One-pot multicomponent synthesis of indol-3-yl-hydrazinyl thiazoles as antimicrobial agents

Article abstract of DOI:10.1007/s11164-016-2478-y

A series of novel mono- and bis(indol-3-yl)hydrazinyl thiazole derivatives were efficiently synthesized via one-pot cyclocondensation of mono- or bis(indole-3-carbaldehyde), thiosemicarbazide, and phenacyl bromides. The structure of the products was confi

Full text of DOI:10.1007/s11164-016-2478-y

Res Chem Intermed
DOI 10.1007/s11164-016-2478-y
One-pot multicomponent synthesis of indol-3-yl-
hydrazinyl thiazoles as antimicrobial agents
Nosrat O. Mahmoodi1 Behzad Khalili1
•
•
Olia Rezaeianzade1 Atefeh Ghavidast1
•
Received: 31 October 2015 / Accepted: 5 February 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract A series of novel mono- and bis(indol-3-yl)hydrazinyl thiazole deriva-
tives were efficiently synthesized via one-pot cyclocondensation of mono- or
bis(indole-3-carbaldehyde), thiosemicarbazide, and phenacyl bromides. The struc-
ture of the products was confirmed by Fourier-transform infrared (FT-IR), 1H
nuclear magnetic resonance (NMR), and 13C NMR spectra. All synthesized com-
pounds were evaluated for in vitro antibacterial activity against Gram-positive
(Bacillus subtilis and Micrococcus luteus) and Gram-negative bacteria (Pseu-
domonas aeruginosa and Salmonella enteritis). Among the compounds screened, a
few were found to be highly effective antibacterial agents. The bis-compounds with
OCH3 donating group exhibited good activity against the Gram-positive bacteria.
Keywords Bisindole Á Thiazole Á Bisthiazole Á Vilsmeier reaction Á Antimicrobial
Introduction
Indole and its analogues represent one of the most important structural units,
exhibiting a wide spectrum of biological activities such as antimicrobial,
antiinflammatory, antifungal, insecticidal, anticancer, anti-human immunodefi-
ciency virus (HIV), and lipoxygenase inhibitor actions [1–3]. Incorporation of
indole with other heterocyclic moieties has resulted in versatile heterocyclic
Electronic supplementary material The online version of this article (doi:10.1007/s11164-016-2478-
y) contains supplementary material, which is available to authorized users.
&
Nosrat O. Mahmoodi
mahmoodi@guilan.ac.ir; nosmahmoodi@gmail.com
1
Department of Organic Chemistry, Faculty of Sciences, University of Guilan,
PO Box 41335-1914, Rasht, Iran
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N. O. Mahmoodi et al.
compounds possessing a wide variety of biological actions [4–10]. Similarly,
thiazole and its derivatives are very valuable compounds in various fields of
chemistry, including medicine and agriculture; For example, the presence of a
thiazole ring in vitamin B1 supplies an electron sink, and its coenzyme form is
important for decarboxylation of a-keto acids [11]. This heterocyclic system has
found broad applications in development of pharmacologically active compounds
for treatment of inflammation [12], hypertension [13], bacterial infection [14], HIV
infection [15], osteoporosis, and breast cancer [16].
Bis-heterocycles with appropriate linkage exhibit various biological properties
such as antitumor, antimicrobial, and enzyme inhibitory actions [17–22]. There has
recently been increased interest in bis-heterocyclic systems containing indole–
thiazole hybrids to identify new drug candidates. The exceptional interest in
heterocycles of this type is due to the fact that substances with greater biological
activity such as antibacterial and radioprotective properties have been found among
them [7, 23–28]. Because of this wide-ranging importance and following our
interest in design and synthesis of chemically and biologically active heterocycle
compounds [29–36], we decided to develop a route for synthesis of novel mono- and
bis(indol-3-yl)hydrazinyl thiazole derivatives and screened their antibacterial
activity.
