Synthesis, antimicrobial and in vitro antitumor activities of a series of 1,2,3-thiadiazole and 1,2,3-selenadiazole derivatives

Article abstract of DOI:10.2147/DDDT.S86054

Three derivatives of substituted 1,2,3-thia- or 1,2,3-selenadiazole (4ac) were prepared and characterized by different chemical techniques. These compounds were evaluated for their antimicrobial and antitumor activities. Compounds 4a (propenoxide derivati

Full text of DOI:10.2147/DDDT.S86054

Drug Design, Development and erapy
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O r i g i n a l r e s e a r c h
synthesis, antimicrobial and in vitro antitumor
activities of a series of 1,2,3-thiadiazole and
1,2,3-selenadiazole derivatives
This article was published in the following Dove Press journal:
Drug Design, Development andTherapy
16 July 2015
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nizar M Mhaidat1,2
Mousa al-smadi3
Fouad al-Momani4
Karem h alzoubi1
iman Mansi2
Abstract: Three derivatives of substituted 1,2,3-thia- or 1,2,3-selenadiazole (4a–c) were
prepared and characterized by different chemical techniques. These compounds were evalu-
ated for their antimicrobial and antitumor activities. Compounds 4a (propenoxide derivative),
4b (carbaldehyde derivative), and 4c (benzene derivative) were active against the yeast-like
fungi Candida albicans. Compound 4a was active against gram-negative Escherichia coli, and
compound 4c was active against the gram-positive Staphylococcus aureus. For the antitumor
activity, both compounds 4b and 4c were active against all tested tumor cell lines, namely,
SW480, HCT116, C32, MV3, HMT3522, and MCF-7. The activity of compound 4c was greater
than that of compound 4b and more than that of the reference antitumor 5-flourouracil against
the SW480, HCT116, and MCF-7 tumor cell lines. In conclusion, a number of the prepared
1,2,3-thia- or 1,2,3-selenadiazole compounds showed promising antifungal, antibacterial, and
in vitro antitumor activities. Further investigations are required to explore the mechanism by
which active compound are inducing their cytotoxicity.
Qosay al-Balas5
1Department of clinical Pharmacy,
Faculty of Pharmacy, Jordan
University of science and Technology,
irbid, 2Faculty of Pharmaceutical
sciences, hashemite University,
Zarqa, 3Department of applied
chemical sciences, 4Department of
applied Biological sciences, Faculty
of science and arts, 5Department
of Medicinal chemistry and
Keywords: thiadiazole, selenadiazole, cell lines, antimicrobial activity
Pharmacognosy, Faculty of Pharmacy,
Jordan University of science and
Technology, irbid, Jordan
Introduction
Microbesarehighlydiverse, andtheirgeneticmakeupissubjectedtocontinuouswavering
in response to environmental settings.1 Human pathogens, both nosocomial and enter-
obacter species, are the most common infectious pathogens.2,3 The induction of highly
resistant pathogens urges researchers to develop new antimicrobial agents from natural
sources.3 Heterocyclic compounds containing sulfur and selenium are attractive due to
their interesting biological and synthetic applications. 1,2,3-Thia- and 1,2,3-selenadiazole
derivativesarewell-known, andtheorganicsynthesisoftheirintermediateshaveattracted
the attention of researchers.4 Numerous substituted 1,2,3-thia- and 1,2,3-selenadiazole
derivatives have been prepared, and most of them have showed noticeable antibacterial
activities against Bacillus subtilis and Escherichia coli. The antifungal activity of 1,2,3-
thia- and 1,2,3-selenadiazole against Aspergillus niger, Cryptococcus neoformans, and
Candida albicans has also been determined.5–7 It has been found that the introduction
of the 1,2,3-selenadiazole ring to known molecules with biological activity will modify
and even improve their biological activity. Other heterocyclic compounds containing
triazole, oxazole, benzoxazole, quinazoline, pyridazoline, pyridazine, pyrazole, and
thiazole have been found to be biologically active substances.8–10
correspondence: nizar M Mhaidat
Department of clinical Pharmacy, Faculty
of Pharmacy, Jordan University of science
and Technology, PO Box 3030, irbid,
22110, Jordan
Heterocyclic ring systems are present in numerous antiparasitic, antifungal,
anthelmintic, and anti-inflammatory drugs.11 The beta-lactam antibiotics derivatized
with a 1,2,3-thiadiazole-5-mercapto moiety have been found to be active against
Tel +962 2 720 1000, ext 23542
Fax +962 2 720 1075
email nizarm@just.edu.jo
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License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further
permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on
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Figure 1 synthesis of compounds 2a: 4-(1,2-propenoxide-3-yl) acetophenone, 3a:
4-(1,2-Propenoxide-3-yl)acetophenone(ethoxycarbonylhydrazone), 4a: 3-[4-(1,2,3-
Thiadiazole-4-yl)phenoxy]-1,2-propenoxide.
