal activity
against C. albicans (CCM 8311) and C. tropicalis (CCM
8268) when amphotericin B is taken as a standard drug in
use. Compounds 3d and 3h were selectively active against
C. glabrata (CCM 8270) and C. albicans (CCM 8311),
respectively.
The investigation of structures–activities relationships in
the series of these species, based on current results, indi-
cated that some of synthesized derivatives exhibited sig-
nificant antimicrobial and antifungal activity: (1) The most
active compounds in particular antibacterial and antifungal
screening seem to be 3e, 3f, 3j and 3m, which is most
probably caused by the presence of electron-withdrawing
All tested fungal strains can be efficiently inhibited by
3e and 3g in contrast to 3a, 3b and 3c which exhibited no
antifungal activity in the studied series. C. albicans as an
123

Med Chem Res
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