Experimental
All chemicals and reagents were purchased from Merck and used without further
purification. NMR spectra were obtained in dimethyl sulfoxide (DMSO) on a
Bruker Avance spectrometer operating at 400 MHz (1H NMR) and 125 MHz (13C
NMR) with tetramethylsilane (TMS) as internal standard. FT-IR spectra of samples
were obtained using a Shimadzu FT-IR-8900 spectrophotometer from KBr pellets.
Melting points were determined with an Electrothermal model 9100 apparatus and
are uncorrected. Chemical shifts are reported in ppm (d) using deuterated solvents
as internal references. Elemental analysis was carried out using a Carlo-Erba
EA1110 CNNO-S analyzer and agreed with calculated values.
General procedure for synthesis of compounds 2–6
Compounds 2–6 were prepared according to reported method [35, 37].
General procedure for synthesis of mono- and bis(indol-3-yl)hydrazinyl
thiazole derivatives 10–18
Thiosemicarbazide 9 (0.09 g, 1 mmol), corresponding indole-3-carbaldehyde 1
(1 mmol), and 2–3 drops of AcOH were added to absolute EtOH (10 mL), and the
mixture was refluxed at 70 °C for 5 h. Reaction progress was monitored by thin-
layer chromatography (TLC, EtOAc:petroleum ether at 4:2). After formation of
intermediate, phenacyl bromide derivative 7, 8 (1 mmol) was then added into the
reaction mixture and reflux continued for another 2 h. The obtained precipitate was
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One-pot multicomponent synthesis of…
filtered, washed with cool water, dried in air, and washed with hot EtOH to afford
pure desired products 10, 11 without recrystallization. Bis(indol-3-yl)hydrazinyl
thiazoles 12–18 were prepared by a similar procedure using corresponding
bis(indole-3-carbaldehyde) 2–6 (0.5 mmol) instead of indole-3-carbaldehyde 1
(1 mmol) [37–41].
2-(2-((1H-Indol-3-yl)methylene)hydrazinyl)-4-phenylthiazole (10)
Brown powder, yield 89 % (0.28 g), m.p. 233–234 °C, FT-IR (KBr, t cm-1): 3430,
3053, 2935, 2834, 1663, 1607, 1569, 1461, 1247. H NMR (400 MHz, DMSO-d6):
1
d; 11.73 (br, 1H, NH-indole), 11.48 (br, 1H, NH-hydrazide), 8.27 (s, 1H, CH=N),
8.24 (brs, 1H, H-indole), 7.86 (d, J = 8.0 Hz, 2H, H-Ph), 7.75 (d, J = 1.6 Hz, 1H,
H-2 indole), 7.44 (d, J = 7.2 Hz, 1H, H-indole), 7.41 (t, J = 7.6 Hz, 2H, H-indole),
7.29 (t, J = 8.0 Hz, 1H, H-Ph), 7.25 (s, 1H, H-thiazol), 7.20 (t, J = 7.0 Hz, 2H,
H-Ph) ppm. 13C NMR (125 MHz, DMSO-d6): d; 164.21 (thiazole-C2), 150.9
(thiazole-C4), 143.6 (HC=N), 141.9, 139.2, 138.1, 134.1, 133.9, 132.8, 126.6, 122.7,
122.1, 121.9, 119.7, 112.3, 108.2 (thiazole-C5) ppm. Anal. calcd. for C18H14N4S
(318.39): C, 67.90; H, 4.43; N, 17.60; S, 10.07. Found: C, 67.52; H, 4.61; N, 17.72;
S, 10.32 ppm.