ꢁE
Figure2synthesisofcompounds2b:Methylglyoxalbis(semicarbazone), 3b:1-(1,2,3-
selenadiazole-4-yl) carbaldehyde semicarbazone, 4b: 1-(1,2,3-selenadiazole-4-yl)
carbaldehyde.
Abbreviation: McPBa, m-chloroperoxybenzoic acid.
gram-negative bacteria, such as Pseudomonas aeruginosa.
4-Methyl-1,2,3-selenadiazole-5-carboxamides have been
described to inhibit tumor cell colony formation.12 In the area
of antibacterial therapeutics, resistance to currently available
drugs has been progressively limiting their utility in treating
bacterial infections. Discovering novel pharmaceutical agents
has become a necessity to combat the increased resistance
of microbes to the current antimicrobial arsenal.13 Advances
in molecular microbiology and genomics have led to the
identification of numerous bacterial genes that code for novel
druggable proteins and could potentially serve as antibacterial
targets.13 Regulatory proteins, such as the two-component
histidine kinases involved in bacterial signal transduction,
have recently gained considerable attention as one such class
of potential targets.14,15 New synthetic compounds and natural
products from plants are showing promising antitumor and
antimicrobial products.16 It was reported that some 1,2,3-
The IR spectra of pure substances were measured as KBr
pellets. Proton nuclear magnetic resonance (1H-NMR) spec-
tra were recorded on a 400 MHz Fourier transform nuclear
magnetic resonance (FT-NMR) system (JNM-ECP400;
JEOL, Ltd, Peabody, MA, USA) with a 300 MHz Bruker
AC 200 spectrometer Bruker Corporation, Billerica, MA,
USA). Tetramethylsilane was used as internal reference.
The spectral data were reported in delta (δ) units relative
to the tetramethylsilane reference line. Carbon-13 nuclear
magnetic resonance (13C-NMR) spectra were recorded on the
100 MHz JEOL FT-NMR system, (75 MHz). Mass spectros-
copy was carried out by using the Finnigan MAT95XP mass
spectrometer (Thermo Fisher Scientific Inc, Waltham, MA,
USA) (field desorption [FD]: 5 kV ionizing energy).
4-(1,2-Propenoxide-3-yl)acetophenone
selenadiazole derivatives show antimicrobial activity against (2a)
highly resistance reference and local nosocomial pathogens A solution of (3.20 mmol) 4-(2-propenoxy)acetophenone(1a)
isolated from the clinical environment.17 As a continuation in (12 mL) dry dichloromethane cooled in an ice bath to
of our previous work on the synthesis of heterocyclic com- 0°C was added dropwise into a solution of (4.32 mmol)
pounds containing 1,2,3-thi- or 1,2,3-selenadiazole rings,18 m-chloroperoxybenzoic acid in (12 mL dry dichloromethane)
in this study, substituted 1,2,3-thiadiazole (Figure 1) or at 0°C under vigorous stirring. After complete addition, the
1,2,3-selenadiazole (Figure 2) were synthesized, and their whole solution was left stirring at room temperature for 6
antitumor and antimicrobial activities were investigated in hours and under reflux for further 3 hours. The precipitated
comparison with control drugs.