2-(2-((1H-Indol-3-yl)methylene)hydrazinyl)-4-(4-methoxyphenyl)thiazole
(11)
Dark-brown powder, yield 94 % (0.32 g), m.p. 242–243 °C, FT-IR (KBr, t cm-1):
1
3416, 3049, 2905, 1621, 1505, 1461, 1247. H NMR (400 MHz, DMSO-d6): d;
12.08 (br, 1H, NH-indole), 11.59 (br, 1H, NH-hydrazide), 8.34 (s, 1H, CH=N), 8.21
(d, J = 7.2 Hz, 1H, H-indole), 7.81 (d, J = 2.4 Hz, 1H, H-2 indole), 7.76 (d,
J = 8.8 Hz, 2H, H-Ar), 7.45 (d, J = 7.6 Hz, 1H, H-indole), 7.22 (t, J = 7.6 Hz,
1H, H-indole), 7.18 (t, J = 7.0 Hz, 1H, H-indole), 7.13 (s, 1H, H-thiazol), 6.98 (d,
J = 8.8 Hz, 2H, H-Ar), 3.79 (s, 3H, OCH3) ppm. 13C NMR (125 MHz, DMSO-d6):
d; 172.1 (thiazole-C2), 161.0, 155.4, 148.7 (thiazole-C4), 145.1 (HC=N), 139.6,
132.2, 128.5, 126.2, 123.3, 122.9, 120.8, 120.4, 116.4, 111.4, 109.4 (thiazole-C5),
56.8 (OCH3) ppm. Anal. calcd. for C19H16N4OS (348.32): C, 65.50; H, 4.63; N,
16.08; S, 9.20. Found: C, 65.38; H, 4.53; N, 16.22; S, 9.11.
1,4-Bis(3-(-(2-(4-phenylthiazol-2-yl)hydrazono)methyl)-1H-indol-1-
yl)butane (12)
Brown powder, yield 83 % (0.57 g), m.p. 244–245 °C, FT-IR (KBr, t cm-1): 3069,
2939, 2858, 2760, 1681, 1594, 1460, 1389, 1293, 1245, 759. H NMR (400 MHz,
1
DMSO-d6): d; 11.59 (br, 2H, NH-hydrazide), 8.24 (d, J = 7.2 Hz, 2H, H-indole),
8.22 (s, 2H, CH=N), 7.85 (d, J = 7.2 Hz, 4H, H-Ph), 7.76 (s, 2H, H-2 indole), 7.52
(d, J = 7.2 Hz, 2H, H-indole), 7.40 (t, J = 7.6 Hz, 4H, H-indole), 7.29 (t,
J = 7.4 Hz, 2H, H-Ph), 7.26 (s, 2H, H-thiazol), 7.21 (t, J = 6.8 Hz, 4H, H-Ph),
4.21 (br, 4H, NCH2), 1.77 (br, 4H, CH2) ppm. 13C NMR (125 MHz, DMSO-d6): d;
169.7 (thiazole-C2), 150.9 (thiazole-C4), 144.5 (HC=N), 142.2, 140.1, 139.0, 138.4,
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N. O. Mahmoodi et al.
138.2, 134.5, 133.1, 126.0, 125.2, 124.1, 122.8, 111.2, 108.4 (thiazole-C5), 46.3 (-
CH2N), 28.1 ppm. Found: C, 69.19; H, 4.48; N, 16.61; S, 9.31. Anal. calcd. for
C40H34N8S2 (690.88): C, 69.54; H, 4.96; N, 16.22; S, 9.28.
1,4-Bis(3-((2-(4-argiothiazol-2-yl)hydrazono)methyl)-1H-indol-1-yl)butane
(13)
Dark-brown powder, yield 87 % (0.65 g), m.p. 242–243 °C, FT-IR (KBr, t cm-1):
3430, 3053, 2935, 2834, 1663, 1607, 1569, 1461, 1247. 1H NMR (400 MHz,
DMSO-d6): d11.47 (br, 2H, NH-hydrazide), 8.23 (d, J = 7.6 Hz, 2H, H-indole),
8.20 (s, 2H, CH=N), 7.78 (d, J = 8.4 Hz, 4H, H-Ar), 7.75 (s, 2H, H-2 indole), 7.51
(d, J = 8.0 Hz, 2H, H-indole), 7.25 (t, J = 7.6 Hz, 4H, H-indole), 7.21 (t,
J = 7.4 Hz, 2H, H-indole), 7.08 (s, 2H, H-thiazol), 6.95 (d, J = 8.4 Hz, 4H, H-Ar),
4.20 (br, 4H, NCH2), 3.78 (s, 6H, OCH3), 1.76 (br, 4H, CH2) ppm. 13C NMR
(125 MHz, DMSO-d6): d; 171.9 (thiazole-C2), 161.3, 154.9, 148.2 (thiazole-C4),
145.3 (HC=N), 140.2, 138.2, 137.3, 128.3, 125.9, 124.6, 123.5, 122.7, 117.1, 110.2,
109.5 (thiazole-C5), 55.8 (OCH3), 47.06 (–CH2N), 27.49 ppm. Found: C, 67.24; H,
5.32; N, 14.51; S, 8.43. Anal. calcd. for C42H38N8O2S2 (750.93): C, 67.18; H, 5.10;
N, 14.92; S, 8.54.
1,4-Bis(3-((2-(4-argiothiazol-2-yl)hydrazono)methyl)-2-methyl-1H-indol-1-
yl)butane (14)
Dark-brown powder, yield 75 % (0.58 g), m.p. 182–184 °C, FT-IR (KBr, t cm-1):
3388, 3183, 3056, 2930, 2860, 1661, 1570, 1431, 1340. 1H NMR (400 MHz,
DMSO-d6): d; 11.59 (br, 2H, NH-hydrazide), 8.30 (s, 2H, CH=N), 8.17 (d,
J = 8.8 Hz, 3H, H-indole), 7.78 (d, J = 8.4 Hz, 4H, H-Ar), 7.47 (d, J = 7.2 Hz,
2H, H-indole), 7.16–7.20 (m, 4H, H-indole), 7.07 (s, 2H, H-thiazol), 6.95 (d,
J = 8.8 Hz, 4H, H-Ar), 4.19 (br, 4H, NCH2), 3.79 (s, 6H, OCH3), 2.58 (s, 6H, CH3),
1.76 (br, 4H, CH2) ppm. 13C NMR (125 MHz, DMSO-d6): d; 171.1 (thiazole-C2),
160.2, 152.7, 148.0 (thiazole-C4), 142.9 (HC=N), 135.3, 128.2, 127.2, 126.4, 124.7,
122.9, 121.2, 116.2, 113.1, 112.9, 109.3 (thiazole-C5), 56.7 (OCH3), 12.6; 31.2 (–
CH2N), 26.8 ppm. Found: C, 67.34; H, 5.42; N, 14.31; S, 8.11. Anal. calcd. for
C44H42N8O2S2 (778.98): C, 67.84; H, 5.43; N, 14.38; S, 8.23.
1,5-Bis(3-((2-(4-argiothiazol-2-yl)hydrazono)methyl)-1H-indol-1-yl)pentane
(15)
Brown powder, yield 82 % (0.62 g), m.p. 198–201 °C, FT-IR (KBr, t cm-1): 3409,
3053, 2931, 1619, 1501, 1300, 1178. 1H NMR (400 MHz, DMSO-d6): d; 11.95 (br,
2H, NH-hydrazide), 8.30 (s, 2H, CH=N), 8.21 (d, J = 7.6 Hz, 2H, H-indole), 7.77
(s, 2H, H-2 indole), 7.75 (d, J = 8.8 Hz, 4H, H-Ar), 7.52 (d, J = 8.0 Hz, 2H,
H-indole), 7.27 (t, J = 7.6 Hz, 2H, H-indole), 7.22 (t, J = 8.2 Hz, 2H, H-indole),
7.11 (s, 2H, H-thiazol), 6.98 (d, J = 8.8 Hz, 4H, H-Ar), 4.17 (t, J = 6.8 Hz, 4H,
NCH2), 3.79 (s, 6H, OCH3), 1.80 (q, J = 7.2 Hz, 4H, CH2), 1.33 (br, 2H, CH2)
ppm. 13C NMR (125 MHz, DMSO-d6): d; 171.8 (thiazole-C2), 161.5, 154.3, 147.5
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One-pot multicomponent synthesis of…
(thiazole-C4), 145.2 (HC=N), 139.9, 139.0, 137.3, 128.4, 125.4, 124.1, 122.9, 122.1,
117.1, 110.4, 109.5 (thiazole-C5), 56.8 (OCH3), 47.0 (-CH2N), 29.4, 24.2 ppm.