m-chlorobenzoic acid was removed from solution by simple
filtration. The filtrate was washed many times with 10%
NaOH followed by distilled water and then dried over
magnesium sulfate. After removing the solvent, through
Materials and methods
chemistry
The melting points (mps) were determined on an electro- evaporation, to dryness, the residue was purified on silica
thermal digital melting point apparatus. The solvents were gel column chromatography using ethanol/dichloromethane
purified by standard procedures. Infrared (IR) spectra were (1:30) as eluent. This compound was obtained as light brown
recorded (in cm-1) using a Nicolet Impact 410 FTIR Spec- viscous oil in 53% yield (2.1 g); 1H NMR (CDCl3): δ =2.27
3
trometer (Nicolet Instrument Corp, Madison, WI, USA). (s, 3H, CH3), 2.61 (q, Jcis =4.3 Hz, 1H, CH2-epoxide), 2.92
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synthesis and activity of 1,2,3-thia- and 1,2,3-selenadiazole
3
3
(t, Jtrans =8.5 Hz, 1H, CH2-epoxide), 3.43 (m, Jcis =4.3 Hz, 4.27 (q, 3Jcis =4.2 Hz, 1H, CH2O), 7.03 (d, 2H, CH-phenyl),
1H, CH-epoxide), 3.95 (q, 3Jtrans =11.2 Hz, 1H, CH2O), 4.27 (q, 7.92 (d, 2H, CH-phenyl), 8.53 (s, 1H, CHS) ppm.
3Jcis =4.3 Hz, 1H, CH2O), 7.13 (d, 2H, CH-phenyl), 7.87 (d, 2H,
CH-phenyl) ppm; 13C NMR (CDCl3): δ =25.9 (1C, CH3), 44.7 Methylglyoxal bis(semicarbazone) (2b)
(1C, CH2-epoxide), 50.4 (1C, CH-epoxide), 69.3 (1C, CH2O), A solution of semicarbazidhydrochloride (1.0 g, 10.0 mmol)
115.9 (2C, CH-phenyl), 127.6 (1C, CC-phenyl), 128.9 (2C, and sodium acetate (1.0 g, 12.0 mmol) in absolute ethanol
CH-phenyl), 159.9 (1C, CO-phenyl) , 195.9 (1C, CO) ppm; IR was heated for 20 minutes under reflux. The product was
(KBr): ν =3,067, 2,889, 1,662, 1,460, 1,251, 1,221, 933 cm-1; filtered while hot to remove precipitated sodium chloride salt.
MS: (5 kV, FD) m/z (%) 192 (100%). Analytically calculated Then one equivalent of methylglyoxal (0.35 g, 4.86 mmol)
For C11H12O3: C, 68.75; H, 6.25. Found: C, 68.79; H, 6.29.
was added to the product solution. This mixture was refluxed
for 35 minutes and followed by thin layer chromatography
(TLC) (chloroform). When the reaction was completed, etha-
nol was removed and the residue was washed with diethyl
4-(1,2-Propenoxide-3-yl)acetophenone
(ethoxycarbonylhydrazone) (3a)
A solution of 4-(1,2-propenoxide-3-yl)acetophenone (2a) ether. The colorless solid of this compound was obtained
1
(2.50 mmol) and ethoxycarbonyl hydrazine (2.60 mmol) in in 89% yield with mp132°C (decomposition); H NMR
dry chloroform (120 mL) was heated under reflux and under (dimethyl sulfoxide [DMSO]-d6): δ =1.46 (s, 3H, CH3),
dean-stark for 13 hours. When no more water was generated, 6.35 (s, 4H, NH2), 8.83 (s, 2H, NH), 9.78 (s, 1H, NCH); 13C
the solvent was removed using rotary evaporator. The residue NMR (DMSO-d6): δ =18.7 (CH3), 147.9 (CH3C=N), 148.2
was washed several times with diethyl ether, and then the (HC=N), 156.8–157.3 (2C, CO); IR (KBr): ν =3,476, 3,148,
remaining ether was concentrated using the rotatory evapora- 2,937, 2,863, 1,755, 1,682, 1,254 cm-1; MS: (5 kV, FD): m/
tor. This compound was obtained as colorless solid in 96% z=186 (M+). Anal Calcd for C5H10N6O2: C 32.26, H 5.38,
1
yield, decomposed at 143°C. H NMR (CDCl3): δ =1.98 N 45.16. Found: C, 32.53; H, 5.60; N, 45.37.