Found: C, 67.46; H, 5.24; N, 14.22; S, 8.41. Anal. calcd. for C43H40N8O2S2
(764.96): C, 67.51; H, 5.27; N, 14.65; S, 8.38.
1,6-Bis(3-((2-(4-phenylthiazol-2-yl)hydrazono)methyl)-1H-indol-1-
yl)hexane (16)
Pale-brown powder, yield 82 % (0.58 g), m.p. 224–225 °C, FT-IR (KBr, t cm-1):
3388, 3183, 3056, 2930, 2860, 1616, 1570, 1431, 1340. 1H NMR (400 MHz,
DMSO-d6): d; 11.69 (br, 2H, NH-hydrazide), 8.24 (d, J = 7.6 Hz, 2H, H-indole),
8.23 (s, 2H, HC=CN), 7.87 (d, J = 7.2 Hz, 4H, H-Ph), 7.75 (s, 2H, H-2 indole),
7.49 (d, J = 8.0 Hz, 2H, H-indole), 7.40 (t, J = 6.7 Hz, 4H, H-indole), 7.29 (t,
J = 8.0 Hz, 2H, H-Ph), 7.26 (s, 2H, H-thiazol), 7.20 (t, J = 7.6 Hz, 4H, H-Ph),
4.14 (t, J = 6.8 Hz, 4H, NCH2), 1.74 (br, 4H, CH2), 1.26 (br, 4H, CH2) ppm. 13C
NMR (125 MHz, DMSO-d6): d; 169.8 (thiazole-C2), 150.9 (thiazole-C4), 144.3
(HC=N), 142.5, 141.8, 141.3, 139.1, 138.2, 134.7, 133.6, 126.1, 125.0, 124.7, 122.3,
112.1, 108.2 (thiazole-C5), 46.9 (–CH2N), 29.8, 27.2 ppm. Found: C, 70.11; H,
5.23; N, 15.63; S, 9.11. Anal. calcd. for C42H38N8S2 (718.93): C, 70.17; H, 5.33; N,
15.59; S, 8.92.
1,6-Bis(3-((2-(4-argiothiazol-2-yl)hydrazono)methyl)-1H-indol-1-yl)hexane
(17)
Brown powder, yield 85 % (0.66 g), m.p. 228–229 °C, FT-IR (KBr, t cm-1): 3416,
3052, 2934, 1617, 1570, 1464, 1250. 1H NMR (400 MHz, DMSO-d6): d; 11.70 (br,
2H, NH-hydrazide), 8.24 (d, J = 8.0 Hz, 2H, H-indole), 8.22 (s, 2H, HC=N), 7.77
(d, J = 8.4 Hz, 4H, H-Ar), 7.74 (s, 2H, H-2 indole), 7.48 (d, J = 8.0 Hz, 2H,
H-indole), 7.22 (t, J = 8.6 Hz, 2H, H-indole), 7.20 (t, J = 7.6 Hz, 2H, H-indole),
7.08 (s, 2H, H-thiazol), 6.95 (d, J = 8.8 Hz, 4H, H-Ar), 4.14 (t, J = 6.6 Hz, 4H,
NCH2), 3.73 (s, 6H, OCH3), 1.73 (br, 4H, CH2), 1.25 (br, 4H, CH2) ppm. 13C NMR
(125 MHz, DMSO-d6): d; 172.2 (thiazole-C2), 161.7, 153.7, 148.8 (thiazole-C4),
145.6 (HC=N), 141.6, 141.1, 137.8, 128.4, 125.5, 124.3, 123.2, 121.9, 117.3, 111.8,
109.4 (thiazole-C5), 56.8 (OCH3), 47.0 (–CH2N), 29.9, 26.4 ppm. Found: C, 67.60;
H, 5.51; N, 14.42; S, 8.16. Anal. calcd. for C44H42N8O2S2 (778.98): C, 67.84; H,
5.43; N, 14.38; S, 8.23.