(t, 3H, CH3), 2.21 (s, 3H, CH3), 2.59 (q,3Jcis =4.2 Hz, 1H,
CH2-epoxide), 2.92 (t, 3Jtrans =8.6 Hz, 1H, CH2-epoxide), 3.43
1-(1,2,3-selenadiazole-4-yl)carbaldehyde
(m, 3Jcis =4.2 Hz, 1H, CH-epoxide), 3.95 (q, 3Jtrans =11.1Hz, 1H, semicarbazone (3b)
CH2O), 4.21 (q, 2H, OCH2), 4.27 (q, 3Jcis =4.2 Hz, 1H, CH2O), Methylglyoxal bis(semicarbazone) (2b) (0.30 mmol) was
7.13 (d, 2H, CH-phenyl), 7.87 (d, 2H, CH-phenyl), 8.86 mixed with selenium dioxide powder (0.60 mmol) and sodium
(s, 1H, NH) ppm; 13C (CDCl3): δ =18.9 (1C, CH3), 25.9 sulfate (2.5 g) in a solution of 1,4-dioxane (15 mL) under vig-
(1C, CH3), 44.7 (1C, CH2-epoxide), 50.4 (1C, CH-epoxide), orous stirring at room temperature. The solution was kept in
60.3 (1C, OCH2), 69.4 (1C, CH2O), 115.6 (2C, CH-phenyl), dark, and the reaction progress was followed up with TLC that
127.2 (1C, CC-phenyl), 128.5 (2C, CH-phenyl), 151.3 showed reaction completion in approximately 14 hours. After
(1C, CN), 159.8 (1C, CO-phenyl), 195.7 (1C, CO) ppm; IR reducing the volume of the reaction mixture to half its original
(KBr): ν =3,223, 3,041, 2,989, 1,608, 1,523, 1,463, 1,251, volume under vacuum, distilled water (10 mL) was added, and
1,241 cm-1; MS: (5 kV, FD) m/z (%) 250 (100%). Anal Calcd chloroform (3×15 mL) was used for extraction. The combined
For C14H18O4: C, 67.25; H, 7.24. Found: C, 67.59; H, 7.28.
chloroform layers were dried using magnesium sulfate. After
removing the solvent in vacuum, the product was obtained as a
light brown solid in 76% yield with mp 126°C (decomposed);
1H NMR (DMSO-d6): δ =6.31 (s, 2H, NH2), 8.76 (s, 1H,
3-[4-(1,2,3-Thiadiazole-4-yl)phenoxy]-
1,2-propenoxide (4a)19
The reaction of 4-(1,2-propenoxide-3-yl)acetophenone(etho- NH), 8.94 (s, 1H, CHSe), 9.81 (s, 1H, NCH) ppm; 13C NMR
xycarbonylhydrazone) (3a) (5.20 mmol) with excess SOCl2 (DMSO-d6): δ =148.5 (HC=N), 157.1 (1C, CO), 136.4 (1C,
(121 mmol) was carried out in an ice bath under vigorous C-Se), 158.6 (1C, C=N) ppm; IR (KBr): ν=3,466, 3,134, 2,926,
stirring for 8 hours. Then the solution was left to warm to 2,848, 1,743, 1,659, 1,213, 941 cm-1. MS: (5 kV, FD) m/z (%)
room temperature for a further 3 hours. The excess SOCl2 was 218 (100%). Anal Calcd For C4H5N5OSe: C, 22.02; H, 2.29;
removed by distillation. The residue was washed several times N, 32.11; Se, 36.24. Found: C, 22.07; H, 2.35; N, 32.05.
with ether and concentrated. This compound was obtained
1-(1,2,3-selenadiazole-4-yl)carbaldehyde
as a colorless solid in 93% yield with mp 76°C–78°C;
1H NMR (CDCl3): δ =2.75 (q, 3Jcis =4.2 Hz, 1H, CH2-epoxide), (4b)
2.94 (t, 3Jtrans =8.6 Hz, 1H, CH2-epoxide), 3.35 (m, 3Jcis =4.2 1-(1,2,3-Selenadiazole-4-yl)carbaldehydesemicarbazone
Hz, 1H, CH-epoxide), 3.97 (q, 3Jtrans =11.1 Hz, 1H, CH2O), (3b) (0.36 mmol) was added to 1,4-dioxane (20 mL) under
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vigorous stirring. The solution was kept in dark, and the as follows: a 100 µL of the heterocyclic compounds at each
reaction progress was followed up with TLC that showed concentration were placed in 5 mm-diameter wells with nutri-
reaction completion in approximately 20 hours. Then, 1M ent agar that was inoculated spontaneously with the tested
H2SO4 (10 mL) was added and the solution was gently heated pathogens. The plates were incubated at 37°C for 48 hours.
to 40°C for 5 hours. After reducing the volume of the reaction The clear zones around the wells were measured as inhibi-
mixture to two-thirds of its original volume under vacuum, tion zones. No clear zone around the well was indicated as
distilled water (30 mL) was added, and chloroform (3×50 mL) a negative activity. The filter paper disk method was carried
was used for extraction. The combined chloroform layers out as follows: Whatman® III filter paper puncture disks
were dried using magnesium sulfate. The crude product (5 mm) were saturated with different concentrations of the
was obtained after solvent removal under vacuum. This tested heterocyclic compounds. They were dried in an oven
compound was obtained as dark brown solid in 85% yield at 60°C for 12 hours. The dried disks were placed on already
with mp 112°C (decomposition); 1H NMR (CDCl3): δ =9.83 cultured nutrient agar plates with the different pathogens.
(s, 1H, CHO), 8.98 (s, 1H, CHSe) ppm; 13C NMR (CDCl3): The diameter of clear zone around the disks was measured
δ =136.7.2 (1C, C-Se), 158.3 (1C, C=N), 192.3 (1C, CHO) after 48 hours of incubation at 37°C. No clear zone around
ppm; IR (KBr): ν =3,057, 1,628, 1,476, 1,412, 1,263, 1,218, the disks indicated negative activity. In both methods, dim-
959 cm-1; MS: (5 kV, FD) m/z (%) 161 (100%). Anal Calcd ethyl sulfoxide (DMSO) was used as a solvent to prepare the
For C3H2N2OSe: C, 22.37; H, 1.24; N, 17.39; Se, 49.04. heterocyclic compound solutions.
Found: C, 22.27; H, 1.75; N, 17.41.
Well diffusion assay
Antibacterial activity of the chemical compounds was tested
1,3,5-Tris(1,2,3-thiadiazole-4-yl)benzene
(4c)
against several gram-positive and gram-negative bacteria,
This compound (Figure 3) was prepared according to the and Candida by well diffusion method. The antibacterial
procedure described,20 and obtained as pale yellow powder susceptibility tests were performed on Muller–Hinton agar
1
in 93% yield with mp 227°C (decomposition); H NMR medium. Briefly, 20 mL agar medium was poured into
(DMSO-d6): δ =8.92 (s, 3H, CH-phenyl), 9.83 (s, 3H, CHS) the plates to obtain uniform depth. The standard inoculum
ppm.
suspensions (106 cfu/mL) were streaked over the surface of
the media using a sterile cotton swab to ensure the confluent
growth of the organism. Each compound was dissolved in 5%
Microbiology
All bacterial strains were obtained from American Type DMSO to obtain stock solution concentrations. Then, 5 mm-
Culture Collection (ATCC) (Manassas, VA, USA). The filter diameter wells were prepared in the medium and filled with
paper disk and the well diffusion methods were applied to 100 µL of each compound. Chloramphenicol (100 µg/mL) and
measure the inhibitory activity as indicated by the diameter cyclohexamide (100 µg/mL) were used as positive references
of the inhibition zone.21,22 The well method was carried out against the bacteria and Candida, respectively, and 5% DMSO
was used as negative control. Finally, the inoculated plates
1
6
were incubated at 37°C for 24 hours, and the inhibition zones
were observed, including the diameter of the well (5 mm). All
the experiments were carried out in triplicate.
1
Determination of minimum inhibitory
concentration (Mic)
The MIC values were determined for the bacterial strains that
were sensitive to the compounds in the well diffusion assay.
The MIC of the compounds was tested in Mueller–Hinton
broth by broth macrodilution method.23 The inoculation of
the bacterial strains was prepared from 4-hour-old broth
cultures, and the suspensions were adjusted to standard tur-
bidity (107 cfu/mL). The compounds were dissolved in 5%
DMSO to obtain 20 mg/mL stock solution. The stock solution
1
6
1
1
1
6
ꢀFꢁ
Figure 3 compound 4c chemical structure of 1,3,5-Tris(1,2,3-thiadiazole-4-yl)
benzene.
Abbreviation: 4c, benzene derivative.