1,4-Bis((3-((2-(4-argiothiazol-2-yl)hydrazono)methyl)-1H-indol-1-
yl)methyl)benzene (18)
Dark-brown powder, yield 76 % (0.60 g), m.p. 265–266 °C, FT-IR (KBr, t cm-1):
3417, 3183, 2928, 1628, 1529, 1464. 1H NMR (400 MHz, DMSO-d6): d; 11.78 (br,
2H, NH-hydrazide), 8.24 (d, J = 5.6 Hz, 2H, H-indole), 8.21 (s, 2H, HC=CN), 7.88
(s, 2H, H-2 indole), 7.78 (d, J = 8.4 Hz, 4H, H-Ar), 7.65 (d, J = 8.0 Hz, 2H,
H-indole), 7.45–7.49 (m, 4H, H-indole), 7.20 (s, 4H, H-Ph), 7.09 (s, 2H, H-thiazol),
6.95 (d, J = 8.8 Hz, 4H, H-Ar), 5.40 (s, 4H, NCH2), 3.78 (s, 6H, OCH3) ppm. 13C
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N. O. Mahmoodi et al.
NMR (125 MHz, DMSO-d6): d; 170.9 (thiazole-C2), 161.1, 154.2, 149.2 (thiazole-
C4), 145.0 (HC=N), 141.7, 138.2, 137.8, 137.2, 126.6, 128.2, 125.6, 124.5, 123.4,
121.9, 116.1, 112.2, 109.1 (thiazole-C5), 56.7 (OCH3), 50.29 ppm. Found: C, 69.24;
H, 4.65; N, 14.12; S, 7.87. Anal. calcd. for C46H38N8O2S2 (798.97): C, 69.15; H,
4.79; N, 14.02; S, 8.03.
Determination of antibacterial activity
A colony of each standard test organism was subcultured to obtain fresh bacteria on
nutrient agar plates at 37 °C for 18 h. To prepare microorganism suspensions (0.5
McFarland), one to two colonies from each plate was dissolved in isotonic saline
solution. Mu¨ller–Hinton agar (Merck) plates were prepared according to manufac-
turer instructions to evaluate the antibacterial activity of the compounds. Sterile
Mu¨ller–Hinton agar plates were inoculated with bacteria. Test sample (0.01 g) was
dissolved in 1 mL dimethyl sulfoxide (DMSO) to obtain stock solution. A
concentration of 100 lg/0.1 mL of each sample was prepared. Prepared sample
(0.1 mL) was dropped into each respective labeled well aseptically. The inoculated
plates were left on the table for 1 h to allow each sample to diffuse into the agar. For
comparison, erythromycin and tetracycline were used as positive control and DMSO
as negative control. The plates were incubated overnight at 37 °C, and zones of
inhibition were measured in millimeters. All tests were performed in triplicate with
the average taken as the final reading. Bacterial strains isolated from clinical
specimens were used in the study and were chosen because of their ready
availability in our school.
Results and discussion
Following our previous efforts towards design and synthesis of mono- and bis-
heterocyclic compounds [29–36], we report herein an efficient one-pot method for
synthesis of mono- and bis(indol-3-yl)hydrazinyl thiazole derivatives via three- and
five-component reactions (3&5-CRs) (Scheme 1). In this effort, the reaction of one
equivalent of indole-3-carbaldehyde 1 or half-equivalent of bisaldehydes 2–6 with
one equivalent of phenacyl bromides 7, 8, thiosemicarbazide 9, and a few drops of
AcOH in EtOH at reflux temperature afforded the desired compounds 10–18 in
good yields [37–41]. To determine the optimal conditions, initially the reaction of
indole-3-carbaldehyde 1, thiosemicarbazide 9, and phenacyl bromide 7 was carried
out in either absolute EtOH or EtOH with catalytic amount of AcOH at reflux
condition. In absolute EtOH, after 12 h, only 55 % yield was obtained, but in EtOH
with catalytic amount of AcOH, 89 % yield was recovered within 7 h. Synthesis of
bisaldehydes 2–6 was carried out according to our reported method by applying
bisalkylation and Vilsmeier–Haack reaction [35, 37].