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synthesis and activity of 1,2,3-thia- and 1,2,3-selenadiazole
was diluted with Muller–Hinton broth to give different con- a specific procedure.19 Ketone 1a was transformed into the
centrations (12, 25, and, 50 µg/mL). Finally, bacteria were corresponding epoxide derivative 2a through oxidation with
incorporated with the chemical compounds and Muller– m-chloroperbenzoic acid. The hydrazone derivative 3a was
Hinton broth to give a final concentration of 107 cfu/mL. obtained from the condensation reaction between compound
The control tubes containing bacteria with chloramphenicol 2a and ethyl carbazate. The 1,2,3-thiadiazole derivative 4a was
(30 µg/mL), cyclohexamide (10 µg/mL), and 5% DMSO obtained from the reaction of the hydrazone 3a with thionyl
were used as control. The culture tubes were incubated at chloride, as described by Li.25 1,2,3-Selenadiazole derivative
37°C for 24 hours. The lowest concentrations that did not 4b was prepared from the corresponding methylglyoxal 1b,
show any growth of the test organism on the culture medium which was transformed into the corresponding methylglyoxal
after macroscopic evaluation was determined as MIC.
bis(semicarbazone) (2b) through condensation with semicar-
bazide. The 1,2,3-selenadiazole derivative 3b was obtained
from the reaction of the methylglyoxal bis(semicarbazone)
antitumor activity
The acute cytotoxic effects of the compounds on a panel (2b) with selenium dioxide in glacial acetic acid, as previously
of cancer cell lines, namely, breast (HMT3522, MCF7), described26 and shown in Figure 2.
colorectal (SW480, HCT116), and melanoma (MV3, C32)
The antimicrobial activity of the three synthetic com-
were determined using 3-(4,5-dimethylthiazol-2-yl)-2, pounds was evaluated against gram-positive Enterococcus
5-diphenyltetrazolium bromide (MTT) assay.24 Briefly, cells faecalis and Staphylococcus aureus, and gram-negative
were cultured in phenol red–free Dulbecco’s Modified Eagle’s Salmonella typhi, E. coli, and P. aeruginosa, as well as
Medium (DMEM) containing 10% fetal bovine serum (Bio against C. albicans, a fungal pathogen. The sensitivity test
Whittaker, Verviers, Belgium) containing the antimicrobial of the three compounds indicated their highly antagonistic
agents amphotericin B and penicillin/streptomycin (PAA activity against the selected microbes except P. aeruginosa.
Laboratories, GmbH, Pasching, Austria). Cells were seeded At 10 µg/mL concentration of each of the three compounds,
at 5,000 per well onto flat-bottomed 96-well culture plates and
allowed to grow for 24 hours before the desired treatment.
Table 1 antimicrobial activity of compounds 4a–c, represented
by the diameter of inhibition zone
Cells were then incubated with a wide range of the compounds
concentrations (0–250 µg/mL) for 72 hours. The antimetabo-
Synthetic
compound
Microorganism
Zone diameter
(mm)
MIC
(µg/mL)
lite anticancer agent 5-fluorouracil (5-FU), at 50 µg/mL, was
used as a control. Cells were then labeled with MTT (at a
final concentration of 1.2 mM) from the Vybrant MTT Cell
Proliferation Assay Kit (Molecular Probes®; Grand Island,
NY, USA) according to the manufacturer’s instruction, and
resulting formazan was solubilized with DMSO. Absorbance
was read on a microplate reader (ELx800, Bio-tek instruments,
plate reader, Highland Park, VT, USA) at 540 nm.
5 µg
10 µg
4a
Candida albicans
Escherichia coli
Enterococcus
faecalis
Salmonella
typhimurium
Staphylococcus
aureus
15
0
0
16
11
0
1.25
6.25
na
0
0
0
0
na
na
4b
4c
C. albicans
E. coli
E. faecalis
S. typhi
S. aureus
C. albicans
E.coli
E. faecalis
S. typhi
S. aureus
E.coli
E. faecalis
S. typhi
S. aureus
C. albicans
19
14
0
10
0
0
0
0
0
0
0
0
0
0
22
25
21
16
12
0
12
0
0
1.25
0.625
1.25
2.5
na
2.5
na
na
na
5
statistical analysis
Data were analyzed using GraphPad PRISM version 5 (La
Jolla, CA, USA). All data points were presented as (mean ±
standard deviation) of three independent experiments. One-
way analysis of variance (ANOVA) followed by Tukey’s
post hoc test were used for statistical analysis. P0.05 was
considered significant.
0
10
25
18
27
23
25
chloramphenicol
cycloheximide
4
4
45
3
Results
1,2,3-Thiadiazole derivative 4a was prepared from the cor-
responding ketone 1a, as described previously19 but with a
different methodology, as shown in Figure 1. The synthetic
procedure started from ketone 1a that was prepared following
0.478
Abbreviations: Mic, minimum inhibitory concentration; 4a, propenoxide deri-
vative; 4b, carbaldehyde derivative; 4c, benzene derivative; na, not applicable.
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Figure 4 antimicrobial activity curves.
Abbreviations: C. albicans, Candida albicans; E. faecalis, Enterococcus faecalis; E. coli, Escherichia coli; S. typhi, Salmonella typhi; S. aureus, Staphylococcus aureus; 4a, propenoxide
derivative; 4b, carbaldehyde derivative; 4c, benzene derivative.
the antimicrobial activity was higher than 5 µg/mL, as 4c varied from 31.91 to 528.10 µg/mL. These results showed
indicated in Table 1. At 10 µg/mL, compound 4B inhibited that compound 4c had higher antitumor activity than did com-
the growth of C. albicans, E. coli, E. faecalis, and S. typhi, pound 4B. Compound 4a had no antitumor activity against
with 25, 21, 16 and 12 mm inhibition zones, respectively; any of the selected tumor cell lines. Comparing the IC50 of
S. aureus was resistant to compound 4b. Compound 4c had compound 4c with the reference antitumor compound 5-FU,
inhibitory activity only against S. aureus. Compound 4a was the IC50 against SW480, HCT116, and MCF-7 was lower,
active against C. albicans, and E. Coli with 11 and 16 mm indicating its higher potential to inhibit tumor cell prolifera-
inhibition zones, respectively. The antimicrobial activity of tion. In addition, results showed that HMT3522 breast cancer
these compounds at 10 µg/mL was similar to antimicrobial cells were highly resistant to both compounds 4b and 4c. The
activity of 5 µg/mL of chloramphenicol or 5 µg/mL of cyclo- rest of the tumor cell lines were more sensitive to compound
hexamide and the antifungal reference compounds. These 4c than to compound 4b.
results proved the promise of these synthetic compounds
as antimicrobial agents. The MIC of the three synthetic Discussion
compounds against reference microbes varied from 0.625 The results of the present study showed the antimicrobial
to 6.25 µg/mL, as shown in Table 1 and Figure 4.
and antitumor activities of the synthetic derivatives (4a, 4b,
The antitumor activity of the three synthetic compounds and 4c), with promising potential in comparison with the
against SW480, HCT116, C32, MV3, HMT3522, and MCF-7 active reference chemicals. Variation in antimicrobial activ-
cell lines showed that compound 4b was active against all ity, as indicated by the diameters of the inhibition zones of
tumor cell lines, with variable half-maximal inhibitory con- the three compounds, could have been due to variation in
centration (IC50) values ranging from 52.17 to 114.79 µg/mL. the genetic makeup of the microbial reference strains used
Compound 4c was more potent than compound 4b against all in this study, variation in compounds metabolic activity, or
tumor cell lines, as shown in Table 2. The IC50 of compound compounds with different resistance or different sensitivity.
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synthesis and activity of 1,2,3-thia- and 1,2,3-selenadiazole
Table 2 antiproliferative activities of compounds 4a–c against different cancer cell lines
IC50 (µg/mL)
Synthetic
SW480
HCT116
C32
MV3
HMT3522
MCF-7
compound
5-FU
4a
48.01±3.6
.2,000
42.61±3.9
.2,000
41.71±3.9
.2,000
53.41±4.8
.2,000
58.87±4.9
.2,000
49.31±4.1
.2,000
4b
52.17±4.2*
31.91±2.8*,$
55.28±4.1*
33.65±3.1*,$
75.39±5.8*
68.56±6.3*
114.79±9.6*
70.86±8.1*,$
495.87±29*
528.10±32*
96.91±6.3*
35.71±4.2*,$
4c
Notes: Data shown represent the mean ± SE of three independent experiments. One-way ANOVA followed by Tukey’s post hoc. *Significant difference from 5-FU (P0.05);
$Significant difference from 4b (P0.05).
Abbreviations: 5-FU, 5-fluorouracil; ANOVA, analysis of variance; IC50, half-maximal inhibitory concentration; se, standard error; 4a, propenoxide derivative; 4b, carba-
ldehyde derivative; 4c, benzene derivative.
Compound 4b showed higher antimicrobial activity of over
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Disclosure
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