The structures of the substituted mono- and bishydrazinyl thiazole derivatives
10–18 were confirmed by FT-IR, 1H NMR, 13C NMR, and elemental analysis. The
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One-pot multicomponent synthesis of…
Scheme 1 Synthesis of mono- and bis(indol-3-yl)hydrazinyl thiazole derivatives 10–18
FT-IR spectra of 10–18 revealed three absorption bands at about 3280–3295,
1615–1635, and 1580–1605 cm-1, which were assigned to NH, C=N, and Ar–C=C,
respectively. Also, the absence of C=S stretching band proves that the expected
cyclization occurred. The 1H NMR spectra of 10–18 revealed a thiazole ring proton
as singlet signal between 7.07 and 7.26 ppm. The singlet around 8.20–8.34 ppm is
assigned to azomethine proton (CH=N). The signals of the H-2 proton of the indole
ring appeared as a doublet at 7.75 and 7.81 ppm with 3J = 2 Hz for mono-
derivatives 10, 11 and as a singlet signal for bis-derivatives 12, 14–18 at
7.74–7.88 ppm. The NH protons of indole and hydrazide for mono-derivatives 10,
11 appeared in the region of 11.73–12.08 ppm and 11.48–11.59 ppm, respectively,
and NH proton of hydrazide for bis-derivatives 12–18 in the region of
11.47–11.95 ppm. The NH proton of hydrazide shifted downfield, close to that
found in similar structures [42–44], compared with endocyclic-NH [45].
The 1H NMR spectrum of 15 in Fig. 1 is symmetrical and rather simple,
revealing a thiazole ring proton Hk at 7.11 ppm, Hi at 8.30 ppm, and Haliphatic a-c,n
and Haromatic d-g and m,l as expected. Additional support for the structures of 10–18
was provided by 13C NMR spectra, which exhibited signals at dc 108.2–109.5,
143.6–145.6, 147.5–150.9, and 164.3–172.2 ppm, corresponding to thiazole-C5,
HC=N, thiazole-C4, and thiazole-C2, respectively. These results are in agreement
with the proposed structures. Geometrical isomerism (E and Z) is possible because
of restricted rotation about the exocyclic C=N bond of the hydrazinyl thiazoles. All
the derivatives prepared in this study can exist in E-form by comparison with known
analogues [42, 43, 46, 47]. In addition, Gaussian [B3LYP/6-311 ? G(d,p)]
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N. O. Mahmoodi et al.
Fig. 1 1H NMR spectrum of 15
geometry optimization calculations indicated the E-form as the more stable isomer
in comparison with Z-form for 13 (2.60 kcal/mol) and 14 (4.02 kcal/mol).
Antibacterial activity
The in vitro antibacterial activity of compounds 10–18 was evaluated against Gram-
positive and Gram-negative bacteria using cultures of four different standard
microorganisms: Pseudomonas aeruginosa (PS) and Salmonella enteritis (SE) as
Gram-negative models and Bacillus subtilis (BS) and Micrococcus luteus (ML) as
Gram-positive models. The results of preliminary antibacterial testing of the
compounds are reported as zone of inhibition in Table 1.
The results of the antibacterial studies revealed that compounds 10–18 did not
show antibacterial activity against PS. Compounds 12 and 16 were inactive against
all the species of bacteria, whereas compounds 13–15, 17 were inactive against
Gram-negative bacteria. Among the derivatives, the p-OCH3 derivatives exhibited
potent antibacterial activity. Compared with the standards erythromycin and
tetracycline, compounds 10, 11, 18 exhibited high activity against all tested strains
except PS, while compound 15 exhibited high activity against ML and BS. Also,
compounds 17 and 14 exhibited high activity against BS and ML, respectively, and
compound 13 was moderately active against BS. Compound 18, carrying benzyl
linkage, showed the best results as compared with the other bis derivatives, with
favorable antibacterial activity.
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One-pot multicomponent synthesis of…
Table 1 Antimicrobial activity of compounds 10–18
Compound
Yield Conc. in Antimicrobial
DMSO activity (zone of
(lg per inhibition in mm)
0.1 mL)
PS SE BS ML
89
94
83
100
100
100
–
–
–
13 11 17
22 12 15
–
–
–
–
–
87
75
100
100
–
–
10
–
–
18
82
82
100
100
–
–
–
–
10 12
–
–
85
86
100
100
–
–
–
13
–
10
9
16
123

N. O. Mahmoodi et al.
Table 1 continued
Compound
Yield Conc. in Antimicrobial
DMSO activity (zone of
(lg per inhibition in mm)
0.1 mL)
PS SE BS ML
Erythromycin
Tetracycline
DMSO
100
100
100
10
18
–
8
7
12 10
14 16
–
–
–
Structure–activity relationship (SAR)
Structure–activity study showed that the antibacterial inhibition exhibited by the
newly synthesized compounds depended on the substituents on the thiazole ring
and the influence of different linkages. The in vitro antibacterial screening
results showed that the thiazoles carrying electron-donating OCH3 substituent
exhibited better activity as compared with the other derivatives. Furthermore,
SAR study revealed that presence of OCH3 substituent on thiazole ring of
bisalkyl derivatives was necessary for inhibitory antibacterial results, the
antibacterial activity of the bis compounds 13, 14, 15, 17, 18 against Gram-
positive bacteria improved in the presence of electron-donating group OCH3,
while they were not sensitive to 12 or 16. The antibacterial screening results also
revealed the role of the linkage, indicating that presence of benzyl linkage
increased the inhibitory activity compared with other compounds in the same
series. The bis derivative 18 with benzyl linkage showed high activity against
SE, revealing a significant influence of the benzyl linkage on the antimicrobial
properties. Also, it seems that alkyl linkage with higher n, leading to greater
distance between the indole groups, can yield better results, maybe due to less
steric hindrance. However, the effect of the substituents on thiazole ring should
not be ignored [29].
In general, Gram-negative bacteria are more resistant than Gram-positive ones,
due to the presence of a two-layered phospholipid membrane as a barrier to efficient
attachment of chemicals to the bacterial surface, whereas Gram-positive bacteria
have one layer. PS is one of the most resistant bacteria in Nature. As seen from
Table 1, BS and ML were generally more sensitive than the two Gram-negative
isolates. However, mono-derivatives exhibited strong activity towards SE, BS, and
ML, which could be due to greater solubility in the phospholipid layer and thus
greater penetration compared with bis derivatives, resulting in a more favorable
effect being observed.
Indolyl thiazoles have also demonstrated powerful cytotoxic effects in vitro
against growth of a wide variety of human tumor cell lines [7, 48], motivating us to
investigate the cytotoxic profiles of these newly synthesized compounds in detail.
Recently, we screened several hydrazinyl thiazole derivatives for their in vitro
antibacterial activity against six strains of bacteria including Staphylococcus aureus,
ML, PS, BS, Escherichia coli, and Aeromonas hydrophila. Some products showed
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One-pot multicomponent synthesis of…
anticancer activity against melanoma cancer cell line A375 with LC50 = 0.55 mg/
mL, slightly selective versus normal cell line (Hu-2) with LC50 = 1.19 mg/mL
[49].
Conclusions
We present an efficient method for one-pot synthesis of novel mono- and bis(indol-
3-yl)hydrazinyl thiazole derivatives in good yields. The compounds are well
characterized by various spectroscopic methods. All synthesized compounds were
investigated for their in vitro antibacterial activity. Among the newly prepared bis-
derivatives, the highest antibacterial activity was found for compound 18 against
SE, BS, and ML, 15 against ML and BS, 17 against BS, and 14 against ML.
Structure–activity relationship study of the bisalkyl derivatives revealed that
substitution of thiazoles with electron-donating OCH3 was necessary for inhibitory
antibacterial results. Also, for bis-derivatives, presence of benzyl linkage increased
the inhibitory activity compared with alkyl linkage. However, mono-derivatives 10,
11 exhibited strong activity towards both Gram-positive and Gram-negative
bacteria.
Acknowledgments This study was supported in part by the Research Committee of the University of
Guilan.
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